What is health, where does it reside in the body? Define health.

Optimal homeostasis irrespective of time. The optimal function of organs. The quality of re-synthesis in response to physics, damage. Seeing past the illusions, the human body however complex is after all engineering relative to physics, and the environment only allows a handful of options in the maintenance of any engineered structure and has explored them all in manufacturing organisms. The artificial heart has a warranty of 5 years, while the analogue heart must pump 70 times a minute for 80 years. A major engineering challenge and a feat. The human body like any machine is subject to physics, the physical environment and the mechanics of any machine, both in the component subsystems that comprise the machine and basic engineering tolerances and specifications. We define health as a state of the physiology and an optimal physiological state (homeostasis or, more ideal, optimal homeostasis), and disease as deviation from an optimal physiological state (dyshomeostasis). If the machine maintains optimal tolerances and ideal operating specifications, there can be no reason for it to fail or break, the organism continues living, but when a pipe is blocked, function is no longer possible and the organism dies. All of this is theoretically quantifiable, a contrast in the definition of both states leaves only disease as the difference, measure the difference, reverse the condition. We currently do not have definitive quantification and even the therapies to theoretically maintain the machine indefinitely in an optimal state. What is the leading cause of death? The pump fails, the pipe gets blocked. No one dies of old age. Humans are basically a kind of robot that eventually stalls out and does not reboot. Tolerance and operating specifications. As long as the system functions engineered tolerances, the state of the body is considered healthy, when the system falls out of tolerance, disability and eventual to cease of function. Without the ability of resynthesis, the human body would barely last 3 years. The human body utilizes resynthesis of components ongoing to achieve its 80 years of function. The human body is an anlogue moving system, the artery got blocked, the pump failed.

What old people die from? 1 , 2 , 3 , 4

Morbidity refers to chronic medical condition, mortality means death. People rarely reach their biological limits, they die of something well before. Myth: No one dies of old age, autopsies show there is a cause to every death.

1. Ischaemic heart disease - reduction of blood flow to heart muscle due to build-up of plaque (atherosclerosis) in the arteries of the heart (heart attack). Most common of the cardiovascular diseases (CVD), followed by stroke and heart failure. 90% of CVD preventable if risk factors avoided. Age as the major risk factor tripling with each decade. Metabolic dysfunction associated with high insulin requirements diet. The human heart cannot regenerate (1 ). Stay young, low insulin requirements diet, go whole food vegan and exercise. Blood Pressure Management. GDF11, HDL:LDL, no transfats or saturated fats.

1. Stroke - 87% are ischaemic strokes, blockage in blood flow through the artery that supplies oxygen-rich blood to the brain. A haemorrhagic stroke, an artery in the brain leaks blood or ruptures. Transient ischaemic attack, blood flow to the brain blocked for only a short time—usually no more than 5 minutes. Blood clots often cause blockages that lead to ischaemic strokes. Stay young, go whole food vegan and exercise. Guessing a weekly/monthly oral dose of plasminogen as a prevention.

1. Cancer - 95% cause by genetic damage and %5 inherited. Some believe the cell reverts to behaving like a single cell organism rather than a multi-cellular organism, ancient DNA code when cells behaved like replicating bacteria. Known carcinogens such as ultra-violet light and possibly other radio waves, smoking, pesticides, asbestos, arsenic. Eliminate carcinogens. Do not make a cell's existence so unbearable that it thinks that it needs to escape to survive by empathizing with your cells and your body, if you were locked in a multi-cellular body with regulating organs, how would you want to be treated? Hint: No arsenic. Carcinogens indicate an evironmental causation, an updated list of known carcinogens is available. Organs that do not change such as the heart do not usually get cancer, skin cancer is the most common probably because it is highly exposed to carcinogens, followed by breast cancer. There are cancer prevention lifestyles such as catabolic diets.

1. Respiratory diseases - upper and lower, pathogens that infect air passages and lungs such as pneumonia, influenza and particles that destroy the lungs such as smoking, bad air quality, chemicals. Immunosenescence. Island peoples may live longer by water surrounding providing a natural air filter. Sanitize your area from bacteria virus especially during sleep to minimize the viral bacterial load and volatile organic compounds (VOC's), car exhausts, etc. Development of broad-spectrum antiviral drugs. See vitamin D supplementation. Salt water mouth washing, isopropyl alcohol gential/testicle spray, vingegar for ear canal infections, respiratory infection filter.

1. Alzheimers, Dementia Disease - believed cause by badly formed sticky proteins (tau tangles) that kill neurons or caused by virus. Correlated with areas of high levels of air or environmental pollution. Immunosenescence role. See exercise, air quality especially during sleep, VOC's, ultra fine particles. Air pollution may contribute to Alzheimer's and dementia risk, Where are the Lowest Rates of Alzheimer’s in the World?, Sauna use has shown to significantly reduce dementia believed due to heat shock proteins and reports that inducing fever protects against dementia, that plaques are formed against bacteria and that anti-biotic use causes biome imbalance and that sugar eating bacteria migrate to the brain. The incidence of Alzheimers has not been the same but has increased exponentially in the last 70 years.

1. Diabetes - insulin resistance, prediabetes, type 2 diabetes. Blue zone diet and exercise. Intermittent fasting autophagy. Type 1 diabetes is different. Two in three diabetics die from heart disease indicitive role of general high sugar diets.

1. Accidents - old person falls over. Loss of muscle and bone mass named sarcopenia and osteoporosis, progressive and generalized loss of skeletal muscle mass and strength correlated with physical disability, poor quality of life and death. Risk factors for sarcopenia include age, gender and level of physical activity. Proposing a mild and safe anabolic steroid or androgenic modulator to treat sarcopenia and osteoporosis and shrink time in mobidity before all cause motality. Balance exercises such as standing on one foot, while moving the head and standing from a floor position.

1. Nephritis - often caused by infections, toxins or autoimmune disorders that affect the major organs like kidneys.

1. Septicaemia - curable with antibiotics. Bacteria causing urinary tract infections, lung infections, such as pneumonia, kidney infections, infections in the abdominal area can lead to sepsis. Hygiene, stay up to date with the latest in hygiene such as UV-C for bathrooms or bedrooms. Toilet cover down before flushing. Caused by infections. Megadose of vitamin C.

1. Liver disease, hepatic disease - various conditions affecting liver. Skin and eyes appear yellowish (jaundice).

1. Digestive disease - various conditions affecting digestive system.

1. Nutritional deficiency - what is the least amount of food that is nutritionally complete, eat once a day, exercise. Human body needs vitamins, minerals, amino acids, Omega 3, water. Focus on daily nutritional needs, eat in one session and water ongoing, not strictly and starve the rest of 24-hour period. Malnutrition and western diet are two worst diets. See high insulin diets and diabetes. See vitamin D supplementation and some exotic substances like herbs. See blue zone diet.

1. Meningitis - both virus or bacteria. Virus; either herpes simplex, chickenpox or shingles virus, enterovirus. Viral meningitis is almost never life-threatening. Many bacteria can cause meningitis the most common are meningococcal, pneumococcal, haemophilus influenzae. Bacterial meningitis occurring alongside sepsis, which is the more life-threatening form, often involves the bacteria invading the blood as well. Sepsis occurs with or without bacterial meningitis. Intravenous penicillin, ceftriaxone or cefotaxime as treatments. Stay up to date on hygiene industry.

1. Parkinson's disease - young adults rarely experience Parkinson's disease beginning in middle or late life, around age 60 and older increasing risk with age. Dementia affects the mind while Parkinson's affects the body. Pesticides believed causation. The brain has a limited capacity to regenerate if damaged. House filter out volatile organic compounds VOC's and ultra fine particles UFP's especially during sleep. Clean vegetables and fruits or buy pesticide free food. Electric vehicles and industry waste sequestration. 1, 2, Mohommed Ali has Parkinsons possibly due to blows to the head.

1. Infectious intestinal disease - many infections of the bowels including: cholera, typhoid fever, paratyphoid fever, salmonella infections, shigellosis, botulism, gastroenteritis, and amoebiasis, etc. Stay up to date on hygiene industry.

1. Hepatitis - virus, 3 main types: A, B, and C. Only A and C are curable. Stay up to date on hygiene industry. Get A + B vaccine.

Jimmy Carter was critical with cancer at 91, he is 97 now, avoiding all cause mortality provides significant lifespan extension. Most people never reach their biological limits, while the body is still able to function a blocked blood vessel or a small cancer leads to catastrophic failure. Preliminary study is the science of getting a person to reach their natural biological limits before any life extension. Avoiding all cause mortality is a valid strategy of longevity in research and in lifestyle.

What centenarians die from?

People who live to 100 are referred to as centenarians, 110+ super-centenarians. Centenarians die of the same conditions as non-centenarians, only a little later on. Do Centenarians Die Healthy? An Autopsy Study. An acute organic failure causing death was found in 100%, including cardiovascular diseases in 68%, respiratory illnesses in 25%, gastrointestinal disorders in 5%, and cerebrovascular disease in 2%, Centenarians, though perceived to have been healthy just prior to death, succumbed to diseases in 100% of the cases examined. They did not die merely "of old age". Super-centenarians are the science of longevity.

The science of lifespan extension is with the super-centenarians, their biology is optimized for longevity and their organs are in fantastic condition well into their hundreds and even when they drink and smoke cigarettes. They require no supplements or medications, some smoke and drink and do little exercise. It seems that super-centenarians would keep right on living if the cause of death did not occur. Could lifespan be infinitely extendable if nothing ever broke? The appearance of centenarians is clearly altered, yet some of them clearly appear younger than they are. Super-centenarians are proof that life extension is possible. Finally, centenarians are hereditary, you get your lifespan from your mother's side.

Jeanne Calment, the oldest person ever to have lived is Jeanne Calment (France), who lived to be 122 years and 164 days, and the oldest man ever is Jiroemon Kimura (Japan), who was born on 19 April 1897 and passed away aged at the age of 116 years and 54 days on 12 June 2013.

Symptoms of aging

Graying of hair, wrinkles, eyesight deterioration, macular and cognitive impairment, neurodegeneration, altered appearance, decline in performance and stamina, healing and recovery time increase. Aches, pains, tired, sluggish, health issues. By every measure compared to young healthy person, aged person shows suboptimal results, in heart function, cell quality, immune system, brain function. Aging is not linear but happens in 3 waves (1 ) (ages 34,60,78) with graying hair and wrinkles starting at about 40. Age of average healthspan 63 and lifespan 79 (US). Aging is the largest cause of the customer base of the healthcare system including medical, pharmaceutical system. A loss of energy that never recedes, loss of libido and motivation, physical dysregulation.

Theories of aging

Traditional biology cannot offer a single theory of aging so the science needs to improve. Modern biological theories of ageing in humans currently fall into two main categories: programmed and damage or error theories. The programmed theories imply that ageing follows a biological timetable (regulated by changes in gene expression that affect the systems responsible for maintenance, repair and defence responses), and the damage or error theories emphasize environmental assaults to living organisms that induce cumulative damage at various levels as the cause of ageing.

1. The Programmed Theory
1. Programmed Longevity, which considers ageing to be the result of a sequential switching on and off of certain genes, with senescence being defined as the time when age-associated deficits are manifested.
2. Endocrine Theory, where biological clocks act through hormones to control the pace of ageing.
3. Immunological Theory, which states that the immune system is programmed to decline over time, leading to an increased vulnerability to infectious disease and thus ageing and death.
4. Aging-US: DNA- and telomere-damage does not limit lifespan: evidence from Rapamycin
2. The Damage or Error Theory
1. Wear and tear theory, where vital parts in our cells and tissues wear out resulting in ageing.
2. Rate of living theory, that supports the theory that the greater an organism's rate of oxygen basal, metabolism, the shorter its life span.
3. Cross-linking theory, according to which an accumulation of cross-linked proteins damages cells and tissues, slowing down bodily processes and thus result in ageing.
4. Free radicals theory, which proposes that superoxide and other free radicals cause damage to the macromolecular components of the cell, giving rise to accumulated damage causing cells, and eventually organs, to stop functioning.
3. Other Theories
1. Disengagement Theory, refers to an inevitable process in which many of the relationships between a person and other members of society are severed & those remaining are altered in quality. Withdrawal may be initiated by the ageing person or by society, and may be partial or total. It was observed that older people are less involved with life than they were as younger adults. As people age they experience greater distance from society & they develop new types of relationships with society. In America there is evidence that society forces withdrawal on older people whether they want it. Some suggest that this theory does not consider the large number of older people who do not withdraw from society. This theory is recognized as the first formal theory that attempted to explain the process of growing older.
2. Activity Theory, is another theory that describes the psychosocial ageing process. Activity theory emphasizes the importance of ongoing social activity. This theory suggests that a person's self-concept is related to the roles held by that person i.e. retiring may not be so harmful if the person actively maintains other roles, such as familial roles, recreational roles, volunteer & community roles. To maintain a positive sense of self the person must substitute new roles for those that are lost because of age. And studies show that the type of activity does matter, just as it does with younger people.
3. The Neuroendocrine Theory, first proposed by Professor Vladimir Dilman and Ward Dean MD, this theory elaborates on wear and tear by focusing on the neuroendocrine system. This system is a complicated network of biochemicals that govern the release of hormones which are altered by the walnut sized gland called the hypothalamus located in the brain. The hypothalamus controls various chain-reactions to instruct other organs and glands to release their hormones etc. The hypothalamus also responds to the body hormone levels as a guide to the overall hormonal activity. But as we grow older the hypothalamus loses it precision regulatory ability and the receptors which uptake individual hormones become less sensitive to them. Accordingly, as we age the secretion of many hormones declines and their effectiveness (compared unit to unit) is also reduced due to the receptors down-grading
4. The Free Radical Theory , this now very famous theory of ageing was developed by Denham Harman MD at the University of Nebraska in 1956. The term free radical describes any molecule that has a free electron, and this property makes it react with healthy molecules in a destructive way. Because the free radical molecule has an extra electron it creates an extra negative charge. This unbalanced energy makes the free radical bind itself to another balanced molecule as it tries to steal electrons. In so doing, the balanced molecule becomes unbalanced and thus a free radical itself. It is known that diet, lifestyle, drugs (e.g. tobacco and alcohol) and radiation etc., are all accelerators of free radical production within the body. The naked mole-rat is a long-lived (32 years) rodent. As reviewed by Lewis et al. (2013) (1), levels of reactive oxygen species (ROS) production in the naked mole rat are similar to that of another rodent, the relatively short-lived mouse (4 years). They concluded that it is not oxidative stress that modulates health-span and longevity in these rodents, but rather other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress. In the naked mole-rat, a likely important cytoprotective mechanism that could provide longevity assurance is elevated expression of DNA repair genes involved in several key DNA repair pathways. Compared with the mouse, the naked mole rat had significantly higher expression levels of genes essential for the DNA repair pathways of DNA mismatch repair, non-homologous end joining and base excision repair. Among birds, parrots live about 5-times longer than quail. Reactive oxygen species (ROS) production in heart, skeletal muscle, liver and intact erythrocytes was found to be similar in parrots and quail and showed no correspondence with longevity difference. These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging (2). It is supposed that longest lived model organisms have more repair genes, more anti-cancer genes, more stress resistant genes against damage (such damage as caused by physics, chemistry, mechanics, environment, lysosomal storage diseases, epigenetic drift, somatic and mtDNA mutations).

1. The Membrane Theory of Ageing, was first described by Professor Imre Zs.-Nagy of Debrechen University, Hungary. According to this theory it is the age-related changes of the cell's ability to transfer chemicals, heat and electrical processes that impair it. As we grow older the cell membrane becomes less lipid (less watery and more solid). This impedes its efficiency to conduct normal function and in particular there is a toxic accumulation
2. The Mitochondrial Decline Theory, the mitochondria are the power producing organelles found in every cell of every organ. Their primary job is to create Adenosine Triphosphate (ATP) and they do so in the various energy cycles that involve nutrients such as Acetyl-L-Carnitine, CoQ10 (Idebenone), NADH and some B vitamins etc. Enhancement and protection of the mitochondria is an essential part of preventing and slowing ageing. Enhancement can be achieved with the above mention nutrients, as well as ATP supplements themselves
3. The Cross-Linking Theory, is also referred to as the Glycosylation Theory of Ageing. In this theory it is the binding of glucose (simple sugars) to protein, (a process that occurs under the presence of oxygen) that causes various problems. Once this binding has occurred the protein becomes impaired and is unable to perform as efficiently. Living a longer life is going to lead to the increased possibility of oxygen meeting glucose and protein and known cross-linking disorders include senile cataract and the appearance of tough, leathery and yellow skin.

It is important for Immortality science to develop a sound theory of aging, and we tend on the side of programmed theory. Aging is “programmed” into the body or planned senescence. Animals generally exhibit identical manifestations of the lifecycle and aging, a baby elephant is identical to a baby monkey is identical to a baby mouse and an old monkey is identical to an old elephant is identical to an old mouse, yet they undergo these phases at different rates. A dog does it 7 times faster than a human being, both exhibit all and the same symptoms of aging before they die. The rate of random damage is believed to be identical regardless of species, a dog not suffering 7 times more damage than a human to succumb 1/7 of the lifespan of a human and one would assume that probability of something going wrong increases with the mass of the organism and so the simpler and smaller the animal the longer the lifespan, the opposite is the case. This indicates that mechanisms of lifecycle and aging are regulated by the organism. For example, the Galápagos tortoise has a heart rate of six beats per minute and lives for 177 years, a rabbit, on the other hand, has an average heart rate of 209 beats per minute and lives only nine years. Are you running out of heartbeats? Identical biological process are occurring at different rates in different species, a fast-paced organism drives a mystery biological process faster than a slow paced organism. These organisms all undergo puberty at their specific paces, the genetic program that dictates onset and time in puberty run relative to lifespan. A recent paper eluded that DNA mutation rates are the cause of aging, taking 18 species and finding that short-lived animals accumulated mutations at a faster rate than long-lived animals, with all dying when the mutation rate reach a specific threshold. It is also widely believed that the accumulation of methylation marks cause aging. How these accumulations coincide with cycles can be assumed. The central location of any regulation must be the brain, and the rest of the body follows. Possibly the hypothalamus or another central circuit signals the pituitary and by alteration of the micro-environment the cells get their information where they configure the chromatin and they in turn signal everyone around them. In reaction to the specific regulated micro-environment, cells go into an auxiliary mode and in such a conservation mode an organism forgoes maintenance and regeneration in preference for basic survival out of energy preservation, melanocytes do not produce hair pigment, stem cells go quiescent, any energy intensive process are forgone and aging is permitted. By placing the microenvironment in a state of scarcity, cells tighten their belts, most energy intensive process are forgone, exposing the organism to biological deterioration until it falls below minimum engineering requirements and the organism can no longer function and dies. Basically the same process of puberty applied to aging, except by switching off maintenance and regeneration the organism is exposed to failure. We know this through biologically immortal organisms such as the Planaria exhibit embryonic regeneration and telomere maintenance and only embryonic regeneration has been shown to significantly affect lifespan, even exhibit immortality. While Turritopsis dohrnii achieves lifespan extension by masterful control of its epigenome. Overriding the microenvironment has not yet resulted in lifespan extension, however there is some initial evidence that it may shrink morbidity (with current therapies possibly not well-designed or well-understood enough). Thus far, we have not seen any one of these systems convincingly returned to homeostasis for example hair follicle pigmentation requires a correct co-ordination of hormone paracrine, stem cells and the immune system, with age hormones decline, stem cells quiescent, and the immune system becomes more cytokine than regenerative. After all, we are eager to make a CRISPR to fix the mutation rates, tinker with methylation, experiment with different media and more to see if they're any effects.

Biology is a mix of practical real world engineering and electronics, pump failure, liquid pressure, blocked pipes, chip failure leading to machine failure. Cutting an engine, robot or human in half causing it to no longer function are identical in each case. Except biology has self-healing technology and by throttling this self-healing technology physical forces take over. The science is to identify the causes of aging and invent novel ways of treating aging.

Lab Animals and Model Organisms

Model animals are studied, while animals are used in experiments. The major issue is are results applicable to humans beings. Mouse Model, the differences between the mouse model and human beings in the testing of therapeutics. 3D printed human cell structures have been used, noted to have saved time and money to assert of efficacy and safety. See Anthony Atala. Some argue that the model is valid if the experimentor is nuanced and expert enough that variables are controlled and kept similar as possible, such as using old wild type mice to test human being aging rather than a phenotype that may or may not be aging. When testing molcules first ascert if the substance is bio-available.

1. Saccharomyces cerevisiae, a species of yeast
2. Caenorhabditis elegans, 1mm worm with a mean lifespan of approximately 18–20 days when cultured at 20°C (1), Scientists find the mechanism that extends worm lifespans by 500 percent.
3. Drosophila melanogaster, 10 and 50 days under optimal ambient temperature. (1)
4. Mus musculus, lifespan of 4 years (captivity)

1. Immortal cell lines have been demonstrated in culture, cancer cells become immortal by invoking a genetic mutation or an epigenetic configuration that can trigger the production of an enzyme, known as telomerase, which prevents telomeres from shortening. HeLa cells have an active version of telomerase during cell division, which copies telomeres over and over again. This prevents the incremental shortening of telomeres that is implicated in aging and eventual cell death. In this way, the cells circumvent the Hayflick limit, which is the limited number of cell divisions that most normal cells can undergo before becoming senescent. The result is unlimited cell division and immortality.
2. Many unicellular organisms age: as time passes, they divide more slowly and ultimately die. Asymmetrically dividing bacteria and yeast also age. However, symmetrically dividing bacteria and yeast can be biologically immortal under ideal growing conditions. In these conditions, when a cell splits symmetrically to produce two daughter cells, the process of cell division can restore the cell to a youthful state. However, if the parent asymmetrically buds off a daughter only the daughter is reset to the youthful state—the parent isn't restored and will go on to age and die. In a similar manner stem cells and gametes can be regarded as immortal.
3. Planaria
4. Hydra
5. Turritopsis dohrnii, the immortal jellyfish is able to revert completely to sexually immaturity, colonial stage after reaching sexual maturity and believed able to do so indefinitely, the jellyfish is biologically immortal. The transformation might be epigenetic under condition of starvation, sudden temperature change, reduction in salinity or damage to its bell. (Dimberu, Peniel M. (2011-04-25). Immortal Jellyfish Provides Clues for Regenerative Medicine. Singularity Hub. Retrieved 26 October 2011). Efforts to adapt the function to mice and humans, Comparative genomics of mortal and immortal cnidarians unveils novel keys behind rejuvenation.
6. Lobsters
7. Axolotl and Newts
8. Salamanders
9. Echinoderms (sea - stars, urchins, cucumbers, etc.), Red Sea Urchin (Strongylocentrotus fransciscanus) (1, 2)
10. Zebrafish, Danio rerio (1)
11. African clawed frog, Xenopus laevis (1, 2)
12. Medaka rice fish
13. Neonates
14. List of different animal and lifespans, Arctica Islandica and Ocean Quahog, shell fish both live for 500 years, Gastrotrichs a marine microorganism lives for 3 days.
15. Bowhead Whale 200+ years
16. Galapagos Giant Tortoise 100+
17. Greenland Shark, 300 to 500 years
18. Lab and medical supply companies (1, 2)
19. Facility and lab design.
20. Ballistic experiment design.
21. Error elimination, catastrophe procedures, relevant protocols, e.g. safety and hygiene.

https://www.jove.com/

History, Art and Observations

The biological limits are rarely reached, while the body may still be theoretically able to continue, a blocked or ruptured blood vessel, a small cancer results in catastrophic failure. Macroscale condition of arteries and organs is important to reaching biological limits before any life extension therapy. The important centers of an organism, the quickest way to die other than instant catastrophic damage is cellular oxygen deprivation, then poison, then renal failure which results in death within weeks, water deprivation, starvation, heart failure within one year. The decline, deterioration, dysregulation of both nuclear and non-nuclear organs such as the immune system, bone marrow, pancreas, metabolism and of critical organs such as heart, kidney, liver lead to ill health and death. The function of these organs decline and change with age and they are inhibited in performing their essential life support roles.

Both embryonic and adult stem cells have superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, DNA Damage in Stem Cells.

The longest lived animals have exceptional regeneration, their stem cell do not age and are pluripotent, they can maintain their telomere and some have masterful control of their epigenome. It is also said they have either extra genes that protect them against cancer or another gene mechanism such as exceptional repair that endows them with extra rezilliance. Damage caused by physics, by-products of chemistry, mechanics such as friction, environment such as caused by toxins, lysosomal storage diseases and inability to breakdown products within the cell, epigenetic, somatic and mtDNA mutations. Lifespan is generally relative to size in animals, heart rate is also mentioned, some mention other collelations such as the rate of DNA mutations. Some suppose hat some types of damage have no repair mechanisms and that is what accumulates. A question is that the multi-cellular organism does not depend on the individual cell, apoptosis and replacement of any non-functional cell is trivial.

Hallmarks of aging (Below Europe 9 pillars vs US 7 pillars, of aging)

1. Telomere Attrition - the body is constantly replacing cells and each time cells divide telomeres get shorter, once they get too short the cell no longer divides, eventually with little to no viable dividing cells in vital organs, the body breaks and the person dies. Long-lived animals do not have more dividing potential, instead their cells divide at a slower rate. See Telomere diseases, dyskeratosis congenita do not resemble people of age by sight. Telomere length has been connected with cardiovascular complications. Telomere attrition leads to cell senescence and the Hayflick limit. The timing of mitosis is said to be genetic regulation. Cancer cells are immortal through telomerase. Up regulation of telomerase requires a cure for cancer. Telomere attrition as a strategy against cell damage and cancer.

1. Stem Cell Exhaustion - stem cell populations dwindle, inability to replace stem cells that have migrated, differentiated, or died. The body replaces itself by replacing individual cells, if the body cannot it breaks, and death. The heart and brain is the least regenerative organs, new cells come from stem cell managed mitosis and stem cells. Your gut is replaced every 4 days, without replacement, complete meltdown eventually.

1. Cellular senescence - a cell state that is dead but remains, zombie cells increase with age and communicate to surrounding cells that they have died, and negative cascade. In a young person, it protects against cancer because it put the immune system on alert.

1. Altered intercellular communication - aging cells show an increase in self-preserving signals that result in damage elsewhere, e.g. hypothalamus down regulates hormones. Cells communicate with one another regarding their condition and make adjustments accordingly. Tell yourself, you feel fine and that your body should also. Tell your friends and family you feel fine, and they ought too as well.

1. Loss of proteostasis - a failure of the protein building machinery of the cell and the accumulation of misfolded proteins, a root cause of age-related diseases, including Alzheimer’s disease. The body is always rebuilding itself, so quality control issues.

1. Deregulated nutrient sensing - the body depends on multiple nutrient sensing pathways to make sure the body takes in just the right amount of nutrition - not too much, not too little. Damaging events deregulate nutrient-sensing molecules and downstream pathways. Age-related obesity, diabetes and other metabolic syndromes result. Western diet, too much sugar!

1. Genome instability - high frequency of mutations within the genome. These mutations include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. DNA is being damaged by UV light, fumes, stress and other causes.

1. Mitochondrial dysfunction - when mitochondria do not work as well, usually due to another disease or condition. Mitochondrial disorders caused by mutations (acquired or inherited), in mitochondrial DNA (mtDNA), or in nuclear genes that code for mitochondrial components. Acquired mitochondrial dysfunction from adverse effects of drugs, infections, or other environmental causes. Tell your mitochondria, they are special, and you love them.

1. Epigenetic alterations, a change in the chemical structure of DNA that does not change the DNA coding sequence. Epigenetic alterations when chemical groups called methyl groups are added or removed from DNA or when changes are made to proteins called histones that bind to the DNA in chromosomes.

The seven causes of aging according to Aubrey de Grey (1)

1. Intracellular waste: transgenic microbial hydrolases; enzymes capable of destroying the waste, which are not present in our bodies.
2. Intercellular waste: stimulation of phagocytosis by our immune system; macrophages in particular, whose role is to eat waste products.
3. Nucleus mutations: KO of telomerase and increase in the number of stem cells; the goal is to decrease the number of cell divisions in order to reduce the risk of mutations, while maintaining a normal level of renewal with stem cells.
4. Mitochondrial mutations: allotropic expression of the 13 proteins encoded by mtDNA through the integration of this DNA sequence into nuclear DNA.
5. Stem cells loss: cell therapy using growth factors and stem cell addition.
6. Increase in senescent cells: removal of senescent cells by targeting, mostly by boosting “suicide” genes.
7. Increase of intercellular protein links: enzymes that can break these protein links between the cells.

There are a limited number of types of failure in engineering. The human body is a kind of robot, comprised of analogue engineering (heart, arteries), electronics (cells) and even software programming (DNA). These are the types of failure in physics.

1. structure, not strong and tough enough to support the load or structure is stressed beyond its critical stress level.
2. fatigue or corrosion, caused by instability in the structure geometry, design or material properties.
3. manufacturing errors, includes improper selection of materials, incorrect sizing, improper heat treating.
4. defective materials, improperly manufactured or damaged from prior use.
5. unexpected problems, vandalism, sabotage, or natural disasters.

The three categories of aging are appearance, morbidity and mortality, three categories of interventions are lifestyle, pharmaceuticals and medical/clincal procedures. Lifestyle, offers the only guarantee. No one can fix the body if it breaks it is far too complicated, so the only strategy is the science of prevention. Let's look at lifestyle...

Metrics, Biomarkers

It would take far too long to test aging therapies on human beings, consecutive 30 year trials are generally not feasible with aging, and this is a real dilemma. Commonly, these therapies are tested on worms which live several months and mice that live several years, however they differ from human beings posing real problems. Studies in aging develop and use biomarkers to try and determine efficacy of an intervention. The issues... are the numbers and changes in numbers connected to aging, cause and effect, causation, is it real? Escape velocity states when the rate of repair equals the rate of damage aging stops, lifespan increases boundless, the formula as biological age + therapies = biological age - 1. You only need enough technology to reverse 1 year of aging every 1 year represented in a definitive aging biomarker system. The issues and supposed improvement with all these testing methods is required. Here is a list of biomarker and metric systems commonly used. Aging interventions are not post-diagnosis of a medical condition and therefore must be safe and minimally-invasive. Biological Age Predictors. A common model organism is mice, C57BL/6 aka Black6 (1).

1. Temperature, lower than baseline temperature as an indicator of disease, such as diabetes, liver disease, hypothyroidism
2. Resting heart rate, as an indicator of heart disease and a prediction of lifespan
3. Large waist circumference, means more belly fat, linked to higher levels of inflammatory chemicals associated with heart disease and diabetes. High waist circumferences had double the mortality risk of those with lower measurements, regardless of weight or body mass index (BMI). Weight and BMI. Obesity risk
4. Dexa scan, Body Fat, Muscle, and Bone Testing, https://dexascan.com/
5. Fitness tests, including age specific tests, frailty test. Cognitive tests, mental age tests
6. Wearables to data centre, with weekly report along with recommendations
7. Bood Pressure, high blood pressure is one of the main risk factors for heart disease, especially heart attacks and strokes. (1)
8. VO2 Max, maximal oxygen consumption, refers to the maximum amount of oxygen that an individual can utilize during intense or maximal exercise. This measurement is generally considered the best indicator of cardiovascular fitness and aerobic endurance
9. Pulmonary function tests, pulse oximeter, measure of respiratory efficiency. Spirometry measures airflow. By measuring how much air you exhale, and how quickly you exhale, spirometry can evaluate a broad range of lung diseases
10. Blood test, Blood-Borne Biomarkers of Mortality Risk: Systematic Review of Cohort Studies Complete blood count, basic metabolic panel and comprehensive metabolic panel, lipid panel, thyroid panel, cardiac biomarkers, sexually transmitted infection tests, coagulation panel, DHEA-sulfate serum test, C-reactive protein test, nutrient tests for levels of vital nutrients, such as iron or B vitamins, enzyme marker tests such as CPK-1, CPK-2, CPK-3, heart and liver enzymes
11. Cholesterol, triglycerides, see lipid panel blood test
12. IGF1, insulin, glucose, insulin resistance, somatomedin C test, also called an insulin-like growth factor-1 (or IGF-1) test, helps doctors evaluate whether a person is producing a normal amount of human growth hormone (hGH, or somatotropin). see blood test
13. Hormone level tests
14. Insulin resistance, diet tests by insulin requirements, non-prick home blood sugar monitors non-clinical application where accuracy can vary, such as the FreeStyle Libre which reads glucose from interstitial fluids just underneath the skin (not a prick pad). For the transhumanists there are permanent sub-cutaneous devices. Imagine such a device constantly measuring everything it can and collating it into reports with diet and exercise recommendations. (1
15. Autophagy, one of the most common ways to monitor autophagy is by measuring the protein levels of LC3-II, which is incorporated into autophagosomes and then degraded in the lysosome. There are many different ways to measure LC3 protein levels, including western blot and immunofluorescent microscopy (1), not a home doable test. How to measure autophagy at home
16. Kidney function, ACR (Albumin to Creatinine Ratio) and GFR (glomerular filtration rate) see blood test
17. Various organ function tests, eyesight...
18. Glycans, heart disease. One of the most reproducible markers of calendar and biological aging is the presence of N-glycans lacking terminal galactose residues linked to Asn297 of IgG heavy chains (IgG-G0) (1)
19. Inflammation, common way to measure inflammation is to conduct a blood test for C-reactive protein (hs-CRP), which is a marker of inflammation. Doctors also measure homocysteine levels to evaluate chronic inflammation. Finally, physicians test for HbA1C — a measurement of blood sugar — to assess damage to red blood cells. See blood test.
20. Imaging:
1. thermography, can show inflammation and circuitory problems
2. ultra-sound, size of prostate with rransrectal ultrasound, and other indicators of disease, using ultrasound artery dilation can be measured. (1). By stopping the blood flow to the arm and then re-permitting blood flow to the arm, the amount of dilation reflects the health of arteries.
3. computed tomography (CT) scan
4. arthrogram, joint problems, such as hip or shoulder pain. MR arthrograms can show ligament, tendon and cartilage issues with clear detail
5. myelogram, spinal imaging
6. nuclear medicine imaging, including positron-emission tomography (PET)
7. magnetic resonance imaging (MRI) and analysis using machine learning, artificial intelligence
8. Other imaging, or a general comprehensive imaging protocol that is analysed by machine learning and a human readable report generated
9. Pre-indicators to all causes morbidity and mortality, "we can see a little bit of diabetes or a little bit, or heart failure"
21. Genomics, genetic test, showing susceptibility to particular disease risk. The study of genes, is making it possible to predict, diagnose, and treat diseases more precisely and personally than ever
22. -omics, multi-omics, the suffix -omics, such as genomics, proteomics, metabolomics, metagenomics and transcriptomics, epigenomics, microbiomics, lipidomics, proteomics, glycomics, foodomics, transcriptomics, metabolism, see Omics, each type of omics data, on its own, typically provides a list of differences associated with the disease (1)
23. Epigenetic clocks, an epigenetic clock is a biochemical test that can be used to measure age. The test is based on DNA methylation levels, measuring the accumulation of methyl groups to one's DNA molecules
24. Biopsies
25. Morgan Levine, phenotypic age calculator 9 biomarker panel, population studies... (1)
26. Grim-age clock and mortality (probability) predictors, also popular
27. Intracellular communication, language interpretation
28. Bioelectric communication, language interpretation
29. Aged.ai (uses 19 biomarkers)
30. Methylation, epigenetic clocks
31. DunedinPoAm (1), a measure of the pace of aging
32. TruAge (principle component)
33. Pulse wave velocity (PWV), velocity at which the blood pressure pulse propagates through the circulatory system. Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events.
34. Biological clocks, telomere length, p16INK4a expression levels (also known as INK4a/ARF locus), multiple linear regression (MLR), the principal component analysis (PCA), the Hochschild's method, and the Klemera and Doubal's method (KDM) (1
35. Biomarkers, markers of all kinds, urine, saliva, faeces (gut health), hair sample...
36. Intestinal Permeability test, sometimes known as the leaky gut test, assesses damage to the lining of the gastrointestinal tract. Changes in intestinal permeability are associated with many health conditions, including autism, autoimmune disorders, food sensitivities and inflammatory bowel disease
37. Hallmarks of Aging (a test for each one)
1. genomic stability test
2. telomere test
3. loss of proteostasis test
4. nutrient sensing test, nutrient sensing pathways are commonly deregulated in human metabolic diseases
5. mitochondria health test
6. cellular sensecense test
7. stem cell exhaustion health test
8. altered intercellular communcation test
9. metabolism tests
10. macromolecular damage
11. epigenetic tests
12. adaption to stress tests
13. proteostasis tests
14. stem cells and regeneration tests, quality of repair tests
38. new clock and methods being investigated all the time, but not represented in this list.

Hilab system, a new point-of-care hematology analyzer supported by the Internet of Things and Artificial Intelligence

Lifestyle, What Goes In Must Come Out

What goes in, must come out. a + b = c, from a and c, b can be determined. If the fluoride, airborne asbestos and so on is not coming back out, then it is most likely destroying the system. It is not a black box, what goes in, must come out. Let's cover lifestyle...

• Invest in research that learns and uncovers how to live healthy, understands common disease and how to avoid it.
• Read the science and live healthy.
• Be proactive about health, a proactive health culture.
• A fitness like culture based on provable science of healthy living
• Pre-disease markers, see the condition at an ultra early stage and take actions, precautions.
• Autonomous self-health-testing.
• Prevention science and lifestyle therapies, prevent the condition in the first place.
• Regeneration.
• Honing the science on understanding causes and effective therapies.
• Avoid morbidity and delay mortality by any means, for as long as possible.
• Avoid being a cause of damage in the human body.
• Learn more about your health.

1. Air quality, as suggest previously oxygen deprivation is the fastest way to die, so in essence human beings are primarily oxygen processing machines. Ultrafine air particles 0.1µm claimed most unhealthy as particle size correlates to bloodstream absorption, as an analogy: a grain of sand can destroy a fine Swiss watch, IQAir: Particle Perspectives, Air filters can scrub out pollutants near highways, reduce blood pressure, Intellipure Ultrafine 468, EnviroKlenz Mobile UV

1. Water quality. The 8 Best Water Filters of 2020

1. Combined Toxicity, the level of toxicity from all sources. All source toxicity.

1. Blue zone lifestyle and diet, places in the world where people live the longest and are the healthiest are named blue zones. Blue zones are the authority on longevity by lifestyle, simply learn and duplicate the blue zone lifestyle. An epidemiology study conducted by Dan Buettner. Mostly vegans, wholefood plant based diet, they all consume legumes, strong sense of family, highly socially engaged, constant moderate physical activity innate to the lifestyle. Note: Vitamin B12, vitamin D, iodine deficiency affect vegans, the solution is fermented yogurts or fermented milks. Blue Zone Food Guidelines Also see centenarians. Much of blue zones is great placebo which acts as natural health pharmaceutical, such Japanese concepts as moai, ikigai and hari hachi bu. Dan Buettner tells a story of a man diagnosed with terminal cancer in Detroit returning to Greece resulting in spontaneous remission.

1. Diet, malnutrition and diabetes are an all cause morbidity. Studies show vegans, wholefood diet followed by vegetarians live longest. Vitamins, minerals, amino acids, omega 3 fatty acids and energy. What is the minimum amount of food that is nutritional complete? Eat at one sitting and drink water the rest of the time. Defining Powerhouse Fruits and Vegetables: A Nutrient Density Approach. Vegan is a difficult diet to get right and requires some disipline. The order of food may also be different, eat vegetables first and eat carbs last. Diet change relative to age, growing bodies require growth factors and slow digesting carbs, adults require far less growth factors. Growth factors are found in eggs, fermeneted yogurt, meat, legumes and peanuts. High dosing of growth factors activates MTOR which controls the size of the organism, conversely MTOR inhibition is associated with lifespan the older one gets but young people are so robust, the rules do not apply. Going androgenic is also advised, paracrine effect during puberty.

watercress, chinese cabbage, cauliflower, chard, beet green, spinach, kale, seaweed, sauerkraut	raw broccoli, broccoli sprouts, garlic, curcumin/turmeric, sweet potato, brussels sprouts, carrots, cantaloupe, ground flaxseeds, onions	avocado, lime, strawberries, tomatos, blueberries, blackberries, raspberries, chia seeds, quinoa, lemon, cherries, grapefruit, pear, apple, apricot, plum, peach, prunes, nectarines, dates, kiwi, grapes, orange, pumpkin	beans, lentils, kidney, legumes, black beans, peas, chickpeas... almonds, walnuts, pistachios, peanuts, cashews, macadamias
variety of olives (possibly olive oil) oleic acid, vinegar, wine, green tea, coffee, Trans and Saturated Fat = bad, Unsaturated = good in moderation	99%+ cacao (dark chocolate)	a1 / a2 / goat milk fermented into kefir or yogurt (1) or yogurt (probiotic) (see sialic acids), 1 raw egg (see TMAO)	vitamin D as a supplement (1000 IU per day)
polyphenols inc. flavonoids like quercetin and catechins in fruits, phenolic acids like lignans and stilbenes in vegetables, polyphenolic amides like capsaicinoids in chili peppers, other polyphenols like ellagic acid in berries. 650mg+, apples, turmeric, (1)	sulphorane Nrf2 pathway and inhibiting NF-κB, broccoli foxo3 onions, apples	omega 3 ALA, algae and phytoplankton are primary source of Omega3 in fish (EPA, DHA or supplement)	spermidine decreases the occurrence of age-related pathology and loss of locomotor ability. cardioprotection and lifespan extension... spermidine in health and disease lentils

Hybrid Diet Graph

• Chemical change aware arising from cooking food, for example A.G.Es.

Low glycaemic (GI) ✔ low insulin ✔ low inflammation (is sialic acids contributing to chronic inflammation) ✔ failing organs friendly ✔ nutritionally complete ✔ There is an association a correlation between insulin / IGF production and health and lifespan (in the many sugar inhibiting molecules, IGF knockout mice, western diet). The higher the insulin sensitivity, the longer the lifespan. Sugar absorption inhibitors increase lifespan by 35%M and 10%F and statistics of western diet are clear, eliminate all sugar and refined carbs and foods should also be kidney, liver, heart, organ friendly. Eat relative to your age and change your diet to reflect your age (why do we lose our teeth or have child teeth and adult teeth? What foods are our teeth designed for). The rate of absorption is critical to not disrupting homeostasis through diet and eating behavior. It is suspect the immune system destroys the aging body using inflammation, eliminate foods that drive inflammation. Vegan tip 1, water bathe fruits and vegetables overnight to detoxify them, then wash, prepare and eat. Tip 2, jar vegetables in vinegar and water for long term storage, wash and eat anytime. Tip 3, stop roasting peanuts, instead boil them or water bathe them. Food sanitation protocols required. Probiotics and exotic nutrition, the gastrointestinal tract, includes over 4,000 square feet of intestinal epithelial lining that controls what gets into your bloodstream. Certain disease is associated with gut microbiome changes, correlation, is not causation. The gut flora are implicated in two all cause mortality pathologies, Alzheimer's and Parkinson's and even multiple sclerosis, Study offers "indisputable" link between Alzheimer's and gut microbiome. Theoretically, a substance in the gut could wind up in the brain, the vagus nerve is one of the biggest nerves connecting the gut and brain, and it sends signals in both directions. Leaky gut and leaky blood brain barrier (BBB) are believed to be the means of possible infection by gut microbiome, either by a pathogen or their endotoxins, secretions. Human teeth indicate diet, 4 canines, 8 incisors, 8 premolars, 8 molars and 4 wisdom teeth (17-25 ages). Canines fish and meats, incisors fruits, premolars berries and while objects that fit in the mouth as opposed to incisors that slice a portion of a food too large to fit in the mouth and molars leaves salads. The wisdom teeth suggest an increase in vegetables in adulthood, and baby teeth mean baby food. The teeth system mirrors the physiology design. The body expects vegetables, greens, berries and low sugar fruits and occasional meats and fish. The wholefood, plant based diet. Dr. Esselstyn Prevent and Reverse Heart Disease, Dr. Valter Longo, fasting and fasting mimicking diet, Dan Buettner and the Blue Zones.

1. Time restricted eating, probably a healthy idea, yeast studies show that over active cells do not last as long. By eating once a day, you maximize the amount of time organs can rest and repair themselves. One meal a day or eating window 8/16, 6/18, 4/20. Water (1 liter per day) cleans the organs, so water is encouraged and exempt from the eating window.

1. 72 hours fast every 2 months. Some people promote a 72-hour fast. Catabolic and anabolic states both activate tissue remodeling, with mTOR inhibition increasing lifespan. Water is acceptable anytime. See Autophagy.

1. Cardiovascular exercise - no sedentary lifestyle. Gymnasium, stay hydrated, exercise, heart rate, HIIT, Cardio. Find the steepest mountain you can find and walk up or run up it as fast as you possibly can, every day. Weight training, body building. As you get older, investigate performance enhancing drugs such as a strong cup of coffee (no sugar) before gym. Endurance, strength, balance, and flexibility. A maximum of 7.5 hours per week.

1. Sleep - major repair occurs during sleep. Conditions for quality sleep (quality mattress, air quality, so on…) Gut molecules implicated in early death from sleep deprivation Can You Survive Without Sleeping? How Long Can We Stay Awake?

1. Sanitation - bacteria and virus cause health issues. Create the sanitary space, load on the immune system. Research products that sanitize the bedroom and bathroom such as UV-C, isopropyl alcohol 70/30, Enviroklenz UV (no aff). Practice sanitation (burn or treat sewage)... Think about the pathogen load of your area. See endotoxins.

1. Oral Health - poor oral health contributes to aging.

1. Meditate and Stress - make time when you lay down and do little and relax, anti-stress. Breathe deeply through the nose to increase nitric oxide.

1. Placebo effect, estimates of the placebo cure rate range from a low of 15 percent to a high of 72 percent. The longer the period of treatment and the larger the number of physician visits, the greater the placebo effect. If you believe it helps, it probably does. The goal is staying pre-clinical out of hospitals and far from doctors for as long possible. Along with placebo see somatic amplification and somatic deamplification.

1. Homesis, homesis is not chronic. Exposure to extreme conditions makes the body stronger and activates strength building mechanisms. What you eat and breathe is chronic, exercise is homesis it activates the paracrine effect.

1. Sex, the many health benefits from periodic sexual activity, from immune system function, to heart disease risk to lowering blood pressure and lowering stress. Obesity, dysfunctional behaviors are bad health effects of no sex with obesity leading to many ill health effects such as heart disease.

1. Wealth, taking advantage of healthy living using wealth is one of the biggest effects on lifespan and health extension, with some of the poorest peoples on Earth living vastly shorter lifespans than wealthier nations. Wealth also elevates one's outlook and placebo, making them want to live on as long as possible to continue enjoying their wealth and life. The Japanese, however, were not so wealthy in times past, but their culture has great placebo while the U.S. has a highly toxic culture making for bad placebo, called nocebo, toxic people and stress that comes with wealth is not a health orientated existence.

1. Other and experimental, verify for yourself such as use only red light at night and light at night, circadian rhythm, melatonin and health, use sunscreen or wear a hat to prevent photoaging, red light therapy, many more, hyperbaric oxygen therapy, Far UV Technologies, EMF Paint, SmartUV Ozone blood treatment, Sauna, heat shock and cold shock. A strategy might be to limit the amount of daily damage, the majority of repair occurs during sleep so therapies during sleep which eliminate sources of damage may prove beneficial such as exposure to x-rays, ozone, cigarette smoking, air pollutants, industrial chemicals, radiation (radio, television, cellular phone 5G, satellite, Wi-Fi electrical broadcast waves, solar ultraviolet rays, various other radiation and radioactive sources e.g. nuclear testing and nuclear reactor accidents, electro smog from electrical appliances and power lines), chemicals, toxins, pesticides, particles in the air, exhaust fumes and fumes in the air, food and drink, pathogens, stress, obesity, lack of exercise and natural cellular and metabolism reactions. Earthing or grounding is an example of an experimental lifestyle therapy. No one can know if there is benefit, so a scientific method is applied, experimentation to determine benefit otherwise we are practicing a religion, this means a study where some people do grounding and others do not with no one knowing who has the real mats and who has the sham mats, their vitals are taken before, during, and after. Health benefits by electrically earthing the human body. By walking barefoot at the park, bathe in the ocean, electrically earthing the body overnight by sleeping grounded, while no products are necessary earthing pads are commonly used. It is about surface area, how much skin is touching earth. Grounding like gym exercise is session based, the benefits protect for a period of time afterwards. Studies: Earthing Grounding Studies.

Even with a perfect diet and exercise, aging proceeds. So it must be going on inside the body. Pharmaceuticals is the second methodology.

Pharmaceuticals

Lifestyle science is superior to supplements and pharmaceuticals, diet and exercise. Food can solve every ill, you just have to find the right food. Obviously the logic is flawed, just as starvation or malnutrition is aided by a good meal it doesn't mean there is a plant or food for every ill, and if you cannot find the right food, just imagine some food does that. Plants generally make chemicals to avoid being eaten, no animal in all nature since all time goes about eating special food to become impervious to ills or to escape mortality. We can expect some benefit with enough poison to kill something that killing patient, but not enough poison to kill the patient, and such is the revolution of modern medicine. Another, labs need patents to make financial sense to investors with oral pills preferred with a hope to hit a cash cow molecule and sell it on to big pharma. Out of patent molecules are dead in the water. It is probably universally accepted that curing aging is beyond the pill format. Pills are instead a great and important way to build widespread acceptance among the lay public so that stronger science can be permitted and conducted, however the problem is when talented scientists are held up in intelligent frivolous activities.

Immortality seeks to build a lab to test longevity molecules. We apply the science and accept the results. Identify individual molecules and then combine the molecules to test for possible cumulative effect, test with low, medium and high dosages to determine optimal dose. These findings dictate what products make it to the e-pharmacy. The e-pharmacy is the official Immortality store in Immortality marketplace. Immortality marketplace products are paid using crypto.

Wrinkles, diets and beauty products which claim to have anti-oxidant properties are unlikely to prevent aging, according to new research. Scientists in England say this is because a key 50-year-old theory about the causes of aging is wrong. Antioxidants Are Unlikely To Prevent Aging, Study Suggests. Scientists can measure the genetic changes using a special machine and then see what interventions can alter the genes back. The pathway to the gene is the endpoint language, lately the epigenome.

Rapamycin, (Sirolimus) the opposite of anabolic is catabolic, anabolic and anti-catabolic substances. mTOR (mammalian target of rapamycin) pathway, growth regulator in relation to available nutrients and environment. Rapamycin (immune-suppressant drug) believed to trigger autophagy, something that occurs naturally after fasting for 24+ hours, autophagy improves cellular condition which is all important for health. Rapamycin is produced by the soil bacterium Streptomyces hygroscopicus. Target of rapamycin complex 1 (TORC1). (1, 2). Rapamycin believed to be a weekly or fortnightly drug with daily use instead life-shortening. 6mg once weekly, common starting at middle age, develop strategy to balance anabolic and catabolic to avoid sarcopenia associated with mTor. Expensive, hard to get, optimal dose unknown, very clean mTor inhibitor, no side effects at longevity dose. The Risky Anti-Aging Pill Men Are Taking Now - Rapamycin, $2m longevity boost for Rapamycin Alzheimer’s study. When taken late in life, Rapamycin increases lifespan by 9%M-14%F, despite the dosage being suboptimal. This possibly equates to more than 7 years of human life.(1). See autophagy.

Metformin, (a diabetes drug) inhibits mitochondrial respiration exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion. Late life metformin limits cell survival and shortens lifespan, Inhibition of mitochondrial respiration and also perhaps inhibition of mitochondrial glycerophosphate, and a mechanism involving lysosome. Another showed that mitochondria bio-genesis was absent in people who took Metformin and exercised versus those that exercised without metformin. Inhibited mitochondria respiration does not come across as beneficial (byproducts of chemistry or volatile leakage of protons). The so-called benefits of Metformin can be acquired with intermittent fasting and exercise both body building and cardio. People who have metabolic dysfunction gain from Metformin, while people who exercise or already have optimal metabolic function not only achieve no gain from taking Metformin but counter-productive. People who exercise have increased mitochondria bio-genesis, but not so in people who take Metformin and even if those that take Metformin exercised. Metformin, having no gain in healthy people or people without Type 2 diabetes. Can people with type 2 diabetes live longer than those without?, the study says No. Is Metformin Really an Anti-aging Drug?, with the experiment, they list 7 reasons, concluding damage accumulates and must cause death eventually, but quasi-programmed aging terminates life first. Molecular damage can become life-limiting, when artificially accelerated or, potentially, when quasi-programmed aging is decelerated.

Nicotinamide adenine dinucleotide, NAD+ cofactor central to metabolism. Deviations in natural human proteins relative to age (25 vs 80) as cause, NAD+ produced by the liver and said to decrease with age, but almost every measure deviates with age. Low levels of NAD+ are said to decrease sirtiun or parp activity, acetylation. People who supplement with NAD+ or a precursor generally feel no benefit, do not appear more youthful and have a placebo effect outlook. It is said that without NAD+ you would die, like oxygen or kidneys. NMN is not bioavailable (sublingual) and Nicotinamide Riboside (NR) does not make it past the digestive system. Chromadex went live with NR before efficacy was proven, and only did one small trial with conflict of interest to conclude their product was safe to eat. It is a complex process, dumping substances into the bloodstream is too simplistic as there are domino effects, cascades, chain reactions. When people supplement the organ that normally produces that supplement loses its ability to do so, such as people who supplement with testosterone, their testicles shrink (hypogonadism) as it no longer produces the hormone, does supplementing with NAD+ cause increased dependency. Termed “shut down”, taking steroid users a year or more to return to normal, with NR methylation deficiency arises from supplementation. It was also said that no matter how much dose was infused, the body regulated the amount of NAD+ in the body, disposing of excess. This leads etiology, why, does it decrease with age? Pterostilbene sometimes sold as a substitute to David Szigeti, Resveratrol which is destroyed by sulphuric acid of the stomach and not bio-available has even less evidence of efficacy and both shown to cause cell stress, it supposed to do the opposite. The advice is take Niacin, Vitamin B3 is a cheap yet equal substitute for expensive NR. I suspect that Vitamin B3 or NR is no more life extending or health promoting than any other vitamin. Clinical Trial of Nicotinamide Riboside Completed NAD+ Restoration Therapy - Risk-Benefit Analysis. A recent human trial of nicotinamide riboside (NR) concluded "no clinical benefit to supplementation". NMN & NR Don’t Work In Humans? Alarming Research. Why not supplement with ATP directly? And bypass the entire mitochondrial system. ATP supplementation does not go intracellular when consumed, so an intracellular version requires receptor binding. Researchers propose new theory of aging. Some new science is showing benefit NAD+ can restore age-related muscle deterioration, research finds Chronic inflammation causes a reduction in NAD+, NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle, derivitive forms are NR, NMN and NMNH, NMNH is a reduced form and more potent.

1. No antioxidant has shown any clinical benefit to date.
2. Not many substances are absorbed orally, bioavailability information is essential prior.

Positive Findings from the ITP

As of Cohort 10, C2014, 7 compounds have shown significant extension of median lifespan:

Aspirin – Increased lifespan in males but not females (Strong et al., 2008).

Rapamycin – Increased mean and maximal lifespan in both males and females when initiated at 20 months of age (Harrison et al., 2009) and when initiated at 9 months of age (Miller et al., 2011). Females responded more robustly than males at equivalent doses; when ~ equal blood levels were achieved, response was also about equivalent in females and males (Miller et al., 2013).

17αEstradiol – Increased lifespan in males but not females, at 4.8 ppm dose (Harrison et al., 2013) and 14.4 ppm dose (Strong et al., 2016).

Acarbose – Increased lifespan in both males and females, but the effects were greater in males, when initiated at 4 months of age (Harrison et al., 2013), but only males responded when initiated at 16 months of age (Strong et al., 2016).

NDGA (nordihydroguaiaretic acid) – Increased mean lifespan in males but not females (Strong et al., 2008), even at doses that gave equivalent blood levels in males and females (Harrison et al., 2013).

Protandim® – Increased lifespan in males but not females (Strong et al., 2016).

Glycine – Started at 9 months. Increased lifespan in males and females (Miller et al., 2019).

ITP - Compounds In Testing

	Melatonin, best longevity drug of 1993, light at night disrupts circadian rhythm, improves sleep, immunomodulatory, short term use only, red light bulbs, red light night modes on phones	Oxaloacetate, research on Drosophila melanogaster demonstrated an average increase in lifespan of 20% following the addition of oxaloacetate to food. Similar results were also obtained with the roundworm C. elegans.	17-α-estradiol, 15-18%M not beta	Benzoxazole, slowed bone aging by up to 31% over the course of a year's treatment in mice	Acetyl-L-carnitine protects brain cells from damage and temporary cerebral ischemia, lipofuscin, contributes to TMAO production causes heart disease	Gaf1 cells without have a shorter lifespan
Alpha Keto-Glutarate improves healthspan more so than lifespan in middle-aged mice. Shrinks mobidity.	Glutathione critical defense system for the protection of cells from many forms of stress, antioxidant automatically produced in cells, very low bioavailability	Deprenyl/Selegiline, used in Parkinson's disease and major depressive disorder.	Phosphatidyl Serine, brain health 1	Sestrins (Sesns) proteins made when a person exercises (mimic exercise) not bioavailable. Also see heat shock proteins (Hsps) chaperones.	Centrophenoxine brain function lipofuscin	Urolithin A cell's ability to recycle the components of the defective mitochondria mitophagy?
L-Carnosine slows the aging of human cells and protects against age-inducing processes such as glycation and mitochondrial dysfunction	GH3 and K.H.3 active agent procaine best longevity drug of 1955	Vinpocetine and/or Hydergine no clinical research suggests that vinpocetine protects against dementia or slows brain aging	Piracetam - treat cognitive impairment in aging, brain injuries, as well as dementia	Aspirin blood thinner anti clotting agent, 8% lifespan	C60 - Buckminsterfullerene disproven, (1)	Metolazone, may not repair mitochondria
Elamipretide, reducing proton leak restores function in aging heart cells	Isrib mental decline	Resveratrol, not bioavailable, questionable efficacy, replace with bio-available polyphenels such as quality extra virgin olive oil	Curcumin active ingredient in tumeric, very poor bioavailability1	R-alpha lipoic acid protects mitochondria	Green tea1 contains stimulant caffeine disrupting sleep patterns	CoQ10, poor bioavailability
PQQ, limited evidence that the supplemental form provides any meaningful health benefits	Astragalus root	Caffeine	Nicotine, not tobacco, highly addictive. Study finds nicotine safe, helps in Alzheimer's, Parkinson's	hydroxycitrate	Tetrahydropyridoethers1, lipofuscin	Beta Cyclodextrins liofuscin, 1
Trodusquemine for atherosclerosis Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming	Marine collagen	Vitamin C megadose, produces medical anomoly in some people. 1	Selenium	D-Ribose	Rhodiol, increase the mean and maximum life-span of the fruit fly up to 24% and 31%, respectively	N-acetyl-L-cysteine, increase in lifespan 5% male flys, others say 24% in mice. Average 24% Max 45% in Mus musculus
Lactic acid, skin repair	Gluconic Acid, believed bad similar to TMAO	Malate	Acetate	Lutein, a type of vitamin called a carotenoid, age-related macular degeneration	Theaflavins, polyphenol	Inositol
Butyrate, produced through microbial fermentation of dietary fibres in the lower intestinal tract and stimulates production of a pro-longevity hormone called FGF21	Glucosamine, Supplementation correlates with 15% lower all cause mortality in human subjects, low bio-availability	Boron, cryopreserved stem cells	Nordihydroguaiaretic acid NDGA, an antioxidant compound found in the creosote bush. The creosote plant has been used in herbal medicine	Protandim	Glycine	Shikimic acid - protects skin cells from UV-induced senescence through activation of SIRT1
Lithium 1	icosapent ethyl (Vascepa)1 2	GlyNAC, or NAC alone - 24% lifespan extension (1, 2)	Epithalamin or Epitalon - 31% an unreplicated Russian pineal peptide from St Petersburg laboratories of Anisimov and Khavinson, others say (1,2) maximal lifespan by 12.3% in mice.	Thymus Peptide 28%	Spermidine 24% Autophagy?	Phenformin
Ethoxyquin	Vanadyl sulfate	Berberine, could be better than metformin, mice avg 16% (1) Rated No1 Longevity drug in The Database of Ageing-related Drugs	Acarbose sugar inhibitor, 11%M-9%F 1, 2 Slow metabolism of sugar improves health increases lifespan, low sugar insulin diet. Also see SGLT2 inhibitors	L-deprenyl, Rattus norvegicus 17%	Low dose naltrexone, cancer prevention, inflammation	BAM15 (1)
Astaxanthin	Ergothioneine	Indolepropionamide (1)	Fucoidan (very sepecific type)	Pcsk9 inhibitor (possible oral version)1	Oridonin, AKT inhibitor. Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens 1

There are 2 known compund pills on the market, one is the AGE pill (Beta-Alanine, d-Ribose, Alpha Lipoic Acid, Rosemary (leaf) Extract, L-Carnosine, Betaine HCl, DMAE Bitartrate, Acetyl-L-Carnitine HCl, L-5-Hydroxytryptophan, Blueberry (fruit) and the other is Novos,(Fisetin 100 mg, Glucosamine 1000 mg, Vitamin C 100 mg, Hyaluronic Acid 100 mg, Rhodiola rosea 300 mg, ginger 80 mg, glycine 2000 mg, lithium 1 mg, pterostilbene 50 mg, magnesium 300 mg / malate 1700 mg (in 2 grams of Magnesium Malate), Calcium alpha-ketoglutarate 1,100 mg, L-theanine 150 mg), Novos Boost contains only NMN. Once of the early players in the field is [Life Extension by Bill Faloon|https://www.lifeextension.com/] WHO Model Lists of Essential Medicines The Database of Ageing-related Drugs Long Long Life Vincent E. Giuliano list 15 new groups of molecules to fight against ageing and protect our cells; one step closer to staying healthy longer, new study shows Two-Drug Combination Accelerates Wound Healing And Reduces Scar Tissue Curated database of geroprotectors Neuroprotection Anti-Aging and Senolytic Molecules Interventions Testing Program (ITP)

Combining therapeutics potentially results in no synergy instead cancelling out, so taking many supplements does not automatically mean more benefit, contrary, possibly result in no benefit or even drawback.

Compounds that affect an all cause mortality but do not in themselves extend lifespan.

Sirtuins, genes that encode a family of signalling proteins involved in metabolic regulation. There are 7 Sirtiuns. Sirt 1 - metabolism, inflammation, Sirt 2 - cell cycle, tumorigenesis, Sirt 3 - Metabolism , Sirt 4 - Insulin secretion, Sirt 5 - Ammonia detoxification, Sirt 6 - DNA repair, metabolism, TNF secretion, Sirt 7 - rRNA transcription, cobB - metabolism, SirTM - ROS detoxification. The attempt is to activate sirtuins using pills, STACs (small molecule sirtuin activators) are drugs for sirt activation, there are no STACs and no known pills that can trigger for example DNA repair. As of 2018, there was no clinical evidence that sirtuins affect human aging. It is believed that there are about 238 genes that can do healthy tasks like DNA repair. As part of the business model, they have to fit it into a pill format, but 238 is way too much and breaks the pill format, so forget 238 how about 6? The commercialization of what might be valid science renders the product questionable, if not toxic. Harvard grape juice, resveratrol is destroyed by sulphuric acid in the stomach and not bioavailable, and Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells Most vitamins and supplements are rejected during digestion and never pass into the bloodstream, with prolonged use not advised due to digestive system damage. Many supplements do not contain the purported active ingredient, wrinkle creams have always been ineffective, except for Retinol. Plastic surgeons are probably psychopaths and not doctors. List of Longevity Genes 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging Emerging Anti-Aging Strategies - Scientific Basis and Efficacy A Trick To Activating "Anti-Aging" Proteins In Worms Could Exist In Humans Proteins prevent synapse destruction in Alzheimer Metabolite Supplement Boosts Health and Lifespan in Mice Resveratrol Anti Aging - It’s Actually Bad For Us?

Mapping all genes related to lifespan extension are https://genomics.senescence.info/longevity/ without any real way to target these genes as a therapy.

Telomeres, are the strands at the end of DNA when they decrease in length ageing accelerates and the cell no longer divides. Apparently, each replication doesn't copy all the way to the end of the DNA strand and when the DNA strand gets too short, the attempt to repair joins it to another DNA, scrweing the whole thing up rather than adding more telomere. The body naturally produces telomerase to maintain telomeres and there are attempts to increase telomeres artificially using telomerase or gene therapy, both short and long telomere length associated disease processes with over lengthening causing cancer, Long telomeres and cancer risk: the price of cellular immortality. Cancer is largely said to be caused by DNA damage or damage to the DNA repair system. The hayflick limit, the amount of times cells can divide is broken with telomerase. It is believed that the body limits replication to avoid replication of DNA damage. Telomere shortening that happens when cells divide may be a way to limit cell proliferation in anticipation of damage. Danazol may or may not be able to lengthen telomeres but has many side effects but generally not a cancer causing agent. Cycloastragenol is a molecule isolated from various species in the genus Astragalus that is purported to have telomerase activation activity. However, there are reports of liver cancer. Dyskeratosis congenita (DKC), also known as zinsser-engman-cole syndrome is characterized by short telomeres. Some manifestations resemble premature ageing (similar to progeria), it might be caused by a gene mutation inhibiting telomerase production. There is a maximum number of times cells can divide to form new cells, 40 to 60 times before they become senescent, called the Hayflick limit which may or may not set the maximum potential human lifespan to 115 years. If telomere length maintained at the ideal length the potential for regeneration increases. Telomere length has been shown to positively correlate to life span, the other big one is stem cell progenitor cell depletion with age. Cells in the human body do not undergo mitosis at the same rate, some do not replicate at all and newly formed daughter cells are not formed with short telomeres, however aged cell morphology insights show short telomeres, decreased replication with age looks like dyskeratosis congenita and progeria. Can science design a therapy to maintain ideal telomere length in vivo. I doubt it. Gene therapy would have to verify and correct DNA systemically prior to lengthening which is technically possible or resulting cancer trivially curable. Study identifies potential drug treatments for telomere diseases Newly discovered interactions between proteins can reduce DNA damage and cancer development A drug treatment for telomere diseases? Telomere Diseases Telomere length: how the length makes a difference Regulation of the cell cycle timing of mitosis, New intranasal and injectable gene therapy for healthy life extension, Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer

Cdc42, targets for amelioration of stem cell ageing, bone marrow condition and stem cells, haematopoietic stem cells and mesenchymal stem cells (multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue). As the body's stem cell generation factory ages it is said they come dysfunctional, sub-optimal and in declining amounts. Cdc42 activity regulates haematopoietic stem cell ageing and rejuvenation. Department of Dermatology and Allergic Diseases, University of Ulm, 89091 Ulm, Germany (1, 2). The decline in haematopoietic function seen during ageing involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to ageing of haematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC ageing remain unclear. In their paper they demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC ageing and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Their data suggests a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell ageing. (immuno-decline and pericyte activation). The prospect that HSCs and even MSCs could be kept very young in vivo and stem cell exhaustion mediated with a small molecule by Cdc42 inhibitor or upregulation of another gene and the simple platform for doing so. Healthy bone marrow stem cell production system is important in ageing. Young Bone Marrow Rejuvenates Aging Mouse Brains, Study Finds Glycogen accumulation, central carbon metabolism, and ageing of hematopoietic stem and progenitor cells Defective immune cells could make us old. Experimental pharmaceutical Cdc42 inhibitors are ZCL278 and AZA197, ML141 (rac1 off target). Mechanisms and rejuvenation strategies for aged hematopoietic stem cells Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging

Senescent cells, are damaged cells that are in cell cycle arrest, stopped from replicating but resident, accumulate with age and are thought to contribute to inflammation, tissue damage and age-related diseases. Senescent cells remove themselves or are removed by the immune system but with immune system decline senescent cells accumulate, immune system cell types are made in the body (bone marrow and T cells are made in the thymus) and form part of blood composition. The innate process is called autophagy. Senescent cells secret senescent associated secretory phenotype (SASP), the increased expression and secretion of a suite of inflammatory cytokines, chemokines, growth factors, and proteases (Coppé et al., 2010a; van Deursen, 2014). Senescent cells are believed to suppress tumor or SASP may increase tumors. Senescent cells are believed to compound ageing in ageing bodies. There are drugs named senolytics that claim to clear senescent cells from the human body, the deleted senescent cells are replaced as part of the bodies natural process, either when an adjacent cell divides or from bone marrow derived pericyte stem cell. These cells must be replaced with better cells and so an optimal cell replacement protocol is also required. Good housekeeping? The effectiveness of senolytic drugs in vivo is uncertain, perhaps removal of 50% of senescent cells with the actual amount varying widely by tissue and drug type - in some tissues, the effect is negligible for the drugs tried thus far. What is required is a highly effective senolytic in the 99% range, and also different types such as for cancer treatment and prevention, scar tissue removal, even pre-senolytic, anticipating cells that are showing first stages of damage, perhaps short telomeres or cancer prevention senolytic. There are also drugs called senomorphics that suppress SASP but do not kill (apoptosis) the cell, we also know that senescent cells occur in the brain, so suppression of SASP in the brain might prove important. Not one senoltyic is effective against every type of senescent cell in the human body, opting for the strategy of a combination or cocktail of senolytics. Once the sensescent cells are cleared their is no more reason to keep taking pills, it is said 1 pill for up to 5 days once a year or 1 injection once a year, important: not an ongoing daily pill. Keep some around as a number of them are beneficial, anti cancer and wound healing.

Types:

1. FOXO4 peptides, FOXO4 can bind with p53 protein to induce cellular senescence.
2. Bcl-2 Inhibitors, family of anti-apototic proteins.
3. USP7 Inhibitors (Ubiquitin-specific processing protease 7)
4. HSP-90 Inhibitors
5. Engineered Car T cells (chimeric antigen receptor), a note is a senolytic for fibrosis as discussed here
6. Src Tyrosine Kinase Inhibitors
7. Crispr/Cas9 BIRC5 Gene Knockout: Crispr/Cas9 is used to trigger apoptosis in relation to a specified gene sequence such as a cancer gene sequence or damage marker sequences. The procedure described in Knockout Of BIRC5 Gene By CRISPR/Cas9 Induces Apoptosis And Inhibits Cell Proliferation In Leukemic Cell Lines, HL60 And KG1. Where targeting common somatic mutations may be a cancer and disease prevention strategy.
8. GLS1, Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders

Drug Candidates:

1. Dasatinib and Quercetin Cocktail - Quercetin is believed to only have weak senolytic properties when used by itself. Oral administration once a day within 5 days of 50 mg of dasatinib and 500 mg of quercetin demonstrated senolytic effect. Others say Quercetin 25mg per kg body weight and Dasatnib 2.5mg per kg body weight, 2 times 1 week apart. (1, 2), Safe at prescribed dosages, bioavailability improves when taken with fats. Injection of Dasatinib + Quercertin twice annually. Risk-Benefit Analysis of Dasatinib + Quercetin as a Senolytic Therapy Preliminary report from a clinical trial of Dasatinib plus Quercetin
2. Fisetin - Found to be effective in senescent fat cells (pre-adipocyte, white adipose tissue), 1000mg - 1500mg at night, for four consecutive days(1) Fisetin Senolytic Therapy - Risk-Benefit Analysis Fisetin is a senotherapeutic that extends health and lifespan. Low bioavailability
3. FOXO4-DRI (1)
4. ATTAC
5. Azithromycin or Roxithromycin - Antibiotics, only ever tested in a petri dish, not recommended, does nothing except destroy your microbiome. (1)
6. Navitoclax, Venetoclax - Bcl-2 inhibitor
7. Piperlongumine - may or may not have senolytic properties
8. SSK1(1)
9. Car T Cells(1)

Using senolytics prior to stem cell infusion may or may not enhance the treatment The Clinical Potential of Senolytic Drugs Ageing, tumour necrosis factor-alpha (TNF-α) and atherosclerosis Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Ageing and Age-Related Diseases Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases Scar-free healing: from embryonic mechanisms to adult therapeutic intervention Senescence can be BETter without the SASP? Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2 Senolytic drugs: can this antibiotic treat symptoms of ageing? Japanese scientists develop vaccine to eliminate cells behind aging

Eugenics, by interbreeding super-centenarians, we could expect a 250-year plus lifespan human. The means of living that long would likely be optimized biology for longevity. No matter what a person did, no practice could ever compare their biology to such a person, a normal biology could never reach that amount of lifespan. Their enhanced physical systems would also be beyond science to analogue. Latest attempts at a program using a combination of genetic engineering, cloning and selective breeding to produce 500 IQ human beings is rumored to go on. Acquired Savants. Ethics is central to such a program, while the religious, political, insane, degenerate, dystopian, psychopathic and megalomaniacs and other types, form personality traits to be excluded from the program.

SaveTime strategies, hair laser removal or permanent hair removal, wheather shopping for more usable days, sleep quality, elimination of repeating or duplicate tasks using delivery services for example.

Broad-spectrum antiviral agents (BSAA) such as DRACO, penicillin for virus and a big chance to knock down 5 of the 16 all cause mortality caused by virus and bacteria (third-generation antibiotics are the broadest but only effective against bacteria not virus). Vaccines utilize the immune system which declines with age, immunosenescence. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus, and additionally found effective against influenza in weanling mice. Reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. In July 2020, a paper from another independent research group about the effects of DRACO in vitro suggests DRACO was nontoxic in uninfected mammalian cells, and cells infected with H1N1 influenza virus showed a "significant", dose-dependent level of apoptosis. Virii produce a unique length RNA that human cells do not produce and through the length of virus RNA thy identify the cell as infected and trigger apoptosis. DRACO is selective for virus-infected cells. Differentiation between infected and healthy cells is made primarily via the length and type of RNA transcription helices present within the cell. Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription. Cell death is effected via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases. The procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell (and the virus with it, nuke the cell to kill the virus). Double-Stranded RNA Activated Caspase Oligomerizer (DRACO): Design, Subcloning, and Antiviral Investigation. A handful of all cause mortality is attributed to virus infections. Broad-Spectrum Antiviral Therapeutics. Oral version Oral antiviral shows promising early results against... Broad-Spectrum Antiviral Agents: A Crucial Pandemic Tool Researchers develop direct-acting antiviral therapy, used gene-silencing RNA technology called siRNA (small-interfering RNA) to attack the virus’ genome directly, which stops the virus from replicating, as well as lipid nanoparticles to deliver the siRNA to the critical site of infection. Treatment with virus-specific siRNA reduces viral load by 99.9%.

Broad-spectrum antiviral agents are related to looking at all cause mortality, morbidity as a strategy, and finding prevention treatments that affect the cause of death specifically rather than general aging. Organizations such as Repair Biotechnologies are set up specifically to solve one all cause mortality.

Bio-Electrical layer, along with the biochemical layer there is a bioelectrical layer as presented by Dr. Michael Levin. It seems that this is how organs get their shape. There may be an interface to chromatin using electricity, certain drugs can change the electrical state of the cell for effect. These drugs are termed, ion channel modulators, perhaps to induce pro-regenerative states. By a specific configuration of open and closed ion channels. Let's assume. The only examples of immortality on Earth has nothing to do with damage and only ever shown to be achieved by regeneration biology, and so we can only conclude that the path to lifespan and healthspan extension can only be through the equipment of regeneration in biology of which the axolotl, the jellyfish and some worms and through regeneration they achieve biological immortality. Understanding this mechanism and chimera it to mortal animals is the challenge, i.e. making it portable. Apparently it has been adapted to frogs. The bioelectric layers may contribute to a regeneration therapy, including by preventing cancer during regeneration or cancer in general. BBI International Webinar Series Professor Michael Levin, Scientists discover how life begins, Electrical signals of the heart. The basis of a touch sense in a Paramecium is the discharge of electricity upon contact. Paramecium show a reaction to current by the interference with the membrane potential which in turn controls the beating of the cilia. Limb Regeneration in Humans: New Research Challenges Long-Held Beliefs

Longevity Pathways, when a certain protein profile arises with a condition, a pathway to genes is elucidated from cell receptor, all the connections in the middle and ending with genes. These pathways are targeted for affect. Premiere longevity pathway shown to extend lifespan in yeast or worms and human homologs are cellular stress response. These include MTOR1 which is a cellular stress response to a lack of excess, contrary the IGF/Insulin pathway is shown to shorten lifespan and cause disease, associated with too much eating, notably too long without essential nutrients also shortens lifespan. Lifestyle activities and drugs are used to target longevity pathways and avoid anti-longevity pathways.

Hypothalamus, reasoning to the hypothalamus is one organ having major importance to ageing while others have minor importance. What happens at the important organ goes systemic and the effect cascades, domino effects, chain reactions, rebounds, feedbacks throughout the body, strategy is to identify and concentrate on the majors. The endocrine system with the hypothalamus being number one and the pituitary gland number two. The hypothalamus controls child growth phase, starts and ends puberty, initiates body changes for pregnancy and menopause and also knows how to keep time, the circadian rhythm or day/night cycle is in the hypothalamus. This small gland is in the most ancient part of the brain, the limbic system and is believed to keep time for an organism's lifespan. When the hypothalamus senses low oestrogen in the blood of a woman it sends a signal to the pituitary gland which in turn sends a signal to the ovaries to produce more oestrogen. Puberty occurs with clockwork regularity, the method and control of which is unknown, perhaps a neural clock perhaps accumulation of methylation acts as a clock, (telomeres can be thought of as a type of cell division clock). That the circadian rhythm is in the hypothalamus makes the organ highly suspicious of being in part the timer for lifespan, such a master clock of the human body is called the (SCN) Suprachiasmatic nucleus consisting of 20,000 neurons, time keeping systems like these in the central nervous system may be dictating the lifespan of an organism. In this case averting death is similar to attempting to avoid puberty, regardless of what you do sooner of later it is going to happen. Centenarians, persons that live up to and past 100 years run in families and different animals have their specific lifespan both suggest genetic lifespan mechanism. Researchers at Albert Einstein College of Medicine conducted a study on mice. They discovered that as mice age, levels of molecules, specifically IKK-β and NF-kB, molecules that initiate inflammatory responses, increase in the brain, particularly in the hypothalamus. The concentration of the pro inflammatory cytokine tumour necrosis factor β also increases. The increases directly cause a decline in gonadotropin-releaseing hormone (GnRH). Mice that produced less IKK-β and NF-kB in the hypothalamus created more neurons and solved mazes more quickly, had greater muscle strength, and exhibited a 20% longer lifespan. The opposite effects were seen in mice that overproduced IKK-β and NF-kB. Zhang G et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-kB and GnRH. Nature 2013 May 9; 497:211. Gabuzda D, Yankner BA. Physiology: Inflammation links ageing to the brain. Nature 2013 May 9; 497:197. Brain cells found to control ageing, Yalin Zhang, Min Soo Kim, Baosen Jia, Jingqi Yan, Juan Pablo Zuniga-Hertz, Cheng Han, Dongsheng Cai. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature, 2017; DOI: 10.1038/nature23282, Has a small trial stumbled upon a way to reverse biological aging?, The pineal aging and death program: life prolongation in pre-aging pinealectomized mice, Pineal control of aging: effect of melatonin and pineal grafting on aging mice, Biological clocks and puberty onset

Transhumanism, there is no hope for life extension without transhumanism. The only long term solution is replacement, artificial parts, replacing body parts with "superior" mechanical prosthetics. The human body is like what is referred to as a Rube Goldberg machine or Heath Robinson contraption, in that it is designed to perform a simple task in an indirect and (impractically) overly complicated way to an extreme degree. If a kidney was made out of non-biological materials, it would end the need for donors. Effectively, it only needs to be made once perfectly to benefit every kidney transplant, thereafter, ever. An artificial pancreas, cure type 1 diabetes and so on. It is too technically challenging for human beings. Organ transplantation should focus completely on permanent mechanical organs, artificial organs made from non-biological materials. The chemistry of the human body is too finicky, overly complex, uncontrollable, impossible. This begins with either trying to make humans either anaerobic or poly aerobic by infusion of engineered mitochondria like organisms or artificial mitochondria. Allowing humans to either run off APK directly eliminating the mitochondria system altogether, or by utilizing many gases rather than just oxygen. The elimination of the lung system means respiratory pathogens and lung diseases are avoided. Artificial mitochondria, mitochondria like organelles, engineered mitochondria could be both biological or nano machines. The second way to begin trans-humanism is by replacing the thymus as everyone undergoes thymus involution, the organ is not real-time critical yet highly beneficial to health. Biomedical engineering are machines that do some function of the human body such as a lung machine, blood purifying, processing machine, dialysis, these machines are nowhere near organ replacement solutions. There is no rejection with metallic machines. The key is fusing bio with the mechanical permanently. Even a permanent IV-port useful for intravenous access appears highly UNdesirable. The focus on internals is probably more attractive than externals as people want an arm, hand and fingers that are identical to their biological version in every way, from the effortless control of the limb to its dexterity and qualifying expectations, if it falls short then it fails almost. We can now have an organ that kills bacteria and virii in the bloodstream, more info. The major issue is that when a person loses an arm or a leg, hospital duration is 6 months and rehabilitation takes years. The advantage is that metal lasts a very long time and is simpler than the body limb, living on Mars or on the Moon becomes applicable as no oxygen is required, and the materials can handle the harsh environments. Another group that says humans download their brain to a mainframe, exist virtually until a clone is made, and the technology exists to download the virtual self back into the clone. Those that are attempting to grow new organs using stem cells to eventually create a brainless clone (doubt it ever). The head transplant experiment a while back should never to be tried again, plagued with far too many issues, has to fade into history and that chapter closed. Cryogenics is freezing oneself and then unfreezing oneself after a time, the guy offered the service without a way to unfreeze them, which is completely bizarre. If they could unfreeze them before offering the service that would be better probably not using ice, a person dissatisfied with modern times would say, put me under and wake me in a hundred years and in a hundred years, come too, spend a year looking around and say nope, put me under for another one hundred years. I think this could be the wildest service out there, but the technology of cryogenic has not moved at all. How to make Voltron? Call four sexy friends "Form Voltron, activate interlock, Go Voltron Force" I prefer Mighty Morphin' Power Rangers. Oh, continue reading then...The Kidney Project, Artificial Heart, Artificial Bio Liver, Progress and challenges of the bioartificial pancreas. Renal failure patients areconnected to the dialysis machine by a venous catheter inserted into their chest, which can lead to infections and blood clots. Anastomosis technology, do you create a biological artery to graft into the existing artery or do you replicate the function in a non-bioogical pipe and work on fusing the two. Artificial artery firm wins award, Manmade blood vessels could save lives: Artificial artery grafts offer hope for children with heart conditions, Usefulness of artificial vascular graft for venous reconstruction in liver surgery, Artificial Kidney: How To Build It And Its Benefits, Blood Filter for Malaria, [Medisievehttps://www.nihr.ac.uk/documents/case-studies/medisieve-ltd/21471], Anastomosis, vascular graft uses the patients own cells to make an donar artery to suture to existing artery. The use of synthetic materials, polymers, teflon are also used. Blood clots are an issue. The implant space is increasing with continuous glucose monitor (CGM) both subcutaneous and prick, such as Eversense, Freestyle Libre 3 and Dexcom G6. Deep brain stimulator, Gastric stimulators, Foot drop implants, cochlear implants, cardiac devices such as pacemakers, insulin pumps.

Hormone therapy, anabolic paracrine signalling of the epigenome is performance enhancing, see Olympics along with strong bones and muscle, increased organ mass. The opposite of anabolic is all the health rage at the moment, catabolic and autophagy see mTOR and there are also muscle retention drugs (anti-catabolic agents). The older a person is, the harder it is to achieve sufficient cardio and enough weight lifting performance to activate the paracrine effect, remodeling of the body. Steroids make working out fun, it makes running and lifting easy. Hormones release a candidate from the catch 22 of less exercise due to reduced hormone levels, progressing frailty. An older person cannot physically achieve cardio, they need a booster before gymnasium. You cannot tell a person who is bedridden or getting older that they need to go anabolic and catabolic, but a shot of human growth hormone (HGH) will get them moving again. Hormones affect body structure bone and muscle strength, energy levels, libido and mood. Until recently hormones required injection as they are not bioavailable orally, some hormones were always bioavailable such DHEA and melatonin, instead a new class of drugs called selective androgen receptor modulators (SARMs), are orally bioavailable hormones. The most progressed SARM against sarcopenia and osteoporosis is possibly Ostarine. Issues with taking hormones… being shutdown means endocrine system dystrophy such as testicle shrinkage and can lead to over a year or longer of no endogenous production. Safety, many hormones have dose dependent safety profiles such as HGH and an increase in IGF-1 shown to shorten lifespan and left ventricular hypertrophy (LVH), testosterone and androgenic effects on the prostate. Certain hormones shorten lifespan, women live longer than males because testosterone shortens lifespan, so we choose a mild safe androgen. Non steroid performance enhancers can be used such as caffeine before gymnasium to achieve more intense cardio, heavier sets. Hormones configure the epigenome which is one essential component that effects aging, another is the mesenchymal stem cell system for mitosis, repairability. Relates to the bone marrow system, stem cells, regenerative system. A hormone biohack by Greg Fahy for thymus involution consisting of HGH 0.015 mg/kg, Metformin 500 mg daily, vitamin D 3000 IU daily, zinc 50 mg daily and DHEA 50 mg. TRIIM-X trial and Reversing Thymic Involution. Secretogogues (1) have been shown to be orally effective and increasing hormone levels. Potent anti-angiogenic with high dose growth factors. The cause of inflammation ageing is thought be decline in immune system function more cytokines activating the innate response, more tendency to autoimmune and less macrophage regeneration. Oral Hormone Therapy (Once A Week - No Injections), Hormones needed for anti-aging, Effects of Ageing on the Endocrine System, Impairment of the Hif-1α regulatory pathway in Foxn1-deficient (Foxn1-/-) mice affects the skin wound healing process, Regeneration of the aged thymus by a single transcription factor, When the Damage Is Done: Injury and Repair in Thymus Function, Does the key to anti-ageing lie in our bones? Why am I tired and frail? Opinion, the tired correlates with HGH decline with age, try some HGH and see if it hits the spot. The frail is androgen decline, bodybuilding clearly shows that androgens cause muscle, bone and organ growth. The theory is the body declines androgen production with age because cancer probability increases with age, as to protect against cancer. Cancer probability increases with age because of the microenvironment. We have the growth factors that initiate regeneration such as IGF-1, TGF-β... mitosis derives from existing ageing cells. What is required is the mitosis to derive from embryonic cells and not already declining cells. That is why you cannot androgen regenerate back in time. Elderly people do not need androgens to get through daily life, they need androgens before gymnasium for full paracrine effect activation both in cardio and weight lifting which they cannot achieve otherwise, it's a matter of the safest androgen, dosage and interval between use. Suzanne Somers was one of the first protagonist of hormones for anti-aging. Other than hormones, genital size may be genetic with genes like like homeobox (Hox a and d) genes, which may have a role in regulating penis size. In humans, the AR gene, located on the X chromosome at Xq11-12, may affect penis size. The SRY gene located on the Y chromosome may have a role to play. Variance in size can often be attributed to de novo mutations. Paracrine, endocrine, autocrine, juxtacrine, perhaps heterocrine. The human body does not care if you're packing fat or muscle, at a certain age both are an extra strain on essential organs and subsequent mobility and mortality.

Peptides and polypeptides, also called biologics, the theory is… a cell probes the environment around itself and uses that information to posture itself, that is specific expression, up regulation and down regulation of the epigenome. If the cell is damaged, apoptosis is activated by a signal to the cell to shut down, that is how a cell dies in the human body. This roughly leaves the body with only a communication system whereby all technology is crining the cell, humans sending in signals to switch genes by lifestyle, diet, exercise and by molecules. Hormones, peptides, are probably the most basic ways of attempting to crine the system. Without an embryonic niche, mitosis degrades the system beyond crining and the current endoenvironment dominates the system against crining. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Proteins that are found in the body are synthesized and injected or orally taken for some effect. Peptides lack conclusive studies. Mitochondrial-derived peptides in aging and age-related diseases, GHK-Cu, Cerebrolysin, BPC-157, CJC-1295, Ipamorelin, Kisspeptin10

Mitochondria infusion, mitochondria require oxygen to make energy, without energy a cell dies. Mitochondria burn food with the oxygen you breathe to produce chemical energy called "oxidative phosphorylation". During a heart attack or a stroke, the blood stops delivering oxygen to the heart and brain and without oxygen the mitochondria stops producing energy and without energy the brain and heart become damaged and even might die. If the oxygen returns in time the mitochondria get overwhelmed and produce free radicals causing additional damage called "reperfusion injury". Researchers find cell free mitochondria in the blood stream, it is not known what they are doing, it is believed they are contributing to cell signalling and that it might be possible that they can translocate from cell to cell. Researchers Find Cell-Free Mitochondria Floating in Human Blood, A Way to Insert New Mitochondria into Cells, Isolated Mitochondria Infusion Mitigates Ischemia-Reperfusion Injury of the Liver in Rats. It is not known if health benefit can be shown by altering the mitochondria and immunogenicity, but mitochondria are important to ageing and doping the body with super youthful mitochondria might prove efficacious. Mitochondrial Infusions Given to Babies with Heart Damage. A recent paper suggests in yeast that there are two paths of ageing. One is mitochondria dysfunction and the other is nucleolus morphology. A programmable fate decision landscape underlies single-cell ageing in yeast, Researchers Discover Two Paths of Ageing and New Insights on Promoting Health. The paper suggests that something in the nucleolus as one path of ageing with mitochondria dysfunction as the other path. Perhaps infusion of high quality mitochondria and high quality proteins may provide some benefit. The nucleolus makes ribosomal subunits from proteins and ribosomal RNA, (rRNA). It then sends the subunits out to the rest of the cell where they combine into complete ribosomes. Ribosomes make proteins; therefore, the nucleolus plays a vital role in making proteins in the cell. Nucleolus is a hot spot of RNA-polymerase-I-mediated tran-scription. Hence, the nucleolus is critical for protein synthesis. In addition, by sequestering regulators of cell cycle, differentiation and stress response, the nucleolus contributes to intracellular signalling. It also appears that the nucleolus plays an important role in processing of various non-ribosomal RNAs and in the maintenance of heterochromatin. The mystery continues. As for the novel remodelling of the master ageing circuit, what does it reveal about ageing? Another paper Proteostasis collapse is a driver of cell ageing and death suggest that intracellular supplementation in the form of chaperones and ribosomes could be beneficial but also makes the statement. Ageing happens when the rate of damage exceeds the rate of repair. Particularly the chaperones become occupied with proteins that are unable to fold causing a collapse. Intracellular infusion that seek to administer components of the molecular biology into the cell to support cell function and extracellular infusion such as immune system components. Infusion may not be the best means of administration but seem likely. Mitochondrial transplantation in humans: "magical" cure or cause for concern? Mitochondria autophagy, mitophagy. What Is Ozone Therapy?, Latest News and Details Of the Incredible Bio-Artificial Kidney That Can Treat Renal Failure And End Dialysis Completely Direct ATP infusion has some health benefits, but what about bypassing the ATP production of the mitochondria, does it geroprotect. Apparently it does not enter the cell from the infusion. To bypass the mT the production must be intra-cellular. Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage, Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation , Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage . Mitchondira might be a better vector than AAV for gene therapy, less toxcity and bigger payload.

Fecal Transplant, old microbial transplant into a young mouse has health ill-health effect or vice versa benefits.

Sub-Organism Evolution, generating an evolutionary environemnt within the organism so that cells of a specific quality have an advantage of cells or another quality while the organism is still alive. This cellular evolution could be exvivo where a super cell is developed outside of the organim and then introduced and grafted into the organim. For example a red blood cell with surperior oxygen processing or an immune cell with some ability. Another is synthetic biolgoy Recombinant microbial systems for the production

of human collagen and gelatin

Yeast Studies, Why Yeast Single Cells Age and Die

Saccharomyces cerevisiae, extensive studies in yeast cells place the causes of aging in two places; a gradual decline in the stability of the nucleolus, more specifically the over-production of ribosomes or extrachromosomal rDNA circles (ERC's). Ribosomes are the basic building blocks of proteins. While the other half age due to dysfunction of mitochondria, the energy production units of cells. There have been many genes identified with longevity and aging, one such database is the longevity map but it can be suggested that one cure is the activation of stress resistant genes. Paper titled Life Expectancy Of Yeast Extended To 800 In Yeast Years, No Apparent Side Effects identifies RAS2 and SCH9 genes. RAS2 is known to down-regulate stress responses, demonstrating that for longevity the ability to recover from stress is at least as important as the ability to mount a stress response(1), while SCH9 effect may be explained by constitutively active oxidative stress response system preventing accumulation of age-related mutations, perturbed sphingolipid levels or, more likely, a combined effect of these factors (2). In maintstream culture many therapies such as calorie restriction and cryotherapy attempt to activate these stress response genes, their efficacy and effectiveness is debatable. Another paper: A programmable fate decision landscape underlies single-cell aging in yeast suggests two modes, half of cells produced daughters with an elongated morphology during later stages of lifespan. In contrast, the other half continuously produced small round daughter cells until death. Aging mode 1: nucleolar decline and aging mode 2: mitochondrial decline. Age-dependent nucleolar enlargement is related to instability of ribosomal DNA. The conserved lysine deacetylase Sir2, encoded by a well-studied longevity gene, maintains rDNA stability by mediating rDNA silencing, (1) while a decrease in heme abundance and HAP activity may drive mode 2 aging. Heme activates the heme activator protein (HAP) transcriptional complex to maintain mitochondrial biogenesis and function(2), bioenergetic dysfunction lies at the nexus of common complex diseases quotes Douglas C. Wallace, Ph.D (UCLA CTSI). In another paper, New technique reveals causes of aging in yeast states...'Our idea is that the increased production of ribosomal proteins is good for young cells,' says Veenhoff. 'It allows them to grow and mature quickly. But this growth programme somehow keeps running and eventually becomes a negative factor.' The paper suggests the overproduction of ribosomes elongates the cell causing cell death. In A Protein that Extends Life of Yeast Cells, The researchers discovered that a gene called NDT80 for exampe, is activated at the same time that rejuvenation occurs. When they turned on this gene in aged cells that were not reproducing, the cells lived twice as long as normal. In aged cells with activated NDT80, the nucleolar damage was the only age-related change that disappeared. That suggests that nucleolar changes are the primary force behind the aging process (1). These papers do not read like theory, so the science is getting stronger for yeast cells at least, determining if the same is applicable in human beings and identifying precise ways of activation is essential to finding out. The technology to manipualte gene expression of one or more genes appears seriously lacking and one highly developed gene regulation system could potentially be portable across many conditions including aging, this would be preferable as thier are too many genes and therefore pathways. In summary, current science writes that cellular aging can be considered as a fate decision process, in which single cells age toward either silencing loss and nucleolar decline or heme depletion and mitochondrial decline. For longevity two essential technologies are required, mutation correction for both genome and mitochondria genome, for Immortality gene therapy proceeds chemical pathways fro both rDNA silencing and mitochondria DNA mutation correction, as well as silencing and expressing genes.

What diseases resemble ageing? Cutis Laxa, Lipodystrophy (does not resemble ageing), Progeria, Lysomal Storage Diseases...

Chemotherapy, accelerates ageing, perhaps.

Cutis Laxa, is a disease that makes people appear far older than they are. Biopsies have shown reduction and degeneration of dermal elastic fibres in the affected areas of skin. Cutis laxa is associated with deficient or absent elastin fibers in the extracellular matrix. This can be related to decreased elastin synthesis or structural defects in the extracellular matrix. This is similar to what happens to aging skin. It can be inherited or acquired, known as acquired cutis laxa, some have symptoms but do not have the associated genetic changes. The ways that proteins generally fail are... genetic mutation, during protein synthesis, misfolding etc, autoimmune response, aneamia of essential nutrients that constitute the protein, (damage to small intestine), perhaps one or two more. It is believed that the cause differs but all result in sub-optimal elastin fibers. A recent study suggests the presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa (1). Cutis laxa has recently been found in patients with abnormal glycosylation. The majority of inborn errors presenting with cutis laxa are related to abnormal Golgi function and frequently related to transport defects and abnormal protein glycosylation. Contrary to patients with Golgi system-related cutis laxa forms, those with PYCR1 and MAP kinase pathway defects show no glycosylation abnormalities. In some of these children mild mitochondrial dysfunction has been observed, but usually they do not manifest metabolic markers of mitochondrial disease (1). It has also been considered that mutations in elastin (ELN) and fibulin-5 (FBLN5) genes can increase susceptibility of elastic fibres to inflammatory degradation in acquired cutis laxa. Idiopathic inflammation and allergic (or other) reactions to medicines such as penicillin, isoniazide and D-penicillamine. Further, preceding factors are hematologic abnormalities like plasma cell dyscrasias and congenital hemolytic anemia, which causes localized acral cutis laxa, as well as infections, especially Borrelia burgdorferi. Other inciting inflammatory disorders like urticaria, angioedema, rheumatoid arthritis, systemic lupus eythematosus, erythema multiforme, nephrotic syndorme, celiac disease and dermatitis herpetiformis have been reported. Finally, it has been associated with paraneoplasia. Type II (Marshall syndrome) occurs in infants and toddlers and develops in response to acute inflammatory skin lesions. Rare associations with alpha 1 antitrypsin deficiency, arthropod bites and Sweet's syndrome have been described. Degradation of elastic fibres through proteolyitc processes is believed to play a role in acquired cutis laxa. This concept is supported by the presence of tissue elastases released after activation of polymorphonuclear leukocytes and monocyte-macrophages in an inflammatory event. IgG and IgA deposits in lesional skin and paraproteinemia have also been reported and raise the possibility of an immunopathogenetically mediated process. Autosomal Dominant Cutis Laxa (ADCL) is caused by mutations in the Elastin (ELN) gene. MACS syndrome is caused by mutations in the RIN2 gene. Gerodermia Osteodysplasticum (GO) is caused by mutations in the GORAB (SCYL1BP1) gene. Occipital Horn Syndrome is caused by mutations in the ATP7A gene. Changes/mutations in the following genes cause each of the subtypes of Autosomal Recessive Cutis Laxa (ARCL): ARCL1A: Caused by a mutation in the FBLN5 gene, ARCL1B: Caused by a mutation in the FBLN4 (EFEMP2) gene, ARCL1C: Caused by a mutation in the LTBP4 gene, ARCL2A: Caused by a mutation in the ATP6V0A2 gene, ARCL2B: Caused by a mutation in the PYCR1 gene, ARCL3: Caused by a mutation in the ALDH18A1 gene. People with these subtypes are also found to have mutations in the PYCR1 and ATP6V0A2 genes. Cutis laxa may be caused by mutations in the genes: ELN, ATP6V0A2, ATP7A, FBLN4, FBLN5, and PYCR1. A related neurocutaneous syndrome may be caused by mutations in the gene ALDH18A1 (P5CS). Cutis laxa may also be seen in association with inherited connective tissue disorders such as Ehlers–Danlos syndromes. Another syndrome associated with cutis laxa is Lenz-Majewski syndrome which is due to a mutation in the phosphatidylserine synthase 1 (PTDSS1) gene. Most of these genes are involved in the formation and function of elastic fibres, which are slender bundles of proteins that provide strength and flexibility to connective tissue throughout the body. Elastic fibres allow the skin to stretch, the lungs to expand and contract, and arteries to handle blood flowing through them at high pressure. The major component of elastic fibres, a protein called elastin, is produced from the ELN gene. Other proteins that appear to have critical roles in the assembly of elastic fibres are produced from the EFEMP2, FBLN5, and ATP6V0A2 genes. Mutations in any of these genes disrupt the formation, assembly, or function of elastic fibres. A shortage of these fibres weakens connective tissue in the skin, arteries, lungs, and other organs. These defects in connective tissue underlie the major features of cutis laxa. In acquired Cutis Laxa precise immune inhibition could provide some effect, genetic therapy otherwise which is many hundreds of years away. 28 year-old woman who looks 80 with "ageing" disorder undergoes Plastic Surgery, Mitochondria in skin health, aging, and disease, Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance, The extraordinary 'Benjamin Button' children with wrinkly skin condition which makes them look years older, Organ Shape: Controlling Oriented Cell Division, Remodelling the extracellular matrix in development and disease, Scientists reverse aging-associated skin wrinkles and hair loss in a mouse model. In aging, wrinkles occurs because the regenerative system forgoes maintenance, it does the minimum.

Grey Hair, canities, achromotrichia. Grey hair and wrinkles are the proverbial canary in the coal mine, the microcosm of aging itself. Explaining and curing both is curing aging and if we cannot solve gray hair and wrinkles, then what chance do we really have? Any lay person can look in the mirror and know if something worked or not, as a result there is little interest in curing wrinkles and gray hair. Researchers pivot towards bespoke and unprovable molecules and rely largely on placebo. Left at wrinkles and gray hair, right and head straight to molecule city and try the slot machines there. Anytime a pathology is reversed that is interesting and these anomalies do happen as they have been recorded with grey hair reversal. Old reactive oxygen species theory of grey hair, oxygen is used by mitochondria to make ATP, if an electron is transferred to oxygen it forms a highly reactive superoxide ion that attacks and rips other molecules apart. An enzyme called superoxide dismutase gets rid of superoxide by converting it into hydrogen peroxide, less dangerous than superoxides but also potentially dangerous as hydroxyl radicals that attack important biochemicals like proteins and DNA. The enzyme catalase further breaks the peroxide down into oxygen and water. However, with age, lower levels of the catalase enzyme and other enzymes like (MSR A and B) causes oxidative stress, the hydrogen peroxide causes melanocyte destruction resulting in grey hair. The combination of high levels of hydrogen peroxide and low levels of MSR A and B disrupts the formation of tyrosinase, the enzyme important for melanin production in hair follicles. The Cure for Grey Hair, like lysosomes, peroxisomes also have a role in metabolism; they contain enzymes that breaks down fatty acids and amino acids, resulting in, among other things, the production of the toxic substance, hydrogen peroxide. The problem is the antioxidant theory is largely debunked as a theory of ageing (1, 2). Supplementation with antioxidants does not cure grey hair. The Anti-oxident myth. The new melanocyte stem cell destruction by the immune system theory, with age the immune system destroys the melanocyte stem cells resulting in grey hair and inhibition of the part of the immune system restores hair pigment. Hello, provable cause and effect science. Repigmentation and new growth of hairs after anti–interleukin-17 therapy with secukinumab for psoriasis. Thymus produces regulatory T-cells as the thymus involutes with age, regulatory T-cells diminish in number dysregulating the immune system into an over-active inflammatory and auto-immune system. With regulatory T-cells as the main switch to turn off the immune system and turn on the regenerative system the immune system slowly destroys the human body. Interventions exist that can regenerate the haematopoietic stem cells system to that of a youthful condition and halting and reversing thymus involution is possible. These two strategies should bring the immune system back into regulation. Prolonged stress leads to hyper physiological levels of cortisol and alters the effectiveness of cortisol to regulate both the inflammatory and immune response because it decreases tissue sensitivity to cortisol (Segerstrom, 2006). As the human body heals, inflammation becomes a response to stress. Chronic stress over activates the immune system leading to the autoimmune attack on the melanocyte stem cells causing grey hair. The dysregulation of the immune system with age is suspect, too many cytokines and not enough macrophages, that may answer the many aspects of ageing such as wrinkles, fine lines and errors in extra cellular matrix (ECM), photoaging caused by ultraviolet (UV) light. In a 2016 study published in Nature Communications, a team of researchers from University College London (UCL) identified the interferon regulatory factor 4 (IRF4) gene as being responsible for regulating production and storage of melanin. Immune Modulation of Stem Cells and Regeneration. IL17 seems overstimulated in the destruction of melanocyte stem cells while acute damage to the thymus (and specifically the depletion of thymocytes) triggers the release of Interleukin-23 (IL-23) from dendritic cells, which induces the production of IL-22 by a group 3 innate lymphoid cells. Expression of IL-22R in the thymus is lacking on thymocytes but detected in both cTECs and mTECs populations. IL-22 acts on TECs to mediate repair. In addition to the thymus, IL-22 also has a major role in the regeneration of epithelial cells in a diverse range of tissues including gut, lung, skin, breast, and kidney. Thus, the ageing immune system is far more auto-immune and inflammatory and less regenerative. Some speculate that this is for cancer prevention as stem cells need to replicate, shutting down regeneration is an energy saver or a safety. Two treatments, one is secukinumab for psoriasis and the other is an experimental treatment named "Team Hair-Us" Melissa Harris lab Going gray isn’t a one-way trip? UAB researcher exploring ways to ‘rejuvenate’ gray hairs, Getting to the root of why and when our hair goes gray, Medication-Induced Repigmentation of Gray Hair: A Systematic Review, Photoaging: What You Need to Know About the Other Kind of Aging. Assume that photoaging is also immune system related where UV activates the immune system and the dysregulation results in wrinkles, however wrinkles are a bad repair, the older the worse the repair until the body opts for fibrosis. The environment to repair embryonically is not there with adult hood and with aging. Hair Repigmentation During Immunotherapy Treatment With an Anti–Programmed Cell Death 1 and Anti–Programmed Cell Death Ligand 1 Agent for Lung Cancer. This has some similarities with psoriasis, while a boil can trigger the surrounding tissue to be attacked, psoriasis has no visible indicator. IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms, Immune Modulation of Stem Cells and Regeneration, Stem-cell therapies use immune system to repair broken hearts. Dysregulation of ageing immune system and strategies for restoration of regulation. Some say the immune system supresses the stem cells out of replication and cancer but the microenvironment is not there and the level of regeneration becomes limited. Hair loss reversed in alopecia areata sufferers. Vitiligo is also autoimmune, do lab work to find the genes that get turned on in the condition, then find a pharmaceutical target to inhibit those genes and relieve the condition. This is the strategy of Janus kinase (Jax) inhibitors for vitiligo, precise inhibition of interleukins in vitiligo might produce an even better result as they also inhibit the memory T-cells that remain in the area. Target immunotherapy is broad potential for many diseases. These therapies if they survive may take 20 years to be approved for use. Vitiligo, generally similar to all auto-immune disease, Senotherapeutic peptide reduces skin biological age and improves skin health markers, Regenerating hair follicle stem cells, Restoring metabolism of myeloid cells reverses cognitive decline in ageing, Want to reverse aging? Try reversing graying, first.

Conversely ultraviolet (UV) light speeds up the production of melanin, photoaging, wrinkles, fine lines and pigmentation. When UV rays hit the skin, they damage DNA, and cells in the dermis scramble to produce melanin in the epidermis to prevent further damage. The UVA rays, with their longer wavelength, are responsible for much of the damage we associate with photoaging. UVA rays penetrate deep into the dermis, where they damage the collagen fibers. This damage causes increased production of abnormal elastin. The unusual amounts of elastin result in the production of enzymes called metalloproteinases. These enzymes, which rebuild damaged collagen, often malfunction and degrade the collagen, resulting in incorrectly rebuilt skin. As this process is repeated with daily UVA exposure, the incorrectly rebuilt skin forms wrinkles, and the depleted collagen results in leathery skin. Scientists have found specific genes related to graying hair. In a 2016 study published in Nature Communications, a team of researchers from University College London (UCL) identified the interferon regulatory factor 4 (IRF4) gene as being responsible for regulating production and storage of melanin. Like lysosomes, peroxisomes also have a role in metabolism; they contain enzymes that break down fatty acids and amino acids, resulting in, among other things, the production of the toxic substance, hydrogen peroxide.

Lysosomal Storage Diseases, are genetic diseases, autophagic compromise as aetiology of aging caused by lysosomal storage dysfunction, childhood dementia(1), include, Aspartylglucosaminuria, Batten Disease, Cystinosis, Fabry Disease, Gaucher Disease Type I, II, III, Glycogen Storage Disease II (Pompe Disease), GM2-Gangliosidosis Type I (Tay Saches Disease), GM2-Gangliosidosis Type II (Sandhoff Disease), Metachromatic Leukodystrophy, Mucolipidosis Type I, II, III, IV, Mucopolysaccharide Storage Diseases (Hurler Disease and variants, Hunter, Sanfilippo Types A,B,C,D, Morquio Types A, B, Maroteaux Lamy and Sly Diseases, Niemann-Pick Disease Types A/B/C1/C2, Schindler Disease Types I, II, Stargardt disease. A six year diagnosed with dementia and an aged person with dementia, perhaps the cause is the same. Lysosomes breakdown parts inside the cell and due to deficient or missing enzymes they cannot perform this action eventually leading to cell death, as the brain is not regenerative when the neurons die irreversible brain damage results. Lysosomes, intracellular are an essential part of autophagy while macrophages intercellular perform the same role outside the cell. Lysosomes contain more than 60 different enzymes and have more than 50 membrane proteins, these enzymes break down a range of molecules, including waste from the cell, and even the cell itself when it dies. The synthesis of these enzymes is controlled by nuclear genes and when these genes are mutated, they will result in more than 30 different human genetic diseases, collectively referred to as lysosomal storage diseases. These genetic defects are closely linked to several neurodegenerative diseases, cancer, cardiovascular disease and ageing-related diseases. They are caused by the inability to decompose unwanted substances, which in turn leads to the accumulation of specific substrates. They believe lysosomal storage disease is a major aetiology of ageing referred to as the garbage theory of ageing. According to Alexei Terman, of Linkoping University in Sweden "Clearly, if all damaged structures were renewed with perfect accuracy, ageing would not occur. But the inevitability of ageing suggests that the biological mechanisms of removal and re-synthesis are not perfect. Of these two processes, the one most suspect in the progression of ageing is that of inefficient removal." The Garbage Catastrophe of Ageing and How to Avoid It. The means of dealing with lysosomal dysfunction is by genetic upregulation or down regulation of genes and pharmacology. Infusion of essential enzymes, drugs with little success in candidate drugs with two stand-outs, β-cyclodextrins or tetrahydropyridoether (remofuscin/soraprazan), trodusquemine for atherosclerosis, more candidates exist, but they are expensive to isolate and develop. Centrophenoxine, also known as meclofenoxate, has properties similar to acetylcholine is falsely believed to remove or halt lipofuscin. Acetyl-L-Carnitine generates TMAO in microbiome which add to heart disease, sub-lingual may be an option by believed not to be effective against lipofuscin. There are many lysosomal diseases but the suspect the accumulation of lipofuscin. Some others include the generation of reactive oxygen species during the production of adenosine triphosphate (ATP), (AGE) Advanced glycation end products, Chemically altered derivative of essential molecules that are sub-optimal that change for example the permeability of the cell wall, Atherosclerosis plaques, Amyloids, amyloidosis, molecules damaged by oxidation and their by-products (e.g., aged collagen, damaged enzymes), damaged mitochondria, SASP by senescent cells, cell membranes change, making them less receptive to oxygen and nutrients and less effective at removing carbon dioxide and other wastes. People with lysomal diseases die within 10 to 20 years. An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration, Remofuscin is being developed for two indications: Stargardt disease and dry age-related macular degeneration. The challenge is the delivery system, getting a trojan into the cell and getting the transporter to take to the lysosome where it unpacks its low pH acids and enzymes. Once that is achieved you can mix and match enzymes relative to the lysosomal disorder. The source of lysosome disorder with age may orginate in DNA mutations or epigenetic dysregulation. The use of mRNA to generate the enzyme such as moderna has shown. Lysosomal Treatments Moringa oleifera.

Progeria, (one of several progeroid syndromes) is an extremely rare autosomal dominant genetic disorder in which symptoms resembling aspects of ageing are manifested at a very early age. Those born with progeria typically live to their mid-teens to early twenties. Progeria is caused by gene mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The histone mark H4K20me3 is involved in Hutchinson-Gilford Progeria syndrome caused by de novo mutations that occurs in a gene that encodes lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized heterochromatin. In normal conditions, the LMNA gene codes for a structural protein called prelamin A, which undergoes a series of processing steps before attaining its final form, called lamin A. Prelamin A contains a “CAAX” where C is a cysteine, an aliphatic amino acid, and X any amino acid. This motif at the carboxyl-termini of proteins triggers three sequential enzymatic modifications. First, protein farnesyltransferase catalyzes the addition of a farnesyl moiety to the cysteine. Second, an endoprotease that recognizes the farnesylated protein catalyzes cleavage of the peptide bond between the cysteine and -aaX. In the third step, isoprenylcysteine carboxyl methyltransferase catalyzes methylation of the carboxyl-terminal farnesylcysteine. The farnesylated and methylated protein is transported through a nuclear pore to the interior of the nucleus. Once in the nucleus, the protein is cleaved by a protease called zinc metallopeptidase STE24 (ZMPSTE24), which removes the last 15 amino acids, which includes the farnesylated cysteine. After cleavage by the protease, prelamin A is referred to as lamin A. In most mammalian cells, lamin A, along with lamin B1, lamin B2 and lamin C, makes up the nuclear lamina, which provides structural support to the nucleus. In 2003, the cause of progeria was discovered to be a point mutation in position 1824 of the LMNA gene, which replaces a cytosine with thymine. This mutation creates a 5' cryptic splice site within exon 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is translated into protein, it produces an abnormal variant of the prelamin A protein, referred to as progerin. Progerin's farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the nuclear envelope with enough structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide. Farnesylated prelamin A variants also leads to defective DNA repair, which may play a role in the development of progeria. Progerin expression also leads to defects in the establishment of fibroblast cell polarity, which is also seen in physiological aging. Progerin may also play a role in normal human aging, since its production is activated in typical senescent cells. Some accelerated aging diseases are Werner syndrome, Cockayne syndrome and xeroderma pigmentosum. The appareance of ageing is a little like progeria, while not cased by Lamin A, conceptually identical. Like progeria a normal human ageing cell also distorts, the rate of cell division also decreases and senescence increases and many more cell biology problems. For example, the pituitary gland begins to lag in performance, becomes deformed, lumpy and shrunken and like nuclear deformation in progeria the cell deformation in ageing causes similar problems. Visually the shape of nucleus in progeria results in a problem, with age the cell also starts to have these kinds of shape defomities at least when compared with a young cell. Inbreeding also expresses defects in the genome that present as pathology, the likelihood of health issues and early death is increased. If they cannot cure progeria, cutis laxa, turn on and turn off puberty at the genetic level, regenerate tooth in old age, then doubt a cure to ageing. Such is the reality check. Progeria is the key insight. Genetic mutations follow on to defective cell function which kills us. Removing Wrinkles Inside Our Cells Might Reverse Aging, Epigenetic Involvement in Hutchinson-Gilford Progeria Syndrome: A Mini-Review, Premature aging disorders: A clinical and genetic compendium. Gene mutations can cause disease and illness. There are mutation rate lifespan clocks, "genomic stability" is a necessary milestone. Common multifactorial genetic inheritance disorders are all cause mortality, heart disease, cancer and Alzheimer's disease. It is important that a therapy exists that can remove these mutations from your genome and my genome. Genetically susceptible to an all cause mortality. Another is the rate of mutation along with mutation in DNA repair genes such as WRN protein gene. Supplementing DNA repair proteins

Gene therapy, an important technology. 3-plus billion nucleic acid base pairs of human DNA, coded on 46 chromosomes, are the hereditary map that encodes production and control of 20,000 to over 100,000 necessary proteins. There are around 6000+ known genetic disorders. Many genetic mutations in these base pairs contribute to the development of disease have been identified. With progeria genetic mutations cause defective cells which ends life likewise with age mutations lead to many errors causing ageing, somatic mutation increase with age so we require gene therapy to repair these mutations. In a study, monozygotic twins are formed when one zygote, one egg and one sperm, splits into two and have similar lengths of life when compared to dizygotic twins, two ovums, two sperms(1, inclining that identical genetics equals identical lifespan. The difference with each child of the same parents is the chromosomes are shuffled leading to wider range of differences. All children born from the same parents are believed to have the same mitochondria, does the monozygotic twins study disprove the mitochondria theory? Centenarians, persons that live more than 100 years run in family, genetic assertion. The body has a genetic repair system but genetic mutations cause many diseases and also increase with age. For our purposes we require systemic error checking; check for mutation, if found then repair, otherwise do nothing. Crispr-Cas9 works just this way, possibly Crispr-Cas9 in an engineered exosome or nano particle to avoid disadvantages with viral vectors and pass the blood brain barrier. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing, Crispr-Cas9 is noted for its off target edits which defeats using Crispr to repair mutations but the latest news is that Crispr-Cas9 has been improved 100 fold against off site edits. The many variants such as Cas-CLOVER advertise undetectable off-target activity and even a variant of Crispr for mitochondria edits or repair. ZNF, Talen, Cas9. Articles: New CRISPR-Free Gene-Editing Tool a Massive Step, Scientists Say, Neuroscientists discover anti-aging molecule that repairs age-related DNA damage, Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases, Single-gene treatment cures mice of Parkinson's within three months, Distal lung epithelial progenitor cell function declines with age, Studies find CRISPR gene-editing of human embryos give rise to unwanted results, Exosomes used by researchers as form of novel gene therapy, Researchers discover 2 paths of aging and new insights on promoting healthspan, Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection, Cancer-derived exosomes as a delivery platform of CRISPR/Cas9, Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting, This Company Wants to Rewrite the Future of Genetic Disease, Super-precise new CRISPR tool could tackle a plethora of genetic diseases, Super-precise CRISPR tool enhanced by enzyme engineering, Editing the Central Nervous System Through CRISPR/Cas9 Systems, Scientists make precise gene edits to mitochondrial DNA for first time, CRISPR meets Pac-Man: New DNA cut-and-paste tool enables bigger gene edits, New Injection Can Gene-Edit Specific Parts of the Brain, Scientists Say, Gene editing successfully lowers monkey cholesterol levels, Targeted In Vivo Inhibition of Specific Protein–Protein Interactions Using Recombinant Antibodies, base editing, prime editing. The use of magnets to get a equal dispersion or attact the vector towards around an organ. The use of a transduction pathway to recieve the vector on a cell receptor but then close the receptor limiting infection, another vector cannot bind to cell receptor and move on to the next cell, in order to get an ordered dispersal, universal coverage of the gene therapy. Certain rejuventating proteins could possibly also use the tranduction path to block the receptor site after a certain amount of saturation or at least establish safe dosage without any optimizing delivery. https://www.science.org/doi/10.1126/sciadv.abm9106, New gene editing tool reduces errors by nicking DNA not cutting. By infusing additional DNA reapir proteins, enzymes perhaps DNA reapir can be upregulated, Human DNA Repair Genes. A list of DNA repair enzymes is available at Mdanderson, Reactome, REPAIRtoire A database of DNA repair pathways Anti-Aging: A New Way to Repair Age Related DNA Damage Discovered Neuroscientists discover anti-aging molecule that repairs age-related DNA damage Exifone Is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration (HepaToxic) Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs New CRISPR gene-editing system can "drag-and-drop" DNA in bulk

Variants: CasΦ (Cas12j) - smallest, SaCas9, StCas9, NmCas9, FnCas9, CjCas9, ScCas9, CasX, CasY, Cas12a (Cpf1), Cas14a, High-Fidelity Cas9, eSpCas9, SpCas9-HF1, HypaCas9, FokI-Fused, dCas9, xCas9, dCas9, Cas13a, Cas13b, Cas13d, Superfi CRISPRoff and genome knowledge base

more papers on the subject…

1. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing, Nonviral CRISPR Delivery Vehicles Lay the Smart Siege
2. Crispr-Cas9 has been improved 100 fold against off site edits

Three people have recently been treated with Crispr Ex Vivo. We require in vivo treatment.

1. Three people with inherited diseases successfully treated with CRISPR
2. The clinical cutting edge - Editas Medicine and Allergan announced that a patient had been dosed with the first ever CRISPR–Cas9-based in vivo therapy.
3. CRISPR nanocapsule limits growth of aggressive brain tumours in mice
4. A new era of mitochondrial genome editing has begun

Many genes have been identified, the total list, https://genomics.senescence.info/longevity/

Recently a paper that correlated gene mutations with lifespan alluding mutation as cause. The types of mutations are...

Types of mutations –

I. Chromosomal mutations –

Duplication

Deletion

Inversion

Translocation

II. Gene mutations –

Point mutation

Silent

Missense

Nonsense

Frameshift mutation

Deletion

Insertion

RNA Supplementation, the infusion of RNA's to manufacture excess proteins of known longevity genes such as SIR activation, repression or DNA repair proteins. Requires a vector.

Jumping Genes, known as transposable elements or transposons — Transposons are self-replicating sequences of DNA that copy and paste themselves throughout the genome (some kinds can also cut and paste themselves). In a way, transposons are viruses that do not like to travel outside the confines of a cell. They do very much the same thing as viral sequences, i.e. make copies of themselves and infect genomes. Some retroviral sequences in the human genome (very old viruses that infected our ancestors and still exist in our DNA) are themselves transposons. Because these transposable elements are mobile they have a disturbing capacity to disrupt important genes by inserting themselves into the DNA sequences and transposons seem to preferentially insert themselves into important and functional genes. Furthermore, because transposons can rapidly alter the DNA sequences in your genome they are thought to play a major role in the processes of evolution and speciation (how one species evolves into a new one). Jumping genes good or bad? Studies show they play a good role while others say bad role. Inhibition of 'jumping genes' promotes healthy ageing, Jumping genes drive many cancers. To jump, transposons express RNA which is translated into proteins called transposases. Transposases allow the transposon to move from place to place in the genome. This scrambled DNA expresses scrambled RNA that can be recognized by the cell as “foreign.” This RNA is chopped up into small fragments, which can be used to identify, target and degrade RNA from normal copies of the transposon. This prevents those transposons from making protein, and thus prevents them from jumping. Purdue scientists identify genetic ‘immune system’ for junk DNA, Transposon-encoded CRISPR-Cas systems direct RNA-guided DNA integration. Transposon inhibitors such as reverse transcriptase inhibitor used against HIV, was shown in aged mice to decrease the activation of retrotransposons. New target identified for treatment of premature aging disease

Horvath age estimation algorithm (2013), found 353 epigenetic bio markers of human ageing, according to which the chronological age of a person can be determined to an accuracy of 1.5 years, your death date can be predicted to an accuracy of 1.5 years. These epigenetic bio marker measurements are not fixed and can change depending on lifestyle, like fasting or exercising so a practice can be investigated to be beneficial or not by its effect on the Horvath age estimation algorithm. The Horvath age estimation algorithm predicts DNAm age based on the methylation levels of 353 CpGs. DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, ageing, and carcinogenesis. Correlation or causation? It is leaning towards causation. There are other biomarker systems to test efficacy of proposed experimental treatments or therapies, any advice currently based on peer reviewed studies also is at the mercy of biological clocks such as the Horvath age estimation algorithm. A person can be tested prior to a therapy and then tested again after to determine value of a proposed therapy. Biomarker signatures of aging.

Epigenome editing, the blueprint to build a human is DNA, genes, genetics, genome. Genes within the XX chromosome builds a girl and XY chromosome builds a boy (sperms make both and adds one during conception). The ovum is a cell and divides to form the human complete, so the human body completely consists of cells and every cell in the human body contains a full copy of the DNA or genome. Not all cells are the same, there are eye, skin, bone, muscle cells and more. So how can they be different? The epigenome is a system that can turn parts of the genome off or on, this is called gene expression, some genes are expressed while others are not without changing the underlying genome. Certain reptiles have an environmental determinate, e.g. hot outside, a male versus cold outside, a female because the temperature communicates with the epigenetic system to express relative to temperature. The ability to communicate with the epigenome is the ongoing challenge. Just like the reptiles, our lifestyle also communicates with the epigenome and using the Horvath age estimation algorithm, we can try some alteration to lifestyle, chemical, restriction... and see if it effects the epigenetic bio markers determine if the behaviour is "healthy" or not. The epigenome is seen as the holy grail, if the epigenome was reset to that of a young person, a person would never age or die. We await the landmark paper, controlled modulation of the epigenome and its effect on ageing. Crispr is used for epigenome manipulation. Epigenome editing, Genetic brain disorder fixed in mice using precision epigenome editing, A new epigenetic editing tool is developed to activate silenced genes, but information on how to localize the treatment or histones. Precision epigenome editing can repair genetic syndrome of intellectual disability, TET Enzymes, The ageing epigenome and its rejuvenation

Autoimmune diseases, 5 people with lupus are in remission after CAR-T cell treatment

, it also turns out that fasting also has the same effect. A measurement if cells that have developed auto-immunity are also canibaslized is possible during fast. Fasting and immune systen reset

Heart Failure and Arterial Sclerosis, the pump and pipes. The pump does not pump properly and the pipes get blocked or explode. Here the best advice is wholefood diet and exercise. The pump has pump in balance between the inlet and the oulet, the walls of the pump need to be the right thinkness and make of the right stuff to pump correctly and if the pipes are blocked or don't hold pressure the pump can pump correctly. If the pump stops you die. If the pump has to strain too much, it might shorten its overall life. The immortality and health of the heart and arteries is hugely lacking. Arteriosclerosis is stiffening of the arteries with age while atherosclerosis is the buildup of plaque. New research found that drug empagliflozin can treat and even reverse heart failure in some patients. The drug is also used to treat type 2 diabetes. About 80% of heart failure patients showed significant improvement in their condition. Empagliflozin Heart Failure, (2) Protein infusion could reduce heart failure risk after heart attack New combination of drugs slows heart decline in muscular dystrophy patients Researchers use stem cell exosomes to induce hearts to self-repair How the right "dose" of exercise can reverse aging-related heart damage Statins beneficial for the heart, beyond just lowering cholesterol Cancer drug that inhibits porcupine enzyme could help hearts Comprehensive study concludes omega-3 fish oil supplements don't reduce risk of heart disease Green tea compound holds promise for preventing heart attacks Problem protein could be new drug target for preventing heart attacks Age-related heart disease linked to gut bacteria metabolite Novel research links an aging gut microbiome with heart disease Eating chocolate linked to reduced heart disease risk Large study affirms link between onset of dementia and abnormal heart rhythm Large meta-study concludes multivitamins don't improve cardiovascular health Nanotechnology and stem cells rejuvenate arteries New CRISPR method strategically targets gene mutations to correct DMD heart defect Avocado seed husks jam-packed with medicinal compounds Nanoparticle helps eat away deadly arterial plaque Gene editing successfully lowers monkey cholesterol levels Scientists solve the mystery of hardening arteries, and find solution in a common drug Immune system discovery could lead to a vaccine for heart disease uofl led clinical trial shows cell therapy improves outcomes in heart failure GDF11 and Cardiac Hypertrophy Molecule fasting vascular system Gut bacteria microbiome heart disease cardiovascular health Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming Cyclodextrin polymer improves atherosclerosis therapy and reduces ototoxicity Atherosclerotic Plaques "Talk" With the Brain Sync breathing to heart rate in heart failure Empagliflozin (Jardiance) for heart failure Stem Cell Therapy for Heart Disease Treatment New study finds 27 proteins that may predict heart disease risk STEMIN and YAP5SA synthetic modified mRNAs regenerate and repair infarcted mouse hearts

Vaccine for Atherosclerosis

1. Heart arrhythmia, abnormal heartbeat. Beat too slow, too fast, or with an irregular rhythm.
2. Coronary artery disease or ischemic heart disease, the pipes get blocked or burst, caused by atherosclerosis. A narrowing and hardening of the arteries due to a buildup of plaque. The heart’s blood flow becomes restricted through narrowed arteries, preventing the heart muscle from properly delivering oxygen and nutrients throughout the body.
3. Heart valve disease, the pump goes faulty. Each valve is covered by flaps of tissue that open and close to direct the blood flow through the different chambers of the heart. Changes in the shape or flexibility of the heart valves can prevent the valves from opening and closing properly. When the flap of the valve protrudes back into the heart chamber after a heartbeat, its called a "prolapse". "Regurgitation" is when blood leaks back into the heart chambers instead of into the arteries due to improper closing of the valve.
4. Rheumatic heart disease, the heart valves are irreversibly damaged by rheumatic fever.
5. Congestive heart failure, inability to pump blood efficiently to supply the body with oxygen. Congestive heart failure is not the same as cardiac arrest, or the sudden cessation of heart function. This heart condition is more common in people above the age of 65. Structural defects in the heart that occur at birth, or congenital heart disease.
6. Congenital heart disease, birth defects.
7. Heart muscle disease, dilated cardiomyopathy is a condition in which the muscle of the left ventricle, the main pumping chamber of the heart, becomes stretched and thin, causing it to significantly weaken. This affects the ability of the heart to pump blood properly.
8. Myocardial infarction, another name for a heart attack. A heart attack happens when the heart’s blood supply from a coronary artery that surrounds the heart becomes suddenly blocked by a clot. This permanently damages the heart muscle, and it’s why you are more vulnerable to other cardiac diseases if you have had a heart attack before.

Decalcification by celating agents, slowly emulcify the calcium using various agents. An update on vascular calcification and potential therapeutics

Cancer, is a genetic disease, so gene therapy is the means to cure cancer by repair of gene sequence using Crispr/Cas9 perhaps. Many advanced regenerative therapies potentially cause cancer such as pluripotent stem cells or telomere lengthening and so we need a cure for cancer before we can advance on regenerative therapies. Here is an untested list of candidates to investigate, sodium dichloroacetate (DCA) might act against cancer cells by depolarizing abnormal mitochondria found in glioblastoma cancer cells – allowing the mitochondria to induce apoptosis (cell death) of malignant cells. Metabolic Modulation of Glioblastoma with Dichloroacetate, Metabolic Modulation of Glioblastoma With Dichloroacetate. Some cancer cells share traits with healthy cells, which keeps the immune system from detecting them. Researchers changed the genes in his T cells – white blood cells that survey the body for infections and other invaders to recognize and attack his leukaemia. After researchers remade Wright's cells in the lab, he got them back intravensously (IV). Then everyone waited for him to get a fever, a sign the T cells are working. Immune system ate the caner. (1). Some vaccines can help prevent — or even treat — certain types of cancer such as the human papilloma virus (HPV) vaccine against cervical cancer. Vaccine Sipuleucel-T used to treat advanced prostate cancer unresponsive to other treatments. Immunotherapy, Anti-Angiogenesis therapy, High dose vitamin C associated with Angiogenesis, Proton therapy, T-cell therapy, CAR T-cell therapy, Monoclonal antibodies. (1), MR1 therapy(1, Why Do Elephants Rarely Get Cancer?. What is required is a gene therapy platform in vivo. Crispr can theoretically halt cancer from progressing by altering its reproduction code but also kill cells that match the mutated sequence. We have not seen effective gene therapies for the tens of thousands of gene mutation diseases but once an effective platform produces one, more may follow. Catalogue Of Somatic Mutations In Cancer, A Census of Human Cancer Genes, Delivery systems of CRISPR/Cas9-based cancer gene therapy, Anomoly 1, Anomoly 2, Low Dose Naltrexone, SABR, Grow and malignant behaviour are regulated at the level of tissue organisation, and tissue organisation is dependent on the ECM and the micro-environment. –Mina Bissel (1) (ECM talks to chromatin). A cell that is not damaged is highly programmable and accessible through the microenvionment, but we do not know the lanaguage of the cell. The possibility exist to learn the language and to even install some new commands. Signal transduction pathway. Damaged cells are replaced yet some cells in the human body cannot be replaced and so damage protection is required and so in the end with all this a nural network and a simple one is all that is required to keep time and after a certain number of pulses shutdown the organism. Each cell is like a fagile fine swiss watch that easily dies instead relies on big protective systems to keep it functioning. Oncolytic virus are virii that target cancer cells. Area of the body in inflammation are more prone to cancer.

1. SF3B1, drives the formation of many cancers. How common genetic mutation drives cancer
2. P53 or TP53, most commonly (50% of cancers) mutated gene in patients with cancer.
3. HER2 & RAS, oncogenes
4. Breast Cancer Gene Mutations (1): BRCA1, BRCA2, PALB2, PIK3CA, HER2, PTEN, TP53, ATM, CDH1, BARD1, CHEK2, NBN, NF1, STK11, MSH6
5. Ovarian/fallopian tube cancer: BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, EPCAM, MLH1, MSH2, MSH6, PMS2, STK11
6. Pancreatic cancer: BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PMS2, TP53, STK11 (ATM and PALB2 require further study)
7. Prostate cancer: BRCA1, BRCA2, CHEK2, (ATM and NBN require further study)
8. Melanoma: BRCA1, BRCA2, PTEN
9. Uterine cancer: EPCAM, MLH1, MSH2, MSH6, PMS2, PTEN, STK11
10. Colon cancer (1): CHEK2, EPCAM, MLH1, MSH2, MSH6, PMS2, PTEN, STK11, TP53
11. Gastric cancer: CDH1, STK11

Prevention of cancer, diagnosed with cancer is vastly different from hedging your bets with some prevention strategy or supplement. If you get cancer you at the mercy of the medical system. The latest theory is, under extreme cellular conditions the cell reverts to a single cell organism and seeks to multiply to survive. The prevention strategy is nursing and contributing to cellular level homeostasis. Age is the greatest risk factor, possibly due to immunosenescence and cellular condition, personal or family history, tobacco 30%, diet 30% as much as tobacco with epidemology prescribing vegan diet, vegetables, peanuts and low sugar fruits with plenty of clean water, obesity 15%, infection some types of viral infections such as human papillomavirus (HPV) 7%, physcial inactivity 5%, alcohol 4%, air pollution (unestimated), specific chemicals, exposure to radiation, including ultraviolet radiation from the sun, mobile phone towers, radio and television waves, nuclear accidents and explosions. Specific Foods other than go full vegan means no meat or dairy (inc eggs or milk), broccoli contains sulforaphane and isothiocyanates which is a plant compound found in cruciferous vegetables. Carrots decreased risk of certain types of cancer. Beans, legumes, peas, lentils including against colorectal cancer. Berries high in anthocyanins, plant pigments that have antioxidant properties. Cinnamon well-known for its health benefits, including its ability to reduce blood sugar and ease inflammation. Nuts, walnuts contain a substance called pedunculagin, which the body metabolizes into urolithins. Urolithins are compounds that bind to estrogen receptors and may play a role in preventing breast cancer. Olive oil. Turmeric is a spice well-known for its health-promoting properties. Curcumin, its active ingredient, is a chemical with anti-inflammatory, antioxidant and even anticancer effects. Citrus fruits such as lemons, limes, grapefruits and oranges. Flaxseed, decrease cancer growth and help kill off cancer cells. Lycopene is a compound found in tomatoes that is responsible for its vibrant red color. Garlic is allicin, a compound shown to kill off cancer cells in multiple test-tube studies. Fish (max once a week or once a month), some research suggests that including a few servings of fish in your diet. Apples, some research suggests polyphenols. Berries, one study shows that anthocyanin, which is a compound in blackberries, lowers biomarkers for colon cancer. Vitamins A, C, and E are notable. Vitamin D plays a role in the production and proliferation of key immune cells. B vitamins—particularly vitamin B6, vitamin B9 (or folic acid), and vitamin B12. Zinc, Probiotics, certain over-the-counter medications, such as aspirin and ibuprofen, may also lower the risk of cancer in some people. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs may lower the risk of many types of cancer in people with an average risk of cancer but are damaging to kidney function.

Source: Healthline.com Cancer-fighting-foods, Healthline.com Anti-cancer-supplements, https://www.medicalnewstoday.com/articles/324193, https://www.cancer.net/navigating-cancer-care/prevention-and-healthy-living/chemoprevention. Cancer cells have high sugar uptake, they can also use ketones (Scot inhibitors) and fats. High pressures of oxygen are damaging to cancer cells use HBOT therapy. (Starving cancer: Dominic D'Agostino at TEDxTampaBay). Ruthenium cures cancer conspiracy. Dichloroacetate (DCA) PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer, small study mismatch repair–deficient colorectal cancer is responsive to programmed death 1. Known-and-probable-human-carcinogens ERX-41, Polyunsaturated Omega3 and Iron selectively apoptosis of cancer cells, Omega3 poly unsaturated fat 10 day load up before megadose iron to selectively kill cancer cells. Gleevec. DMSO dimethyl sulfoxide, Laetrile, amygdalin, 50 Cancer Test, Blushwood berry to be nature's hidden cancer cure, EBC-46 Stelfonta

Many regeneration therapies has a cancer side effect, so we need to cure cancer as a pre-caution to human regeneration therapies.

Possible Cancer Treatments

Surgery - Surgery remains one of the most effective weapons against multiple kinds of cancer. Many cancers, however, are inoperable (because of location, for example), and many operable cancers require traumatic surgery. Doctors and scientists are devising new techniques to reduce the trauma of surgery, such as lymphatic mapping with dyes and radioactive tracers, which may help surgeons be more selective and less invasive when removing cancers.

Radiation - Radiation has been used for decades as a tool for eradicating many kinds of cancerous cells (especially in the prostate, solid tumors in internal organs, and lymphomas), but it is also harmful to the body's healthy cells. Doctors and scientists are in the process of perfecting radiation techniques that use 3-D images to home in on individual cells, aiming precisely at the cancer and sparing healthy tissue.

Chemotherapy - Chemotherapy is an increasingly important aspect of cancer treatment. Alkylating agents, which work by impairing cell division, and antimetabolites, which interfere with the enzymes that allow cancer cells to thrive, are used to attack malignant cells. Chemotherapy has serious drawbacks, however, as the drugs destroy both healthy and cancerous cells and can result in terrible side effects. Work is being done on tumor specific agents that attack only cancer cells.

Anti-angiogenic drugs - Anti-angiogenic drugs contain organic or synthetic molecules that can block the formation of new blood vessels in the body and destroy existing abnormal blood vessels. Since growing tumors secrete substances that stimulate new blood vessel growth in order to receive the nutrients they need to live and enlarge, anti-angiogenic drugs may help to "starve" tumors and inhibit the progression of many kinds of cancer. At this time, anti-angiogenic drugs are available only in clinical trials. Their utility has not yet been clinically proven.

Anti-metastatic drugs - The most lethal aspect of any kind of cancer is the possibility of metastatic spread from one primary tumor to other points in the body. Scientists now understand that cancer cells are helped along in their journey through the body by special enzymes that allow them to pass easily through capillary walls. Anti-metastatic drugs, which are still being tested in clinical trials, may be able to block these enzymes and confine cancer cells to the primary tumor. As with anti-angiogenic drugs, the utility of anti-metastatic treatments are as yet clinically unproven.

Anti-oncogenic drugs - In order to grow, tumor cells produce chemical growth factors by switching on oncogenes. Many tumors rely on a mutation of the RAS oncogene in order to develop. Scientists hope that new anti-oncogenic drugs designed to inhibit the growth-inducing signals produced by the RAS oncogene could stop cancer cells in the breast, colon, pancreas, and lung in their tracks early on in their development.

Chemoprevention therapies - Chemoprevention therapies aim to prevent the recurrence of cancer in patients who are in remission. In the case of breast cancer, for example, the drug Tamoxifen has been shown in some women to effectively block estrogen from feeding the growth of potential tumors in the breast.

Young blood or parabiosis, when discussing aging we are really referring to one experiment, parabiosis. By surgically connecting a young mouse to an old mouse so that they share a common blood stream, it is said the blood supply of the young mouse causes the old mouse to get younger. In the mid-1800s, parabiotic experiments were pioneered by Paul Bert.

The old mouse gets younger and young mouse gets older. Is it the young blood or the young organs? A television show that evoked interest Silicon Valley episode The Blood Boy depicts human to human parabiosis as a practice of the eccentric wealthy. Next, Ambrosia by Jesse Karmazin went clinical with blood transfusions using young blood, some laughed, some cheered, some scorned, but they were attacked by the US government and forced to shut down, (should have operated out of Central America like the growing list of US medicals in exile). The well established colleges were also working to understand the results of parabiosis for the prospect of a cash cow pill. Wait, what? Umbilical cord blood, Wharton's jelly? Ok, here goes... Bone marrow, adipose, embryonic, placenta, fetal, induced pluripotent (IPSC), amniotic tissue, Wharton's jelly cord tissue are a source of stem cells while umbilical cord blood, amniotic fluid and blood composition relative to age are a source of blood factors. Not strictly, but the study differs. Factors are molecular chemical structures while more complex cells are the building blocks of the body. This section strictly relates to blood composition differences with age or blood factors, while not eliminating any valid factors, the reference, blueprint or comparison is the biological difference between the haemographics of a young athlete, possibly aged 25 and every one else and can be measured. What is happening in infant blood and pregnancy offer clues and prospects.

So it was a simple matter of blood transfusion with young blood. Well, according to Tony Wyss-Coray, young people have levels of blood factors (components in blood) that are rejuvenating while old people have levels of blood factors that promote ageing, age promoting secretions increase and age demoting secretions decrease making the proposed therapy more technical, that blood transfusion is incorrect by cause some blood factors need to be added while other blood factors require removal either completely or to synchronize the blood composition to that of a young person. The theoretical therapy would be an exchange transfusion which means total replacement of blood, 5 litres out and 5 litres blood in, which is the most complex form of blood transfusion although performed around the world routinely, successfully. There are protocols to follow for professional transfusion practice, and all should be well-trained in the protocols before attempting blood exchange. Blood transfusions from strangers are not rejected, like transplanted organs. As the source of blood is a young person, there are technical and supply issues as the therapy is not a serious medical use of blood, those interested in blood composition experimentation require a safe, cosmetic protocol, one that does not require the "blood of children", identify the factors and only alter those, take only the ageing factors out and add only rejuvenating factors and even using synthetic factors. See apheresis.

A recent study, Reversing age: dual species measurement of epigenetic age with a single clock, the results are significant enough to prompt further interest.

College labs in their search for a cash cow pill prompted them to dissect blood, but they were soon disappointed, as the complexity of the human body cannot be treated in a pill. Interested parties put resources into isolating a single protein, but that possibility is long gone and much of the interest with it. While, one protein cannot make it rain, perhaps one protein might still be useful for some pathology. Reluctantly, we are led into the labyrinth of factors. What are the factors? What is the formula? And the results any better than parabiosis? In a recent paper by Irina and Michael Conboy known as "Doctors Conboy". Diluted blood plasma found to reverse aging in mice suggest by replacing the plasma of mice with a "neutral" mixture they achieved the same or better tissue rejuvenating results as parabiosis. They did not add young blood factors, instead they removed some blood and injected saline/albumin, a neutral replacement, to achieve the same results. Mystery deepens, some say albumin is not a neutral substitute, the Conboys say it is not significant and blood services (TPE) should replace plasma with albumin. According to the Conboys, 1. The increase in aging factors are due to the deficient performance of organs in an aging person, in a young person the organs maintain the proteome, an answer to the parabiosis question of organs vs. blood. 2. Aging factors have a dominant effect when compared to youthful factors, to such a degree that extracting aging factors is enough to slow aging even without adding any youthful factors. Dilution of aging factors, meaning there are less aging factors total in blood. They report that injecting young blood into an old mouse is not beneficial, but injecting old blood into a young mouse is devastating to the young mouse. It has also been stated previously that heating the blood cancelled its rejuvenating factors, discrepancy? We know that heat destroys both cells and proteins. I do not think the body is producing extra bits in blood for no reason, factors is still in the mentality, however they make the point that effective cell culture serum in vitro might be the ideal media in vivo and exceeding performance of in situ plasma is possible and the therapy a simple dilution.

The last implications the Conboys put forward is speculative, that maybe there are no factors at all and that the benefits come from an interruption in intercellular communication, perhaps if the cell is not reacting to a condition then it better uses time to do some housekeeping or its homeostasis is subjective to signals from the external environment rather than anything real or its actual state. Messages are saying it is old, so it acts old. Chromatin communication is an active area of research.

Paper in question, Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Whole blood, plasma only or major factors, what delivers the best results? What about going synthetic? What about a computer composition machine where tens of thousands of proteins can be auto analysed and auto normalized?

CSF, Cerebral spinal fluid infused into the brains of older mice also showed improvements.

There are many that do not believe in the whole blood thing, they ought to ask themselves... How are cells grown and maintained in a Petri dish? Media, so it is blood that provides the nutrients alongside the cells so that they can live. It is called fetal bovine serum, blood from a cow foetus sustains cells in a petri dish. In vitro as the cell culture serum degrades starvation leads to reduced cell survival, increased apoptosis and wide-ranging effects on cell health, quality and rates of expansion, media needs to be replaced every 24 hours for cells to keep on living. In vivo the media is blood, the analogue is identical. The composition of media in vivo degrades with age and cascades, "aging" until the body breaks. As blood deviates with aging in quality, levels, ratio and composition, cells alter their homeostasis and eventually die. The media provides two effects,, one is nutrients for the cell material structure and the other is epigenetic communication. Egypt is a gift of the Nile, all that the body manufactures is probably found in the bloodstream with 20,000 to over 100,000 proteins, enzymes, signal molecules, secretome and many types of cells analyzing each one is a monumental feat, let alone synthesizing. As well as providing nutrients for cells, it is believed components in blood communicate with the epigenome to regulate cellular condition. There are 2 to 3 thousand G protein-coupled receptors (GPCR's constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses, see ligands and receptors) in each cell accessing, switching genes constantly, what we send into the blood also speaks to the genetics. If the cell detects bad media, it re-configures itself. Surface Plasmon Resonance.

Biohackers Perform First Plasma Dilution Experiment on Humans

Therapeutic Plasma Exchange (TPE) is a procedure in which the patient's blood is passed through an apheresis machine, where the filtered plasma is removed and discarded with reinfusion of red blood cells along with replacement fluid such as plasma or albumin in to the patient.

Therapuetic blood exchange (TPE) cannot be achieved using regular blood donation. You can log your metrics, complete blood panel including organ conditions, then simply head on in to your local blood bank every month and give blood plasma. Take another blood test after some months and blog your metrics.

Parabiosis: the Dilution Solution?

Before this, the method was injecting young blood into person. To quote a statement by Mina Bissell, "The ECM and the micro-environment speak to the chromatin".

Notes on Experimental TPE Apheresis and Haemotology

The experiment in vitro is to bathe cells in different formula of media to see if one formula performs better than another. Cell culture serum formula impacts cell culture results. This is the analogue of vascularization. A number of petri dishes with identical human cells and a percentage of different human blood and a percentage of different cell culture serums. The best performers are the formula to test in vivo. While measure of cell condition along with changes to expression.

Some mentioned media

1. TPE alone
2. Young blood alone
3. Old blood alone
4. FSB (fetal bovine serum) alone
5. Young blood with FSB
6. Umbilical cord blood
7. Old blood with FSB
8. Giant tortoise blood, factors in long lived animals that may be infused into humans
9. Salamanders, adapting their regeneration to human chinaera components.
10. Dragon blood or dragon tears
11. Various animal free serums
12. and so on...

The field is named haematology. It is also known that the leading cause of death of people over 65 concern clotting factors, blood viscosity and cellular morphology of heart, blood vessels and so on.

These alterations of blood generally require no blood donors as was the lay concern, with eventually an apheresis pheresis machine as required to do full blood composition auto analysis and auto normalization using the blood composition formula described above and haematology contributions. Areas of study for optimal blood composition or blueprint are young people, young athletes, centenarians in their youth and so on. All substances should be natural occurring in the body, implement the blueprint as an ongoing therapy. Human body does not naturally work on pharmaceutical products, so it is not correct, no polypharmacy, no foreign substances. Exotic factors like TIMP2. Here is an example of what a machine could be like. The machine in the video takes a specified component out of blood and then returns the same blood, while our machine is dedicated and can analyse, normalize, remove, add and so on.

A section of blood is removed and sampled by Real-time ELISA for Continuous Blood Testing and a computer takes the inputs, removes and adds as required or just rather than sample, filter, centrifuge, normalize each protein individually or 20,000 to 100,000 proteins, the complexity of the machine could be minimized by removing dominant ageing factors in an effort to cause a beneficial cascade on the rest of the proteome automatically such as chaperones and proteasomes. A monthly treatment. No cosmetic industry like packages. The analysation of blood can translate to advisory on lifestyle and dietary changes.

Fetal Bovine Serum, all cell culture therapies rely upon fetal bovine serum. FBS is not a fully defined medium because defining the medium takes too much work but the industry must find animal free FBS alternatives. Fully Define and Synthesize Fetal Bovine Serum For Industrialization of Lab Meat FCS-free Database A change in (cell) culture: exploring alternatives to fetal calf serum

The leading causes of death of people over 65 suggest factors for, tissue strength, stronger muscle tissue factors and stronger bone tissue factors - No 1 (cause of death) is heart disease and No 8 is accidents, fractures. Cancer prevention factors, relating to immune system decline, apoptosis. Immune system decline, the count and quality of white and red blood cells and platelets. Haematopoietic stem cell age reversal factors, bone marrow health. Clotting factors, stroke. Remove and maintain normal levels of clotting factors. Investigate the cause of stroke and make the blood less likely to clot and cause stroke. Blood pressure is an ident of stroke. Ischemic stroke is the most common type of stroke, making up 87% of all cases. A blood clot prevents blood and oxygen from reaching an area of the brain. Slowly remove any existing clots and maintain normal levels of clotting factors month by month. Neurogenesis, neural health protection factors. Alzheimer's Disease, bacterial and viral filtration - blood is filtered to remove virus, bacteria, toxins, gases. Senescent Factors, synolytic and removal of SASP factors. Blood viscosity, increases with age. Normalize. Haematological conditions such as myeloma, clonal haematopoiesis. Vitamins, Minerals, Amino acids, quantity and condition of cells and more, so on...

Here is a small list of major identified factors,

• Oxytocin - Add - Dosage unknown. Hormone secreted by the posterior lobe of the pituitary gland, believed major component of rejuvenation declines with age 1, 2 (Is Not OxyContin)
• TIMP2 - Add - Dosage unknown. Found only in umbilical cord blood 1
• THBS4 - Add - Dosage unknown. Decreases with age 1
• SPARCL1 - Add - Dosage unknown. Decreases with age 1
• Lipoprotein receptor-related protein 1 (Lrp1). Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice.
• MANF - (mesencephalic astrocyte-derived neurotrophic factor) Add - Dosage unknown 1
• HDAC1 - Add - Dosage Unknown 1
• GDF11 - Disputed - Dosage unknown - has been reported to increase the generation of neurons in aged mice1, while this has also been disputed showing degeneration in mice, may be depending on dose. Do not use.
• GnRH - More research needed - rejuvenation factor 1
• Wharton's Jelly - factors surround births. See Umbilical cord-derived Wharton’s jelly for regenerative medicine applications Harvard researchers find protein that could reverse the aging process
• Collagen, Elastin, Fibrillin - see cutis laxa.

• Eotaxin-1 (Chemokine CCL11) - Remove - Dosage unknown. Increases with age, believed major component causing aging found in old blood and less in young blood, has been shown to impair young brain function, a growth-inhibiting chemokine. 1,2, 3
• TGF-β - Remove - Normalize to levels of young person. Dosage Unknown. Increases with age 1, 2, 3
• IL1ß & IL-18 - Remove - Normalize to levels of young person. Dosage Unknown. 1
• NFkB, a cytokine which triggers inflammation, MSC's home in on inflammation to perform repair, without the cytokine message how can they know where to go?
• Wnt, a growth promoter. Essential for repair is the right amounts. Much research on Wnt.
• Klotho, perhaps https://newatlas.com/medical/anti-aging-young-blood-particles/

Hormones

• LH (luteinizing hormone) & FSH (follicle-stimulating hormone), associated with ovulation in women and sperm production in men. Increase late in life for both men and women.
• Estradiol, a female sex hormone
• Melatonin, from pineal gland, controls daily cycle of sleep and waking
• DHEA = dehydroepiandrosterone is a precursor of sex hormones and steroids
• Ubiquinone = CoQ10 is an anti-oxidant and electron transporter, used in mitochondria for energy production
• Thyroxine, produced in the thyroid, regulates many other hormones, stimulates activity
• HSP70, heat shock protein, protects against muscle loss with age
• Progesterone, involved in menstruation, sleep cycle, mood; downregulates growth, increases insulin sensitivity
• HGH = human growth hormone, may or may not be beneficial
• Testosterone, primary male sex hormone - may or may not be beneficial
• Estrogen, several primary female sex hormones - may or may not be beneficial
• Cortesol and ageing, unknown, normal levels may be required 1
• IGF1 - may or may not be beneficial
• GDF11 - may or may not be beneficial

Demethylation Targets, these are not proteins, these are gene expression targets for epigenetic editing e.g. Crispr/Antisense demethylation targets.

• Transcriptional modulator CREB - Unknown 1
• Cell adhesion and developmental fate regulator β-catenin - Unknown 1
• Tet2 - expression decreases with age 1, 2

WO2021059266 - ANTI-AGING COMPOSITIONS AND METHODS OF USE THEREOF

Our strategy is to first develop a provable or correct theory of aging and then develop therapies based on that theory to cure aging. Is is supposed that their is an upstream point of access or a numerous amount of downstream therapies.

Maintenance of blood composition, maintenance of ideal cell morphology, ideal ECM composition and recomposition, genetic/epigenetic regulation, remove all the pathogens from inside the body to eliminate those variables. Cell morphology disorders and condition improvement. High quality nutrients, high quality proteome to override the degraded proteome, e.g. iron accumulation in the brain caused by misfolded proteins, so that iron can be metabolized. Increase the capacity of the stem cell regenerative system to counter regenerative system decline, gene therapy to correct genetic mutations and correcting epigenetic configuration. Understand the ideal state and its difference to reference against.If we can enrich the blood, we believe that overall health would improve.

More studies: Undulating Changes in Human Plasma Proteome Profiles Across the Lifespan Blood serum study reveals networks of proteins that impact aging Plasma Proteomic Signature of Age in Healthy Humans Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice Role of circulating factors in cardiac aging Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment Scientists Find Surprising Age-Related Protein Waves In Blood AMBAR, an Encouraging Alzheimer's Trial That Raises Questions Scaling the Alzheimer’s Cure Ability to eliminate spent proteins influences brain aging and individual life span Protein Folding: The Good, the Bad, and the Ugly Hemorheological Changes During Human Aging Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function Red blood cell deformability during storage: towards functional proteomics and metabolomics in the Blood Bank Immune cell transplant reverses effects of aging in mice Blood iron levels could be key to slowing ageing, gene study shows Rejuvenation of regeneration in the aging central nervous system Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues Parabiosis in Mice: A Detailed Protocol Plasma dilution improves cognition and attenuates neuroinflammation in old mice Removal of intracellular waste products by hemofiltration Rejuvenating the blood and bone marrow to slow aging-associated cognitive decline and Alzheimer’s disease Removal of intracellular waste products by hemofiltration Fixing spinal cord injuries with ​dancing molecules

Mesenchymal Stem Cells and Exosomes, cytostomes, amniosomes, we have all heard of the immune system and their is another system called the regenerative system, a complex system that performs self-healing, simply if we cut ourselves the body heals. It is all about taking these healing and repair systems to their ultimate level.

Mesenchymal stem cells (MSC's) are multipotent stem cells found in bone marrow that are important for making and repairing skeletal tissues, such as cartilage, bone and the fat found in bone marrow. These are not to be confused with haematopoietic (blood) stem cells that are also found in bone marrow and make our blood. They home in on inflammation by following inflammatory factors to locate sites to perform repairs. Inflammation is the normal response to injuries or infections. Cells of the immune system travel to the site of injury or infection and cause inflammation. You want to prevent inflammation and when inflammation occurs you want the repair team to be well funded. When a person cuts themselves or bumps their head the area becomes inflamed or swells and the human body activates its regenerative system to begin the repair process.

Inflammation increases with ageing and this may be due to ageing immune system plays up and autoimmune damages the cell. The regenerative response becomes severely limited with age, known as stem cell exhaustion, therefore either the internal system is investigated to be regenerated or a foreign source of the components is infused. This system is shut down as aging progress. Super-centenarians have shown to have very little inflammation naturally.

There are various places that stem cells are harvested, bone marrow or fat tissue, but the stem cells there are at the same age as the patient, the richest source of these regenerative factors is from umbilical cord, Wharton's jelly, amniotic tissue, placenta. The stem cells are called mesenchymal stem cells (MSCs) and lately just the exosomes which MSC's manufacture. Extracellular vesicles (EVs) are submicron-size microparticles and the nanometer-size are called exosomes. recently the gonads have been suggested, inorder to get a embryonic and multi-potent source that can pass the immune system.

Cells are purchased, expanded in culture and infused or injected into a person, where they home in on inflammation and conduct systemic repair work (apoptosis, cleaning, signal adjacent cells into mitosis and more). Non bone marrow or fat tissue cells do not have matching DNA with the recipient, (but they are said to have immunomodulation abilities) eventually the immune system eats them, and they do not become part of the recipient.

There is still no way to have young stem cells become part of the foreign body due to immune system rejection which is an unrealized potential as stem cell depletion is a major indicator of ageing.

These sources of stem cells are ethical if they are expanded using non-animal serums otherwise they use foetal bovine serum which is unethical and unsustainable.

The use of aborted babies as a source of ideal stem cells, in some places abortion laws have been quietly altered to facilitate the harvesting of aborted babies. Foetal stem cells are the remains of aborted babies and there are some people that want to absorb them, turning the remains into a lysate and infusing or injecting the remains into themselves. The wealthy and the royality are also living longer than they used to, lifespan usually runs in families. . Which should I have, exosomes or mesenchymal stem cells or both? Exosomes are extracted from mesenchymal stem cells, believed that exosomes from healthy cells carry much of the regenerative proteins of mesenchymal stem cells and also exosomes fit the definition of nan particles. Nano particles are very small and can penetrate the blood brain barrier in hopes it regenerates the brain. It is believed that much or all of the positive outcomes believed to have been attributed to mesenchymal stem cells for the treatment of neurodegenerative disorders are due to the exosomes derived from mesenchymal stem cells. Many scientists now believe that you are skipping right to the regeneration process by using exosomes as opposed to mesenchymal stem cells. MSC fanboys say you need the full signalling capacity of which only the MSCs can provide and not just the exosome.

Exosomes have messenger RNA, micro RNA and proteins and are made by cells and transfer these contents to other cells. Cells produce exosomes, so there might be a way to make a transgenic cow that produces human exosomes in the milk, already shown to be possible using mice Do the microRNAs we eat affect gene expression?, as they are nan particles they are bio-available and the milk orally consumed. Not all exosomes are identical, the constituting RNA and proteins are information and can communicate differently so the age of the cell is importan, young exosomes are communicating different information than old exosomes, so exosomes produced by a theoretical transgenic cow would have to code for the right types or mix of one or more optimal exosomes. There are several places that offer mesenchymal stem cells or exosomes treatments, some claim great success others not. I do not believe that bone marrow or adipose stem cells are effective in comparison to umbilical cord derived stem cells. The therapy is required either every year or every three years and constitutes one IV session lasting one hour, with beneficial effects progressing over several months. Some say they have had better results with senolytic treatment prior and some say slim down and get fit before getting them. Expertise is crucial, the most established practitioners are possibly the Riordan clinic in Panama (MSCs), and PRmedica exosome clinic in Mexico. A session might cost ,000 (USD), unless they have opted for non-animal serum stem cell therapies rely on foetal serum to grow stem cells. Extracellular Vesicles, Ageing, and Therapeutic Interventions, Stem Cell-Derived Exosomes Prevent Aging-Induced Cardiac Dysfunction through a Novel Exosome/lncRNA MALAT1/NF-κB/TNF-α Signaling Pathway, Biotech companies leading the way with exosome human clinical trials, Mesenchymal Stem Cells for Regenerative Medicine Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

VSEL stem cells – very small embryonic-like stem cells. You have a small number of very small embryonic-like stem cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159118/

It has been suggested that platelet rich plasma enhances the effect of exosomes or MSC's. No anti-inflammatory as the MSCs use inflammation, so expose the inflammation might get a better result.

What is the information in the exosomes communicating? No one really knows at the moment. Database of exosomes, ExoCarta - Exosome database Exosome RNA

Casein has been proposed for the maintenance of stem cells, possibly Casein Kinase role.

Yamanaka Factors, in 2006 Sir John Gurdon postulated the long term possibility of elucidating nuclear reprogramming, reprogramming a skin cell diretly back into an embryonic cell. Shinya Yamanaka recieved the Nobel prize in 2012 when in 2007 he released his paper on induced pluipotent stem cells from skin cells using 4 genes. Now known as Yamanaka factors, transcription factors are proteins that bind to DNA-regulatory sequences (enhancers and silencers), to modulate the rate of gene transcription, resulting in increased or decreased gene transcription, protein synthesis, and subsequent altered cellular function. Yamanaka factors are a group of transcription factors, 4 proteins injected into the cell or bathed in medium that can turn a differentiated cell back into an embryonic stage cell just like Turritopsis dohrnii, the immortal jerryfish and also re-differentiate cells from for example a skin cell back to embryo and then into a liver cell if given the right chemical signals. In 2006 Dr. Shinya Yamanaka, a stem-cell researcher at Kyoto University, amazed biologists by showing that a cell's fate could be reversed with a set of four transcription factors — agents that activate genes — that he had identified. A cell dosed with the Yamanaka factors erases the marks on the epigenome, so the cell loses its identity and reverts to an embryonic state. Erroneous marks gathered during aging are also lost in the process, restoring the cell to its state of youth. Dr. Yamanaka shared the 2012 Nobel Prize in medicine for the work. Before this everyone thought the cells cycle was fixed in one direction only. Yamanaka factors are (Oct4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their over-expression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signalling network necessary for embryonic stem cell pluripotency. In age reversal we do not want to turn the cells back into embryonic stage. In 2016, Juan Carlos Izpisua Belmonte, of the Salk Institute for Biological Studies in San Diego, found that the two effects of the Yamanaka factors — erasing cell identity and reversing ageing — could be separated, with a lower dose securing just age reversal. He achieved this by genetically engineering mice, but if a mouse gets too much the cell becomes an embryo and starts dividing leading to cancers, tumours. Izpisúa Belmonte believed there might be a way to give mice a less lethal dose of reprogramming. He was inspired by salamanders, which can regrow an arm or tail. Researchers have yet to determine exactly how amphibians do this, but one theory is that it happens through a process of epigenetic resetting similar to what the Yamanaka factors achieve, though more limited in scope. With salamanders, their cells “just go back a little bit” in time, Izpisúa Belmonte says. In 2016, Belmonte's team devised a way to partially rewind the cells in mice with progeria. They genetically modified the mice to produce the Yamanaka factors in their bodies with condition the mice would produce those factors only when given an antibiotic, doxycycline. Some mice were allowed to drink water containing doxycycline continuously while others got it just for two days out of every seven. “When you give them … doxycycline, expression of the genes starts,” explains Reddy. “The moment you remove it, the expression of the genes stops. You can easily turn it on or off.” The mice that drank the most quickly died but the mice that drank a limited dose did not develop tumours. Instead, they became more physically robust, their kidneys and spleens worked better, and their hearts pumped harder. In all, the treated mice lived 30% longer than their littermates. A Stanford team confirmed Salk Institute, extracted aged cartilage cells from patients with osteoarthritis and found that after a low dosage of Yamanaka factors the cells no longer secreted the inflammatory factors that provoke the disease and also found that human muscle stem cells, which are impaired in a muscle-wasting disease, could be restored to youth. Members of the Stanford team have formed a company, Turn Biotechnologies, to develop therapies for osteoarthritis and other diseases. Another company is AgeX and GenuCure developing various treatments, heart tissues, osteoarthritis, aging-related muscle loss, rejuvenating cartilage. 1. Other scientists are experimenting with the factors, by leaving some out or another derivative cell quality improves and cancer is less probable while others are including more factors than the four, OSKM. c-Myc is an oncagene and 20% of mice developed cancer. Since then another forumula is Oct 3/4, Sox 1/2/3/15/18, Klf 1/2/4/5, c Myc, Nanog.

The major problem is separating ageing from IPSC, the ability to get significant age reversal before going too far, high dose and reverting the cell to IPSC. Recently a team proposed 30 year reversal was achieved in skin cells. Once mechanism is to revert back as far as possible while adding factors to maintain cell identity in effect disabing the dedifferentiation, another is go back to pluripotent and then return it, redifferentite back into the same phenotype. Vecotrs are also required here as they are in gene therapy, the use of naked RNA's which degrade quickly, have no permanent effect and have the possibility to be systemic perhaps in a vesicle. Any proposed therapy even modest must be safe. The situation might require a reprogramming blocker, after an RNA partially reprograms, another RNA makes the cell immune to further re-programming allowing systemic uniform partial reprogramming. The RNA eventually dissolves and the cell becomes partially reprogrammable again.Yamanaki Factors Prolonged Life In Mice by 30%.

Vittorio Sebastiano at TurnBiotechnolgies states that Naked RNA offer the best control, that different organs of the body age at different rates and require different dose. Unclear if factors injected into the area or if a magnetic capture in vivo as used for nano-particles to control the naked RNA to a specific organ. Assumed that someone has a simple effective terratoma treatment just in case. However Vittorio is set on going in vivo which keeps us checking back on his progress.

Theoretical Cell Replacement Therapy In Situ

What if the inate regeneration system that is locked in human beings could be activated to maintain organs insitu rather than organ transplants. Using embryonic stem cells or IPSCs to replace aged tissue cells and maintain a baseline physical state.

The body is largely made of cells, extral cellular matrix. Cell quality, its genetics and epigenetic all important for function. Cells degrade and get damaged and most are replaced, with age these system are defective and suppressed. With an estimated 30 to 40 trillion cells in every human being. Cells are highly complex and need to function correctly and optimally all the time for a person to be healthy. It is estimated that each day 50 to 70 billion cells die (signalled to self-destruct, apoptoses) and are replaced as part of body's natural process. Cell replication is called mitosis, some cells can divide (skin cells) and use a neighbouring skin cell to replace a cell, other cells partially lose their ability to replicate (liver cells) and require the body's regenerative system, mesenchymal stem cells to activate non dividing cells into mitosis, moreover other cells lose their ability to repair such as brain neurons and are never replaced. Various people argue for saving the cell as if the exact same cells exist in the body for ones entire life, in fact the body replaces cells ongoing to maintain optimal body.

1. Do liver stem cells come from bone marrow
2. One-time treatment generates new neurons, eliminates Parkinson's disease in mice

Some organs are highly regenerative while some not so much, often stated that on average that cells in the human body are replaced every 7 to 10 years. Red blood cells 4 months, white blood cells over 1 year. Skin cells: 2 or 3 weeks. Colon cells: ~4 days. Brain cells typically last an entire lifetime (neurons in the cerebral cortex, for example, are not replaced when they die), brain cells: 200+ years?. Neutrophil cells (a type of white blood cell) might only last 2 days, while the cells in the middle of your eye lenses last your entire life. Eye lens cells: Lifetime, Heart muscle cells: 40 years, Intestinal cells (excluding lining): 15.9 years, Skeletal muscle cells: 15.1 years, Fat cells: 8 years, Haematopoietic stem cells: 5 years, liver cells: 10-16 months, Pancreas cells: 1 year and so on.

It is assumed these cells require replacement because of damage, otherwise replacement would not be required while it is not possible for damage to not occur in any analogue system.

When 50 to 70 billion cells die each day and are replaced, how do we get better cells to take their place? Not only the 50 to 70 billion cells each day but also as a regeneration and maintenance of organs in situ therapy.

Grading cells to see if they are functioning completely correctly at an optimal level? some pharmaceutical cell removal agents called synolytics are possibly of questionable effectiveness. The immune system plays the major role of daily disposal of damaged cells, there is autophagy after fasting, but what about manually verify, detect and remedy damaged cells. Could we say cell number 1 trillion does not have the stop sequence or potassium delivery in cell number 2 trillion is sub-optimal? There seems to be nucleus deformation on cell 1 billion, sub-optimal ATP production in mitochondria cell number 7 trillion and so on. Tag those and remove. Perhaps a kind of imaging machine that can perform this task on a cell by cell basis, prehaps using pharmaceuticals.

Along with, the manufacture the higher quality cells outside the body and then introduce them into the body (exvitro) along with the various additional proteins the body dispatches when there is a wound. These cells are younger than existing cells in the body and with enought treatment the body is slowly replacement with better cells than before, providing young cells, practically biologically new cells that the body cannot achieve on its own.

The reason we have not seen large scale stem cell treatments is immune system rejection, just like in organ transplants. The field is called “stem cell immunobiology”. They have been saying for over 10 years that stem cells have the potential to create organs without immune rejection. That is not the case. Groups seek to produce off the shelf stem cell product that is not rejected by the immune system. To quote Dr. Sonja Schrepfer “Our team used CRISPR to create the first pluripotent stem cells that are functionally 'invisible' to the immune system, a feat of biological engineering that prevents rejection of stem cell transplants and brings the promise of regenerative medicine a step closer to becoming reality” and “In our paper, we describe how, by altering the activity of just three genes in pluripotent stem cells, these triple-engineered stem cells are able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems.” Hypo immunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. The first time I heard of this was by Claudia Mitchell, Ph.D., CEO Seattle, WA of Universal Cells in 2017.Collaborate to Engineer Universal Locally Immune Protected Cell Therapies for Type I Diabetes and Hemophilia A, its trial use in humans dated June 2020.

Mesenchymal stem cells are able to go to the destination of inflammation and differentiate in tissue cells without teratoma formation. The research and ultilization of autologous stem cells to importantly, make the replacement better than the before, each time.

If what she states is correct, possibility of having modest cell replacement therapies. These cells offer regenerative medicine and it is all that we want. But... in my opinion, the immune system cloak of knocking out the three genes come with potential problems. The function of these three genes is so the immune system can detect and destroy the cell because it is malfunctioning and without this monitoring of the cell, when these universal cells become dysfunctional the immune system is blind to their state. If a virus gets into one of these cells it replicates indefinitely and the immune system blind to the source leading to death. Do these cells come with their own white blood cells? The solution might be in finding biomarkers of cell dysfunction and attaching those markers to apoptoses using genetic engineering, or there might be other ways for universal stem cells to pass the immune system check without gene editing and that would be a better case. What if the cells are generated in the body, does the familiar environment provide some critical identification factor making them pass the immune system?

It really the potential to make humans transgenic. One of these cells take up residence in the human body, that body is regarded as transgenic. Transgenic means Genetic Engineering Or Genetic Therapy. These cells can be genetically engineered to do any actions as much as

intelligence can instil in a cell. The stem cell is a programming platform, hopefully an open source platform. Once that cell is expanded the genetic program is in every cell. If you cahnge the code in a the zygote or oocyte, the entire offspring is permanently changed but if changes in the adult is not inherited in offspring because babies come from one cell and replicated in every cell.

Such a therapy for universal stem cells, each month a person would come in and be infused with a bag of universal stem cells, as the body is replacing cells all the time the infused cells are utilized and incorporated. These stem cells should be younger than the body's own cells and also have special abilities that have been genetically coded into them. If a person has an issue with an organ that requires organ transplant, intentional wounds are made to the organ in order to remove as many diseased cells in a session, this can be done using a sonic scalpel called histotripsy can destroy a certain amount of for example liver cells in the patient (who has the liver problem). Causing the body to attempt to repair the liver, at the same time inject the patient with universal stem cells (along with the identical mixture the such MSC's) and hope the body utilizes the lab grown cells instead of the body's cells for the repair. Repeat the procedure until the liver is replaced. Scar free healing is a field of regenerative medicine.

Scar tissue treatments, cirrhosis, scarring (fibrosis), there are no systemic pharmaceutical agents for scar tissue removal. Envisage an injection that targets the fibrosis cell and apoptoses. This is a field called scar free healing, Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Scar free healing is used in conjuction with scar tissue pharmaceutical agents. This could be done with Car-T cells as discussed here

It is a simple idea, the ongoing continual renewal of cells from young universal stem cells has the potential to have a major effect on ageing. No person is able to get younger cells, ageing organs and cells are made biologically new and kept biologically new in an ageing body, perhaps leading to the discovery of organs relating to longer lifespan.

1. Improving the safety of human pluripotent stem cell therapies using genome-edited orthogonal safeguards
2. Advances in production of retinal cells for treating blindness
3. Direct in vivo application of induced pluripotent stem cells is feasible and can be safe
4. Why Does Your Body Reject Your Own Stem Cells?

1. Transplants without Immunosuppressant Drugs UCSFs Transplant and Stem Cell Immunobiology Lab. Finding Genius Podcast with Dr. Schrepfer and Dr. Deuse.

Yamanaka Factor Therapy

Yamanaka factors as a theoretical therapy. Firstly, in normal humans and secondly in transgenic humans. The major problem is how do get systemic, 1 cell, 1 dose so that each cell in the body gets the same dose. With transgenic the alteration is specified in the ovum and replicated throughout the organism, allowing for uniform activation later on. As genetic engineers do not have such a level of control without going transgenic, reveals that effective Yamanaka factors treatment has not been used in humans, possibly other than some haphazard lysate or a vector for self experimentation.

Old people should be able to regenerate new teeth when they fall out just as young people do. Gene expression control theoretically would allow for the activation of tooth regeneration in an old person, but where is it? The code to do this still exists for a persons entire life but is locked from expression. How to turn it back on? What is important is that Yamanaka factors are also still in the human genome. If we can regenerate teeth we could also partially activate Yamanaka factors. Currently, no means to control genetics easily. Partial reprogramming in vivo is not outrageous, there are some real potential medical applications discussed openly.

A list of papers…

In vivo amelioration of age-associated hallmarks by partial reprogramming
In vivo transient and partial cell reprogramming to pluripotency as a therapeutic tool for neurodegenerative diseases
Partial reprogramming in vivo enhances wound repair in mice
Regeneration through reprogramming adult cell identity in vivo
Aging, cell and tissue repair, renewal and regeneration, inflammation and the sasp

In vivo reprogramming for brain and spinal cord repair
In vivo reprogramming of adult somatic cells to pluripotency by overexpression of Yamanaka factors
In vivo cellular reprogramming: The next generation
AAV vector-mediated in vivo reprogramming into pluripotency
De novo mutations in mitochondrial DNA of IPSCs produce immunogenic neoepitopes in mice and humans
Partial cellular reprogramming reverse aging Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

Immersed In A Pool Of Water

Fully body immersion in a pool of water, a lysate with Yamanka factors possibly as naked RNA. The time spent in immersion relative to dose can be generally controlled, while not an internal therapy, instead a skin therapy, external therapy. Simple, safe, easy. These kinds of small controllable therapies allow for safe study on humans.

Traditional Gene Therapy In Humans

A safe protocol for Yamanaka factor therapy in humans.

The major issue is if the dose is too much, the cell becomes an induced pluripotent stem cell, leading to cancer or death. It has been established that the right dose reverses ageing markers in a linear curve that ends at age 0. How do you deliver the correct dosage into the body, some cells overdose while others untreated. If you infuse, likely concentration around the liver or kidney with overdose effects. You need to control where it goes and the more control you have over cell dosage the better the treatment.

1. Ideal BMI required.
2. Perhaps a senolytic, clear the body of senescent cells prior to infusion. It is not a bright idea to reverse age markers on senescent cells. The senolytics available today are not effective enough. There are some immune cells that act like senolytics, perhaps they are better.
3. For extra insurance and to make up for ineffective senolytic, you may need to develop a T-cell to target possible cancer cells.

The only therapy that I heard about is, custom RNA using an exosome. The exosome is produced ex in vivo and then infused, it travels until it enters a cell where it releases RNA and the cell produces the Yamanaka factors. Both the RNA and exosome eventually dissolve and a repeat infusion at some time interval.

Say for example you got a cow producing your custom exosomes with factors in milk and you harvest them or whatever. The ideal case in infusion is every cell gets 1 dose with 1 infusion. The closest to that goal is the ideal practice but how do you guarantee appropriate dose?

Yamanaka Factor Therapy has been tried in transgenic mice.

Bring the body to uniform systemic partial preprogramming with safety, the theoretical procedure is, exosomes are injected into the body. These exosomes have custom RNA that code for Yamanaka factors. These enter cells randomly, the problem is many exosomes entering the same cell means over production of OKSM and full reprogramming. To remedy this, we also encode the RNA to produce an OSKM neutralizing molecule. After a certain number of factors are produced, extra molecules are also produced, having affinity for Oct8 and binding to Oct8 thus neutralizing Yamanaka factors rendering the further cell reprogramming immune. The extra production of the neutralizing molecule means any new exosome making their way into the same cell disabled, neutralized from effecting the cell further. This all done in sync allows for one treatment to be fairly uniform, systemic and safe against full reprogramming. Eventually the cell cleaned out and the receptoris cleared away and subsequent treatment can occur again. Exosomes are made by cells for intercellular communication containing RNA and proteins. Agonist or Antagonist.

Secondly, looking at the matter as probabilities and ascertaining the best protocol based on probabilities. Dosage, injection area and dispersion area. Many small doses rather than one big dose and so on. Some cells never receive a dose, while some receive every dose. Targeting areas or organs by place of injection.

Thirdly, there are some cells that concentrate relative to cell signalling system, such as certain stem cells that concentrate around inflammation. These behaviours might localize the effect and aid in probability, because once the inflammation is dissolved the gene therapy cannot go there twice. Inflammation might be a positive tag for the treatment.

Fourthly, liquid engineering, a dispersion lysate. A lysate added to the infusion to aid in a more ideal dispersion and against multiple infection of the same cell.

Fifthly, there are approximately three thousand GPCRs receptors on each cell, cell receptors for example produce vitamin D in response to light. Is there one that allows for favourable manipulation to control a vector, for the purpose of single dose to a single cell and binding for the duration of the treatment. Control the vector by magnetism. Beta blockers. Systemic AAV Vectors for Widespread and Targeted Gene Delivery in Rodents

At the very least probably experiment with a skin cream to test the saturation and dispersion or a localized area. The challenge is one of expertise, optimization. This therapy is not extreme or invasive but requires expertise. The path is mice, test on human skin, organs, and eventually full body infusion.

Transgenic Human Experiment

What would happen in the Yamanaka factors were installed in the germ line of human being. The same exeriment as the transgeneic mouse expressing Yamanaka factors. Once a human being has reached maturity it has trillions of cells, in terms of gene therapy the ability to communicate with each individual cell is a challenge. Instead, the genetic program could be installed in the ovum and during gestation when the body is made the program replicated in every cell thereafter, providing some interface for later access. This is called a “transgenic human”. Such a person could have extra abilities, such as, “safe Yamanaka factor expression in a transgenic human experiment”. The person would theorectically momentarily turn on safe Yamanaka factor expression with stimuli in order to maintain an ideal physical age in every appearance and measure, even if the person were to be of age 70, they would always look and feel like a 21-year-old. The experiment is currently possible to do. The transgenic human lives a normal life but never age, instead stop ageing at their ideal age. An ability we would all like to have. If the person wanted to age normally they would opt not to express the factors and age normally.

The companies at the forefront of human in vivo Yamanaka factor therapies are Turn Biotechnologies and Youthereum Genetics.

Finally,

https://medlineplus.gov/ency/article/004012.htm
https://news.mit.edu/2011/cell-aging-0624
https://www.nature.com/articles/npjamd20164
https://www.sciencedaily.com/releases/2018/06/180620125933.htm
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008429

Why do scientists always experiment on yeast?

Urine, ammonia as well as 4,000 chemicals are flushed by kidney renal function, so it proves there are many chemicals in the human body that need to be expelled. Death by renal failure occurs in several days which is nowhere near the massive tissue damage of only several minutes from oxygen interruption. The estimated number of damaging chemicals could be as high as 40,000 chemicals from an estimated production of over 100,000 chemicals in every cell. Cause dysfunction, toxicity, ageing, and cell death (see Free‐Radical Theory of Ageing). The presence of waste products changes the structural organization of the cell. Cellular components are displaced by these waste products and cellular functions such as cell signalling, transport of cellular molecules, and metabolic functions are impeded. Accumulation of waste materials within the cell can also cause damage, secondary to their toxicity, for example by the accumulation of toxic protein oxidation products in the cell or by an increased amount of reactive oxygen species.

Additional variables are the air we breathe and trace poisons such as arsenic, asbestos and exhausts and the food we eat and the pesticides, mercury and toxins in them. Another danger inadequate production due to malnutrition. There are other sources of toxic chemical reactions, such as endotoxins along with inhaled and ingested chemicals.

At the cellular level the human body is extremely fragile. The human body is highly technical and sophisticated operating on tight tolerances. Just how fragile, the potential of hydrogen (pH) of water in the human body is maintained at 7.365 (7.3 and 7.4). If pH drops to 6.9 the result is coma. At 6.8, death (same if pH rises to 7.8). If oxygen supply in your blood is interrupted for 4 minutes you are brain-dead, and 6 more minutes you are dead, anything lower than 4 minutes and massive tissue damage. Body temperature about 37°c with a deviation of 1 degree feeling illness and 42°c death. Normal fasting blood sugar levels are less than 100 mg/dL, with a deviation of 50 mg/dL, coma. Two out of three people with diabetes die from cardiovascular-related episodes, such as a heart attack or stroke.

The human body would cease to function if the outside world entered the tightly regulated inside world.

What keeps the outside world from instantly destroying and killing us are regulating systems, big organs. The false sense of strength comes from these regulating systems. These oprgan systems protect the ultra fragile inner system. Pancreas controls glucose, kidney filters blood. These systems detect changes and must move fast for these deviations cause tissue damage, coma, death. With aging these system lose their performance and result in declining health and death. While the young have robust regulation, with age your behaviour must adapt to account for natural dysregulation, you probably should not eat like a 25-year-old or even 40-year-old.

This means finding out about the performance of our organs and regulating systems and not contributing to the dysregulation, instead nursing. These include, Kidney function, Liver function<, Pancreas function

DNA is also under assault. Another belief is that renewal with perfect accuracy only gets you the maximum 122-year-old and life extension is a gene source or a neural time network source such as the suprachiasmatic nucleus in the hypothalamus. A healthy 25-year-old is a mean optimal health state. I have always thought if that state were implemented in anyone older they would be immortal. Some say that even if we implemented that state perfectly, a person would still die, given with no health issues and a maximum lifespan. We would then suspect programmed cell death or clock systems are ordering lifespan, a neural network in the brain, intercommunicating with peripheral clocks in organs or an abstract clock in the cell. Yeast also has programmed cell death machinery and the greatest extension of yeast lifespan are not damage ointments but regulation of genes.

The human body has repair systems, sometimes termed the regenerative system, an immune system, we also have regulation systems.

Immortalization, of an organism using evolutionary algorithms, performing diagnostic to elucidate these pathways and then proving these new pathways to a non-immortalized organism. Such organisms could be c.elegans or gastrotrichs. We have immortalized individual human cells and even yeast cells as a research tool, but I have not seen immortalization extended to an organism. Here we propose, using evolutionary algorithms, immortalize simple multicellular organisms and then do diagnostics as to the changes in the organism and then therapy into a normal lifespan length organism and then move to more complex organisms. We can use Planarian to chimera components if that aids, or perform the experiment on immortal planarian and attempt to immortalize a mortal planarian. Eventually attempt immortalization on a mammal, a mouse, and keep moving on up. After single cells, perhaps move to C.Elegan having 959/1031 cells. Immortality is this case, as we do not want to wait would be tripling the lifespan before attempting diagnostics with some candidates permitted to live beyond the exercise.

Article ends here. I hope you have enjoyed the article. There are many companies working in the field, if you are working on anything not mentioned in the field, please contact us and let us know and we will update the article. While being certain to exclude psychopathic, moronic, sadistic, insane, dangerous, invasive and painful procedures, they are many people that could be treated on compassionate grounds, such as attempting neurogenesis in demnetia patients.

Link List...

• https://www.fightaging.org/
• https://joshmitteldorf.scienceblog.com/
• https://www.cell.com/
• https://scihub.wikicn.top/
• https://www.lifespan.io/
• https://www.worldhealth.net/
• https://www.anti-agingfirewalls.com/
• https://www.vincegiuliano.name/
• https://www.sens.org/
• https://www.biorxiv.org/
• https://geroscience.com/
• https://www.longevity.technology/
• https://barefacedtruth.com/
• https://elifesciences.org/
• https://booksc.org/
• https://www.age-regression.com/
• https://www.antiaging-systems.com/
• https://www.longecity.org/forum/
• https://forum.age-reversal.net/
• https://foresight.org/tech-tree/

Video Channels...

• Lance Hitchings
• Brad Stanfield
• Life Extension Advocacy Foundation
• Bill Faloon
• Conquer Aging Or Die Trying!
• Institute of Human Anatomy
• blueprint.bryanjohnson.co

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