Interesting story: He Got Schizophrenia. He Got Cancer. And Then He Got Cured
Summary of article: doi: 10.1038/s41569-018-0064-2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146930/
The articles elucidates inflammaging to some degree. We want to identify to mediate the inflammasome. Low levels of inflammation is an observation of centenarians. We want to understand the immunosuppressive properties of Rapamycin and its effectiveness at mediating the inflammasome or building a poly therapy to cleanly and safely mediate the inflammasome.
The inflammasome also effects age-related decline of regeneration.
Rapamycin is the premiere drug with lifespan extending properties and has interesting qualities beyond MTORC 1 inhibiton. Prolonged use of Rapamycin inhibits both MTORC1 and MTORC2 when only MTORC1 is needed. Achievable blood levels are inadequate due to immunosupressive qualities, there is some evidence that higher blood levels of Rapamycin would be more beneficial but these levels cannot be achieved with Rapamycin. Rapamycin does not cleanly mediate inflammaging.
Can we build a surperior version on paper? Or is Rapamycins life extending properties not related to MTOR1 inhibition at all.
The paper states that the immune system inhibits regeneration leading to cardio-vascular disease and general organ failure and is the source of frailty. This is done by exhausting the system by being over-active, inhibiting the regeneration system with mediators that block regeneration and even attacking the regeneration system in an autoimmune way.
It suggests that the aging immune system locks the body into a catabolic state, where androgenic and tissue building is blocked. It promotes calorie restriction and exercise, regardless of age.
Recently scientists released a full map of the immune system here, how the maps differs from young and old is unknown.
The recurring thought is to measure inflammation not in circulating factors but tissue by tissue, find its cause and refrain and change lifestyle. For disease to occur, even dementia, inflammation was the pre-condition because it is a sign of damage occurring. So testing similar to the continuous glucose monitors for instance would be a definitive class of pre-condition information.
Along with bringing the immune system back into homeostasis, there are inhibitors and receptor agonist molecules along with the potential toxcitity, side effects and safety.
- IL-1 receptor antagonist protein (IL-1RN)
- C-reactive protein (CRP)
- Transforming growth factor-β (TGFβ)
- Tumour necrosis factor (TNF) and its soluble receptors (TNF receptor superfamily members 1A and 1B)
- Serum amyloid A
A genome-wide association study comparing >2,000 Chinese centenarians to middle-aged controls found that the SNP rs2069837 in IL6 was significantly associated with extreme longevity, confirming the role of IL-6 in conditioning morbidity and mortality, especially in old age. Confirming the role of IL-6 in health, in a large Mendelian randomization analysis, the IL6R SNP rs7529229, marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala), was associated with increased circulating IL-6 levels. Variants in the IL6R gene have been found to be associated with increased risk of coronary artery disease, rheumatoid arthritis, atrial fibrillation, and abdominal aortic aneurysm, and with increased susceptibility to asthma, type 1 diabetes, and depression. Multiple SNPs in the CRP gene are associated with higher CRP levels and increased risk of myocardial infarction and CVD-related death.
Adipocytes in abdominal, intramuscular, liver, and pericardial fat can produce pro-inflammatory and chemotactic compounds, such as...
- C-C motif chemokine 2 (CCL2)
as well as hormones that modulate inflammation, such as...
The visceral fat tissue of obese individuals is infiltrated by T lymphocytes, macrophages, and monocytes. T lym-phocytes secrete IFNγ, which stimulates the production of several chemokines from adipocytes, including CCL2, CCL5, C-X-C motif chemokine 9 (CXCL9), and CXCL10, which further amplify tissue T cell migration. The number of B lymphocytes and macrophages in visceral adipose tissue from obese individuals is also increased and is correlated with BMI55. Studies with animal models suggest that a specific subset of B cells expressing the TNF ligand superfamily member 9 and producing TNF, IFNγ, and granzyme B is increased in the peritoneal cavity during ageing. Cytokines released by B cells contribute to the phenotypic switch of adipocytes in the visceral cavity, causing them to release adipokines, other pro-inflammatory markers, and cell debris. Activated monocytes that give rise to M1 and M2 macrophages produce even more inflammatory compounds that probably appear in the circulation.
Under-represented at older ages
Over-represented at older ages
Rapamycin: an anti-cancer immunosuppressant?
The mTOR signaling network contains a number of tumor suppressor genes including PTEN, LKB1, TSC1, and TSC2, and a number of proto-oncogenes including PI3K, Akt, and eIF4E, and mTOR signaling is constitutively activated in many tumor types. Rapamycin appears to inhibit tumor growth by halting tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis. Rapamycin immunosuppressant actions result from the inhibition of T and B cell proliferation through the same mechanisms that rapamycin blocks cancer cell proliferation. Rapamycin decreases the frequency of tumor formation that occurs in organ transplant experiments when combined with the widely used immunosuppressant cyclosporine compared with the tumor incidence observed when cyclosporine is used alone.
Evidence suggests that ageing is associated with a reduction in beneficial commensal microorganisms — such as...
— as well as a decrease in the Firmicutes: Bacteroidetes ratio
This category of microorganisms is enriched in the gut of older adults and is primarily dominated by facultative anaerobes — such as...
— a state that has been associated with increased levels of inflammatory cytokines in plasma
As beneficial intestinal bacteria decrease in abundance with ageing, other bacteria increase in relative abundance, including symbiotic bacteria that can become pathogenic under inflamed conditions, often termed pathobionts.
Centenarians, who can be considered extreme examples of healthy ageing, have an enrichment of...
in their intestinal flora, which promote positive immune function, have anti-inflammatory activity, diminish the effects of obesity, and contribute to metabolic homeostasis.
The list of these molecules is not comprehensive, and the molecules can vary on the basis of cell type and triggering factors but usually include...
- growth-regulated-α protein)
- growth factors (fibroblast growth factor 2 and hepatocyte growth factor),
- metalloproteinases (interstitial collagenase (also known as MMP1)
- stromelysin 1 (also known as MMP3)
- collagenase 3 (also known as MMP13))
and other insoluble proteins and extracellular matrix components. These secretory molecules mainly function in a paracrine fashion and can facilitate the development of cellular senescence in neighbouring cells, but some of the soluble mediators are released into the circulation and are likely to contribute to inflammageing
Impaired recycling and elimination of degraded cellular material may lead to imflammaging.
Under pathological conditions, molecules are released by stressed cells undergoing necrosis (such as during ischaemia– reperfusion or severe infection). These molecules, called DAMPs, include reactive oxygen species (ROS) from damaged and unrecycled mitochondria, extra-cellular nucleotides such as ATP, oxidized cardiolipin, free nuclear and mitochondrial DNA fragments or histones, high-mobility group protein B1, oxidized LDL, amyloid-β, islet amyloid polypeptide, and particulates such as monosodium urate and cholesterol crystals, in addition to many others. If not promptly removed, these molecules accumulate and possibly contribute to inflammageing.
Accordingly, inflammageing is proposed to originate from an imbalance between the production and disposal of cellular debris, misfolded proteins, and/or misplaced self-molecules that develops with age. For example, accumulation of DAMPs is sensed by the NLRP3 inflammasome and causes NLRP3 oligomerization, resulting in caspase 1-dependent secretion of the inflammatory cytokines IL-1β and IL-18. In humans, IL-18 blood levels increase with ageing, and strong evidence from mouse studies indicates that blockade of the NLRP3 inflammasome extends healthspan, attenuating multiple age-related degenerative changes that have been linked to inflammageing, including insulin resistance, thymic involution, T cell senescence, and bone loss as well as physical and cognitive function decline. Of note, ROS produced by dysfunctional mitochondria can also trigger an inflammatory response by activating the NF-κB signalling pathway.
Intrinsic defect in immune cells contributes to inflammaging
Gene-expression studies show that CD4+ lymphocytes from older individuals have higher intrinsic activation of the NF-κB pathways than those from younger individuals. After stimulation with anti-CD3, the production of pro-inflammatory cytokines in vitro is lower in cells from older individuals than in cells from younger individuals, a phenomenon that might be related to altered metabolic activity. However, because these studies have been performed only in small populations, their relevance to inflammageing is unknown.
Latent State Pathogens and Chronic Infections
Both latent state pathogens and chronic infection lead to over-active immune system and inflammaging, especially chronic infections, such as oral infection, asymptomatic chronic infection in the urinary and biliary tracts, and hidden intestinal infections, are associated with the release of PAMPs into the circulation, which elicits a persistent inflammatory state is believed to contribute to inflammaging. Proposes a strategy of protecting the immune system from pathogens.
This assumes that non-pathogenic, yet environmental cause of immune system activation should also be understood and avoided. So we have become the 911 operator for the immune system so that the immune system is activated only when its cause is legitimate and constantly spammed and pranked.
Potential causes of inflammageing
Several genetic variants associated with high levels of inflammatory markers or increased response to inflammatory stimuli have been identified; the most relevant factors are indicated in parentheses. In central obesity, visceral fat tissue is infiltrated by T cells, macrophages, and monocytes. T cells secrete IFNγ, which stimulates the production of several chemokines by adipocytes, including C-C motif chemokine 2 (CCL2), CCL5, C-X-C motif chemokine 9 (CXCL9), and CXCL10, which further amplify tissue T cell infiltration. The number of B cells and macrophages in visceral adipose tissue from obese individuals is also increased and is correlated with BMI55. A specific subset of B cells expressing the tumour necrosis factor (TNF) superfamily ligand superfamily member 9 and producing TNF, IFNγ, and granzyme B accumulates in the abdominal cavity of older individuals56. Cytokines released by B cells contribute to the phenotypic change of adipocytes in the visceral cavity, causing them to release adipokines, other pro-inflammatory factors, and cell debris52. Activated monocytes that give rise to M1 and M2 macrophages produce even more inflammatory compounds57. Damaged mitochondria that cannot be repaired by repeated cycles of fission and fusion and are not recycled owing to defective autophagy release damage-associated molecular patterns (DAMPs) that trigger the NLRP3 inflammasome and lead to caspase 1-dependent production of IL-1β and IL-18. Oxidative stress is one of the possible triggers of cell senescence, which can be induced by several other stressors, including epigenetic alterations. Senescent cells, through the senescence-associated secretory phenotype (SASP), secrete large quantities of cytokines, chemokines, and other molecules, locally triggering more cell senescence (paracrine senescence) and contributing to inflammageing. Studies have emphasized the role of age-related changes in the microbiome and increases in the gut mucosa permeability that lead to bacterial product release into the blood and stimulate an inflammatory response, in part through the NLRP3 inflammasome. In addition, part of inflammageing is probably caused by chronic infections (for example, human immunodeficiency virus (HIV) or human Cytomegalovirus (CMV) infection) and intrinsic defective mechanisms in immune cells that might involve metabolic stress as well as age-related changes in microRNA transcription. Of note, other important triggers of cell senescence, such as genomic instability, the activation of oncogenes, and the inhibition of tumour-suppressor genes, are not shown in the figure but might be part of the same mechanism.
Inflammageing is a risk factor for multiple chronic diseases.
Inflammageing, defined as an age-related increase in the levels of pro-inflammatory markers in blood and tissues, is a strong risk factor for multiple diseases that are highly prevalent and frequent causes of disability in elderly individuals but are pathophysiologically uncorrelated. Mild chronic inflammation is generally considered to be a biomarker of accelerated biological ageing or one of the mechanisms by which the ageing process is associated with increased global susceptibility to all diseases. Cardiovascular diseases, chronic kidney disease, cancer, depression, dementia, osteoporosis, sarcopenia, and anaemia are shown in the figure as examples because extensive evidence indicates that inflammation contributes to the development of these diseases in old age, but the list is far from exhaustive3,138,139,142,143,196. Concordant with this view, elevated blood levels of pro-inflammatory markers (such as IL-6) are a powerful risk factor for multimorbidity (the number of coexisting diseases) and predict future rates of change in multimorbidity. Unsurprisingly, inflammageing is also a strong risk factor for typical geriatric conditions, such as physical and cognitive disability, frailty, and premature death. Although this effect is primarily mediated by multimorbidity, evidence also indicates that inflammation interferes with the maintenance and repair that constantly occur in all tissues, leading to accumulation of damage that contributes to frailty.
Cholesterol crystals and other DAMPs present in the atherosclerotic lesion activate the inflammasomes within macrophages, leading to the release of IL-1β, IL-18, and other pro-inflammatory cytokines that are chemotactic for other inflammatory cells, including T cells and B cells, which are major drivers of atherosclerosis.
Observation that Rapamycin inhibits proliferation of T and B cells.
Cells in advanced atherosclerotic plaques often show markers of senescence, such as p16INK4A and tumour suppressor ARF (commonly known as p14ARF in humans and p19ARF in mice), and express a SASP that further fuels inflammation while producing metalloproteinases that degrade the extracellular matrix, further destabilizing the atherosclerotic plaque.
Mendelian randomization analyses in large populations suggest that CRP is a predictive biomarker that is not causally related to atherothrombosis. By contrast, IL-6 and IL-1 contribute to atherosclerosis and should be considered to be therapeutic targets, mentioning IL-6 receptor blocker tocilizumab, IL-1β signalling pathway has been suggested to be a promising target for atherothrombosis protection. New compounds that interfere with IL-1 and IL-6 signalling are under investigation, anti-inflammatory therapy with canakinumab, a human monoclonal anti-IL-1β antibody, significantly reduced recurrent cardiovascular events, anti-inflammatory therapy with canakinumab, a human monoclonal anti-IL-1β antibody, significantly reduced recurrent cardiovascular events.
In addition, because IL-1β production is a secondary effect of NLRP3 inflammasome activation, which is induced by cholesterol crystals and other DAMPs, the IL-1β signalling pathway has been suggested to be a promising target for atherothrombosis protection. New compounds that interfere with IL-1 and IL-6 signalling are under investigation. The CANTOS trial has revealed that anti-inflammatory therapy with canakinumab, a human monoclonal anti-IL-1β antibody, significantly reduced recurrent cardiovascular events in >10,000 stable patients who had residual inflammation after myocardial infarction, independent of lowered lipid levels. The ongoing CIRT trial is testing the hypothesis that low-dose methotrexate, a drug that suppresses IL-1β production by mononuclear cells in addition to other functions, reduces major vascular events in patients with previous myocardial infarction and either type 2 diabetes or metabolic syndrome. In a small pilot study (the LoDoCo trial), anti-inflammatory treatment with colchicine seemed to be effective for secondary prevention of CVD. Larger RCTs, such as the ongoing LoDoCo2 trial and COLCOT trials, are needed to confirm these findings.
Treating inflammation in non-CVDs.
Treatment with TNF inhibitors in psoriasis is also associated with decreased incidence of major adverse cardiac events. However, anti-inflammatory treatment does not always yield beneficial effects. For example, in patients with congestive heart failure, the levels of pro-inflammatory cytokines, especially TNF, IL-6, and IL-1, are markedly elevated, and the TNF level is a negative prognostic factor. However, clinical trials with the TNF inhibitor etanercept yielded no beneficial reductions in mortality or hospitalization due to congestive heart failure, whereas high doses of infliximab, a TNF antagonist, did not improve and even worsened moderate-to-severe congestive heart failure.
Multimorbidity and frailty
Diseases most often associated with multimorbidity are diabetes, chronic kidney disease, anaemia, chronic pulmonary disease, depression, and dementia, all involve inflammageing as an important risk factor. Inflammation has a central role in age-related neuro-degeneration and in neurodegenerative diseases, such as Alzheimer disease. Inflammation is a causal factor for cancer initiation, promotion, malignancy, and metastatic dissemination.
The collective evidence suggests that chronic inflammation is a risk factor across multiple diseases, some of which are traditionally viewed as pathophysiologically unrelated, such as CVD, diabetes, chronic kidney disease, cancer, depression, and dementia.
The first reponse to damage in the human body is inflammation. Inflammation can drive inflammation and be exhaustive and damaging to the human body. A pro-inflammatory immune system inhibits regenerative compnents of the immune system and even attack stem cells.
Inflammation is associated with reduced synthesis and activity of insulin-like growth factor I (IGF1), a growth factor that is essential for muscle regeneration and maintenance of muscle integrity and that is protective against plaque instability in atherosclerosis. In vitro studies have shown that IL-1α, IL-6, and TNF inhibit IGF1-mediated anabolism and that IL-6 reduces the production of IGF1 and IGF-binding protein 3. In observational studies, high levels of IL-6 and low levels of IGF1 synergistically correlate with lower muscle strength and power, effectively predicting progressive disability and death. Inflammation impairs endothelial reactivity and muscle perfusion, interfering with the uptake of long branched-chain amino acids that are essential for muscle energetics and protein anabolism. Dysfunctional mitochondria that are not recycled owing to defective mitophagy produce ROS that stimulate the production of pro-inflammatory cytokines and catabolism via increased NF-κB-dependent protein ubiquitylation and proteasome degradation. Moreover, inflammation impairs satellite cell regenerative function
Inflammation is associated with anabolic resistance in muscle, which is caused partly by inhibition of the perfusion adjustment to anabolic stimuli and partly by inhibition of IGF1 production and signalling. Chronic inflammation causes anaemia via direct inhibition of iron absorption and recycling as well as interference with erythropoietin production and signalling. Evidence indicates that inflammation causes insulin resistance. In particular, TNF receptor superfamily member 1A and Toll-like receptor 4 block insulin signalling through Janus kinase activation, which causes serine phosphorylation of insulin receptor substrate 1 and 2, contributing to insulin resistance. Conversely, evidence also indicates that insulin resistance promotes the accumulation of M1 macrophages and fosters inflammation in adipose tissue through the production of CCL2. Pro-inflammatory cytokines — including IL-1β, IL-6, IL-11, IL-15, IL-17, and TNF — stimulate bone resorption and almost certainly contribute to osteoporosis285. For example, bone resorption is increased in patients with inflammatory diseases, such as rheumatoid arthritis286. Studies in cultured cells show that IL-1β, IL-6, and TNF induce mitochondrial dysfunction with reduced ATP synthesis-driven respiration, reduction of the NAD+:NADH ratio, and reduced mRNA levels of PPARGC1A (encoding peroxisome proliferator-activated receptor-γ co-activator 1α; PGC1α), suggesting that mitochondrial biogenesis is impaired287. Studies conducted both in vitro and in animal models suggest that inflammation in general, and IL-1β and IFNα in particular, inhibit neurogenesis and reduce the magnitude of neurogenesis that is normally induced by exercise.
Interestingly, results from the CRATUS trial demonstrated that administration of allogeneic human mesenchymal stem cells improves measures of lower-extremity performance and reduces inflammatory biomarkers in age-related frailt.
Consistent with this observation, both higher baseline levels and increasing accumulation rates of IL-6 predict accelerated longitudinal accumulation of multiple chronic diseases in older individuals.
Understand what triggers inflammation and avoid the triggers but we have no means to measure.
During an infection that unleashes an inflammatory response, the physiological and metabolic state of the organism is focused on defence, and all other anabolic activities are paused, including nondefensive functions of the immune system, such as surveillance of damage and continuous repair in tissue, which mostly rely on growth factors. If this condition is temporary, turnover and repair of macromolecules, organelles, and cells can be delayed, avoiding irreversible damage. However, in older individuals, inflammation remains chronically activated, either because of continued stress from the inflammation source or because of a primary immune dysregulation. In the absence of macromolecular and organellar recycling, the accumulation of damage can reach a critical threshold, thereby causing severe functional consequences that become difficult or impossible to reverse, conferring the clinical syndrome of frailty.
Inflammageing induces a catabolic state.
Inflammation causes pathological states linked with frailty, cardiovascular disease, and ageing. Sarcopenia: the induction of anabolic resistance in muscle inhibits the perfusion adjustment to anabolic stimuli as well as insulin-like growth factor (IGF1) production and signalling. Anaemia: chronic elevation of IL-6 levels causes anaemia through the production of hepcidin, reduction of the transmembrane iron transporter ferroportin, and inhibition of iron absorption and recycling as well as interference with erythropoietin (EPO) production and signalling. Insulin resistance: tumour necrosis factor receptor superfamily member 1A (TNF-R1) and Toll-like receptor 4 (TLR4) block insulin signalling through Janus kinase (JAK) activation, which causes serine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2, contributing to insulin resistance. Osteoporosis: TNF, IL-1β, IL-6, and TNF ligand superfamily member 11 (RANKL) contribute to osteoporosis by stimulating osteoclast growth and activity and inhibiting the production of osteocalcin. Mitochondria biogenesis: studies in vitro show that TNF, IL-1β, and IL-6 induce mitochondrial dysfunction with reduced ATP synthesis-driven respiration, a reduced NAD+:NADH ratio, and reduced mRNA levels of PPARGC1A (encoding peroxisome proliferator-activated receptor-γ co-activator 1α; PGC1α), suggesting impairment in mitochondrial biogenesis. Neurogenesis: pro-inflammatory cytokines interfere with the biological activity of neuronal growth factors, such as brain-derived neurotrophic factor, thereby affecting neurogenesis and plasticity. Accordingly, the addition of IFNα to human hippocampal progenitor cells reduces neurogenesis. These are just few examples of how chronic inflammation promotes a catabolic state, suggesting a possible unifying hypothesis. During an acute bout of inflammation, induced for example by an infection, the surveillance of damage and continuous repair functions in multiple tissues are chronically inhibited, leading to accumulated damage in organelles and macromolecules. Over time, this damage accumulation across different tissues and organs could become so severe that it cannot be compensated for and causes irreversible frailty.
- High levels of pro-inflammatory markers in the blood and other tissues are often detected in older individuals and predict the risk of cardiovascular diseases, frailty, multimorbidity, and decline of physical and cognitive function.
- In individuals with obesity, visceral fat produces pro-inflammatory and chemotactic compounds and is infiltrated by macrophages, lymphocytes, and senescent cells with a senescence-associated secretory phenotype that contributes to inflammageing.
- Mechanisms potentially underlying inflammageing include genomic instability, cell senescence, mitochondria dysfunction, microbiota composition changes, NLRP3 inflammasome activation, primary dysregulation of immune cells, and chronic infections.
- Clinical trials suggest that modulating inflammation prevents cardiovascular diseases, but studies to explore the effects on other chronic diseases, frailty, and disability are scarce and controversial.
- Inflammageing can complicate the clinical features of cardiovascular disease in older individuals by causing an energetic imbalance towards catabolism and interfering with homeostatic signalling, leading to frailty.
There are more pro-inflammatory cytokines such as IL33, IL-15, IL-17 Promoting tissue regeneration by modulating the immune system
Some proposed supplements that lower inflammation.
- PQQ - Pyrroloquinoline Quinone, Suppress IL6, CRP
- Vit K2 - Menaquinone-7, Suppress IL6 and genes involved in acute inflammatory response
- Vit D - Increases IL10, Decreases IL6 & TNFalpha, activates MKP-1 Interrupting LPS inflammation
- Acetyl-L-Carnitine, documented anti-inflammatory
- Ubiquinone (CoQ10), Decreases LPS-induced NFkB activation, PGE-2, IL1 and IL6 and proteases such as collaganese (MMP-1)
- Melatonin, Blocks TNF alpha, IL6, and IL1 beta
In conclusion, the table of charts for cytokines and chemokines.
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