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

While people generally do not know what health is, asking many medical doctors, and academics how they define health, they do not know either. The human body however complex is after all engineering in physics, and the environment only allows a handful of options in the maintenance of any engineered structure and nature 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. The human body is a material structure that is subject to physical laws, tolerances and specifications. We define health as a state of the physiology and an optimal physiological state (homeostasis and 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 if a pipe is blocked, function becomes impossible and the organism dies. Jets suffer structural fatigue with use, and fuel pumps decline in function after an engineered amount of cycles. The human body is an analogue moving system, the leading cause of death is a pipe got blocked or the pump failed. All of this is theoretically quantifiable, a contrast in the definition of both states leaves only disease, measure and reverse. We currently do not have definitive quantification and even the therapies to theoretically maintain the machine indefinitely in an optimal state, unlike a restored vehicle, there are no replacement parts and any replacement parts are not compatible. Humans are basically a kind of robot that eventually stalls out and does not reboot. As long as the system functions in engineered tolerances, the state of the body is considered healthy, when the system falls out of tolerance, disability and eventual cease of function. Biota's super-power is self-healing, which extends the lifespan of the body, 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. Optimal performance of organs is priority important, as is the quality of re-synthesis.

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