Fight Aging!

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Contents

• RAS/MAPK Pathway Inhibition as an Example of the Way in Which Cancer Research Informs Aging Research
• An Interesting Delivery Method for GDF11
• Mitochondrial Stress Provokes Inflammation via Fragments of Mitochondrial DNA
• A Few Years of Difference in Life Expectancy Between Poorest and Wealthiest in Spain
• In Health and Mortality, Do Human Genetic Variants Matter More With Age Or Less With Age?
• GATA4 and Cellular Senescence
• Patients Suffering From More Age Related Conditions Exhibit a Greater Risk of Dementia
• More On Depletion of Soluble Amyloid-β in Alzheimer's Disease
• Is Blood-Brain Barrier Dysfunction Cause or Consequence in Alzheimer's Disease Pathology?
• Cellular Senescence and Abdominal Aortic Aneurysm
• Centrophenoxine Is Not That Interesting
• Cancers Force T Cells into Senescence
• A Complex Systems View of the Biology of Aging
• Cognitively Healthy Centenarians are Resistant to Age-Related Brain Pathology
• High Allostatic Load Correlates with Greater Risk of Cancer Mortality

RAS/MAPK Pathway Inhibition as an Example of the Way in Which Cancer Research Informs Aging Research
https://www.fightaging.org/archives/2022/10/ras-mapk-pathway-inhibition-as-an-example-of-the-way-in-which-cancer-research-informs-aging-research/

A sizable number of potential approaches to slowing aging via metabolic manipulation were first tested in the cancer research community. In part, this is because that side of the research community has tested near every compound in the libraries at some point in time, but it is also the case there are deep ties between approaches that might impact cancer and changes that might slow aging. This is particularly the case in the matter of cellular senescence, of great relevance to both cancer and aging, and the first senolytic drugs to clear senescent cells had already seen some success in the cancer field. In at least one case, dasatinib, this success is likely precisely because it is a senolytic, and senescent cells encourage growth of the leukemias that the dasatinib is used to treat.

More often, however, the outcome for aging is not as dramatic as is the case for senolytics. Slowing aging is a usually a marginal affair, achieved by triggering cellular stress response mechanisms, or influencing growth and energy metabolism in some way. The gains in humans will most likely be much smaller than those achieved in mice, judging from the existing points of comparison, such as practice of calorie restriction, or populations with loss of function mutations affecting growth hormone signaling, such as Laron syndrome. Today's open access paper is an example of this sort of age-slowing intervention, well-explored in the cancer research community, and which may gain some interest in the aging research community. Yet we shouldn't expect this to result in any wondrous new therapies to treat aging in humans.

Molecular inhibition of RAS signalling to target ageing and age-related health

Ageing research in model organisms has led to the rapid discovery and genetic dissection of key ageing pathways, including the RAS/MAPK signalling pathway. Genetic interventions that modulate signalling through RAS proteins and their downstream effectors have been shown to increase lifespan in these model systems and to improve multiple parameters of health, both during normal ageing and in animal models of age-related disease. RAS/MAPK signalling therefore adds to an emerging theme that manipulating cancer-promoting pathways, either by inhibiting the function of oncogenes or by increasing the activity of tumour suppressors, can affect healthy ageing.

Examples from rodent models that extend lifespan include Myc haploinsufficiency, extra genomic copies of the Ink4/Arf locus, that elevate expression of its encoded tumour suppressor proteins p16 and p14, and increased gene dosage of the tumour suppressor Pten, or mimicking its activation through genetic inhibition of its direct target, PI3K. Interestingly, although some these models had reduced cancer incidence, researchers also observed lifespan extension in cancer-free animals, suggesting that delayed ageing may not simply be a consequence of protection against cancer.

The prominent role of RAS/MAPK signalling in cancer has led to the isolation of several small molecule inhibitors of the pathway, and some are already in clinical use. Recent work with model organisms suggests that these same compounds may provide beneficial effects on age-related health. Thus, repurposing these anti-cancer treatments could provide a useful strategy to develop novel interventions to promote healthy ageing. Moreover, other pro-longevity pharmacological interventions may elicit their effects on ageing and age-related health, at least in part through perturbations in RAS/MAPK signal transduction. It should be noted, though, that compounds like metformin, acarbose, dihydromyricetin, and statins have much broader effects, and, although they have an impact on RAS/MAPK outputs, they do not exclusively target this pathway.

However, cancer therapeutics, including small molecule inhibitors of RAS/MAPK signalling, are notoriously toxic and can elicit severe side effects. Effective strategies to limit these adverse effects will therefore be essential for clinical implementation. Determining the critical time periods during the life course when RAS/MAPK inhibition modulates ageing, and assessing the effect of intermittent dosing, could be one such approach to minimise side effects. Careful titration will also help to provide the geroprotective effects of these drugs without side effects or drug resistance.

An Interesting Delivery Method for GDF11
https://www.fightaging.org/archives/2022/10/an-interesting-delivery-method-for-gdf11/

GDF11 was one of the earliest allegedly beneficial factors identified in parabiosis experiments, in which young and old mice have their circulatory systems joined. Researchers saw higher levels of GDF11 in younger mice, and proposed that increased GDF11 signaling was a meaningful mechanism to explain the observed improvement in function of tissues in older mice. Following on from that, there has been considerable, continuing debate over whether or not this is in fact the case.

A company, Elevian, was founded to build GDF11-based therapies, and claims to have resolved much of that controversy. Still, later studies have demonstrated very convincingly that parabiosis benefits derive from a dilution of harmful circulating molecules in the circulation of old mice, rather than the delivery of beneficial molecules from young mice. It remains to be seen as to where this broad area of research will lead, an increased interest in plasma dilution and replacement of albumin are the latest developments.

Along the way, a few studies have suggested that delivery of recombinant GDF11 or upregulation of GDF11 expression can produce benefits in mice, such as reduced inflammatory signaling or other improvements in metabolism. Today's open access paper is a recent example. It is noteworthy for the delivery method used, which is quite intriguing. The researchers produced a yeast lineage that expresses GDF11, and fed the yeast to the mice in their diet, resulting in delivery of that GDF11 to the circulation. One might wonder how many other proteins would survive the oral administration route via this approach.

Dietary intake of GDF11 delays the onset of several biomarkers of aging in male mice through anti-oxidant system via Smad2/3 pathway

Since the discovery of GDF11 as a "youth factor", it has become a "hot" molecule in the field of anti-aging study. Yet there is still controversy over the age-related change in concentration of GDF11 and its role in the genesis of rejuvenation conditions. With the aid of a highly specific anti-GDF11 antibody, here we show that GDF11 concentration declines with age in male mice, confirming the results of ours and others that blood GDF11 abundance reduces with age in both fish and mouse as well as humans.

In this study, we displayed rGDF11 on the surface of the yeast Yarrowic Lipolytica, and proved the bioavailability of the yeast-displayed rGDF11 by oral delivery in aged male mice. On the basis of these findings, we started to explore the anti-aging activity and underlying mechanisms of displayed rGDF11. It was found that dietary intake of displayed rGDF11 had little influence on the body weight and biochemical parameters of aged male mice, but delayed the occurrence and development of age-related biomarkers such as lipofuscin and senescence-associated-β-galactosidase, and to some extent, prolonged the lifespan of aged male mice.

Moreover, we demonstrated once again that dietary intake of displayed rGDF11 enhanced the activity of anti-oxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX), reduced the reactive oxygen species (ROS) level, and slowed down the protein oxidation and lipid peroxidation. Importantly, we showed for the first time that rGDF11 enhanced the activity of CAT, SOD, and GPX through activation of the Smad2/3 signaling pathway. Our study also provided a simple and safe route for delivery of recombinant GDF11, facilitating its therapeutic application in the future.

Mitochondrial Stress Provokes Inflammation via Fragments of Mitochondrial DNA
https://www.fightaging.org/archives/2022/10/mitochondrial-stress-provokes-inflammation-via-fragments-of-mitochondrial-dna/

A large body of evidence links mitochondrial dysfunction with chronic inflammation. These are both features of aging, but it appears that dysfunctional, stressed mitochondria are a meaningful cause of inflammatory signaling. Mitochondria can generate molecular fragments, such as pieces of mitochondrial DNA, that are recognized as potentially threatening by the innate immune system. These damage-associated molecular patterns are present in much greater amounts in old tissues, and the immune system reacts to them to produce lasting, unresolved inflammation, harmful to tissue function rather than protective.

In today's research materials, scientists report on their investigation of how exactly it is that mitochondrial DNA fragments are ejected from cells to then provoke an immune response. Understanding the details of the processes involved may reveal points of intervention that can be used to suppress age-related chronic inflammation. The researchers here suggest FEN1 inhibition as a possibility, as this protein is involved in producing the fragments of DNA that then exit the cell to act as damage-associated molecular patterns.

How Mitochondrial Damage Ignites the "Auto-Inflammatory Fire"

When stressed, damaged or dysfunctional, mitochondria expel their DNA (mtDNA), oxidized and cleaved, into the cytosol - the fluid within a cell in which organelles float - and beyond into the bloodstream, triggering inflammation. In autoimmune conditions like lupus and rheumatoid arthritis, the amounts of circulating oxidized mtDNA correlate with disease severity, flare-ups, and how well patients respond to therapies. An unanswered question that has plagued the field is whether oxidized mtDNA is simply a biomarker or indicator of disease or something more: a critical player in disease pathology.

In a new study, researchers describe the biochemical pathway that results in the generation of oxidized mtDNA, how it is expelled by mitochondria and how it triggers the complex and destructive inflammatory response that follows. "In addition to charting a new pathway responsible for the generation of inflammation-provoking fragments of oxidized mtDNA, this work opens the door to the development of new anti-inflammatory agents."

Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

Mitochondrial DNA (mtDNA) that escapes from stressed mitochondria acts to provoke inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation.

Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 base pair fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.

A Few Years of Difference in Life Expectancy Between Poorest and Wealthiest in Spain
https://www.fightaging.org/archives/2022/10/a-few-years-of-difference-in-life-expectancy-between-poorest-and-wealthiest-in-spain/

Wealth, and the closely related construct of socioeconomic status, correlate with life expectancy. Wealth also correlates with environmental exposure to air pollution, as wealthier people tend to live in better surroundings, intelligence, education, access to and effective use of medical services, lifestyle choices that impact health, and a range of other line items that are also correlate with life expectancy.

Picking out the important mechanisms that directly impact long-term health and mortality risk is a challenge, for all that it is tempting to point to the obvious candidates of excess weight and smoking habits, both of which are individually accompanied by a great deal of evidence for the size of effect and strength of correlation. There are always other mechanisms! Intelligence is suggested to have genetic contributions that overlap with those determining physical robustness, for example.

This is the usual story in human epidemiology: correlations abound, but identifying actionable, harmful mechanisms for intervention is difficult. There is a very good mechanistic argument that reducing particulate air pollution will reduce chronic inflammation and cardiovascular mortality. But is that a significant contribution in comparison to the choice to smoke, or the choice to become obese? Individuals can look at the research and make sensible choices in an environment of uncertainty surrounding the details, to the best of their ability, and that may be all that can come of it at the end of the day.

Association of socioeconomic deprivation with life expectancy and all-cause mortality in Spain, 2011-2013

Life tables summarise a population's mortality experience during a time period. Sex- and age-specific life tables are needed to compute various cancer survival measures. However, mortality rates vary according to socioeconomic status. We present sex- and age-specific life tables based on socioeconomic status at the census tract level in Spain during 2011-2013 that will allow estimating cancer relative survival estimates and life expectancy measures by socioeconomic status.

Life expectancy (LE) at birth was higher among women than among men. Women and men in the most deprived census tracts in Spain lived 3.2 and 3.8 years less than their counterparts in the least deprived areas. Overall, we found a consistent LE gap at birth according to socioeconomic status for both sexes in Spain during the 2011-2013 period. However, the gap was wider among men than among women, with the least deprived male group experiencing shorter LE at birth than the most deprived female group. Furthermore, we found a geographical pattern characterised by shorter LE at birth in the southwest for both sexes in Spain.

Furthermore, our results on LE at birth by deprivation are consistent with those of other European studies. In the UK, LE at birth in 2005 presented a similar pattern, with the highest LE in the most affluent groups compared to the most deprived group, with a gap between 2.7 and 5.0 years for males and between 2.5 and 3.6 years for females. Overall, differences in LE are seen by deprivation and by region, and the regions with higher LE are also the least deprived. Similar to the geographical pattern found in Spain, a regional pattern characterised by a clear north-south gradient was found in the UK, with deprivation explaining most of the geographical variation in LE.

In Health and Mortality, Do Human Genetic Variants Matter More With Age Or Less With Age?
https://www.fightaging.org/archives/2022/10/in-health-and-mortality-do-human-genetic-variants-matter-more-with-age-or-less-with-age/

To what degree do genetic variants drive the observed differences in human life expectancy? The old consensus guesstimate was that environment determines 75% of life expectancy, and genetic variants the other 25%. Further, it is the common wisdom that gene variants become more important to life expectancy in later life, either by providing greater resilience to specific forms of damage and dysfunction, or slowing the pace at which that damage and dysfunction accumulates. A great deal of medical research is based on the insight that gene variants are thought to provide on disease processes.

Views on genetic variants are changing, however. Modern research that makes use of genetic databases that cover very large populations is trending in the direction of demonstrating that ever smaller contributions to life expectancy arise from genetic variants. As the importance of genetic variants diminishes, the importance of environmental factors and lifestyle choices becomes ever greater, and the value of research into genetic variations and aging becomes more questionable.

Today's research materials discuss a recent study in which the authors provide data to suggest that gene variants become less important with age, that their contribution to emergent differences in cell metabolism is outweighed by other factors. This, like the genetic studies on large populations, is an attack on the value of research programs that focus on gene variants in the context of age-related disease. There are a great many such programs, as well as ongoing searches for new variants that might be useful to investigate more deeply. If gene variants largely do not tend to usefully predict cell and tissue behavior across an aged population, then then other high-level research strategies may well prove to be more cost-effective in the long term.

Age vs. genetics: Which is more important for how you age?

In a study of the relative effects of genetics, aging, and the environment on how some 20,000 human genes are expressed, the researchers found that aging and environment are far more important than genetic variation in affecting the expression profiles of many of our genes as we get older. The level at which genes are expressed - that is, ratcheted up or down in activity - determines everything from our hormone levels and metabolism to the mobilization of enzymes that repair the body.

while our individual genetic makeup can help predict gene expression when we are younger, it is less useful in predicting which genes are ramped up or down when we're older - in this study, older than 55 years. Identical twins, for example, have the same set of genes, but as they age, their gene expression profiles diverge, meaning that twins can age much differently from each other. The findings have implications for efforts to correlate diseases of aging with genetic variation in humans. Such studies should perhaps focus less on genetic variants that impact gene expression when pursuing drug targets.

The findings are in line with Medawar's hypothesis: Genes that are turned on when we are young are more constrained by evolution because they are critical to making sure we survive to reproduce, while genes expressed after we reach reproductive age are under less evolutionary pressure. So, one would expect a lot more variation in how genes are expressed later in life. "Across all the tissues in your body, genetics matters about the same amount. It doesn't seem like it plays more of a role in one tissue or another tissue. But aging is vastly different between different tissues. In your blood, colon, arteries, esophagus, fat tissue, age plays a much stronger role than your genetics in driving your gene expression patterns."

Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Overall this work has several important implications. Our results shed light on recent work on the prediction accuracy of polygenic risk scores (PRS) which found that numerous factors, including age, sex, and socioeconomic status can profoundly impact the prediction accuracy of such scores even in individuals with the same genetic ancestry. Our results highlight that genetics exhibit varied predictive power in several different tissues as a function of age, potentially playing a role in differential PRS accuracy between young and old individuals.

This also has important implications for disease association and prediction approaches that leverage expression quantitative trait loci (eQTLs) to prioritize variants. If a significant proportion of eQTLs exhibit age-associated biases in their effect size in a tissue of interest, then these approaches may be less powerful when applied to diseases for which age is a primary risk factor such as heart disease, Alzheimer's disease, cancers, and diabetes.

GATA4 and Cellular Senescence
https://www.fightaging.org/archives/2022/10/gata4-and-cellular-senescence/

Researchers have in the past connected GATA4 expression to various age-related conditions, such as scarring in heart tissue. Here, they link GATA4 to cellular senescence, which is also implicated in many of the same conditions. Senescent cells accumulate with age, and their pro-growth, pro-inflammatory signals are disruptive to tissue function throughout the body. In recent years the evidence for clearance of senescent cells via senolytic therapies to be beneficial in older individuals has prompted greater research to connect cellular senescence to many other lines of research in the context of aging and age-related disease.

DNA damage can activate Ataxia telangiectasia-mutated serine/threonine kinase (ATM) and Rad3-related serine/threonine kinase (ATR), after which p53 activates p21, stopping the cell cycle and inducing cell senescence. GATA4 is a transcription factor that regulates signal response processes in many organs, such as cardiac precursor cell differentiation, cardiac development, cardiac hypertrophy, and resistance to apoptosis, as well as mediating the effects of genetic mutations caused by congenital heart disease.

GATA4 regulates proteins in a context-dependent manner, thereby performing multiple functions. It has been reported that GATA4 is regulated upstream by the DNA damage response (DDR) pathway co-opting ATM and ATR, and downstream in a manner different from the conventional DDR pathway, leading to senescence. GATA4 is regulated by ATM and ATR, which inhibit the binding of p62 and GATA4 to inhibit selective lineage autophagy of GATA4, thereby activating NF-κB, leading to cellular senescence. In addition, alterations in the GATA4 signaling pathway have been frequently observed in various age-related diseases, including atherosclerosis and heart failure.

This paper reviews the mechanisms through which the DDR signaling pathway leads to cellular senescence, the involvement of the GATA4 factor in these processes, as well as the link to atherosclerosis and heart failure. This provides many possibilities to invent a drug to inhibit GATA4 activity and thereby prevent cell senescence, but there are still many problems to be solved.

Patients Suffering From More Age Related Conditions Exhibit a Greater Risk of Dementia
https://www.fightaging.org/archives/2022/10/patients-suffering-from-more-age-related-conditions-exhibit-a-greater-risk-of-dementia/

The growing burden of age-related cell and tissue damage, and consequent dysfunction, manifests in later stages as the presence of age-related conditions. The more age-related diseases that a person has, the greater the risk of the later onset of other conditions, simply because the underlying level of dysfunction and damage is high. Thus in this epidemiological study we see the expected correlation between the existence of multiple age-related conditions and greater risk of the onset of dementia. The best path forward to improve health in later life is to focus on the underlying damage, not the conditions themselves. Striking at the root of aging, successfully reversing the cell and tissue damage that causes aging, will improve all aspects of health.

Individual conditions have been identified as risk factors for dementia; however, it is important to consider the role of multimorbidity, as conditions often co-occur. This study investigated whether multimorbidity is associated with incident dementia and whether associations vary by different clusters of disease and genetic risk for dementia. The study used data from the UK Biobank cohort, with baseline data collected between 2006 and 2010 and with up to 15 years of follow-up. Participants included women and men without dementia and aged at least 60 years at baseline. The presence of at least 2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity.

A total of 206,960 participants (mean age 64.1 years) were included in the final sample, of whom 89,201 participants (43.1%) had multimorbidity. Over a mean of 11.8 years of follow-up, 6,182 participants (3.0%) developed dementia. The incidence rate was 1.87 per 1,000 person-years for those without multimorbidity and 3.41 per 1,000 person-years for those with multimorbidity. In Cox proportional hazards models adjusted for age, sex, ethnicity, education, socioeconomic status, and APOE-ε4 carrier status, multimorbidity was associated with an increased risk of incident dementia (hazard ratio [HR], 1.63).

The highest dementia risk was observed for the hypertension, diabetes, and coronary heart disease cluster (HR 2.20) and pain, osteoporosis, and dyspepsia cluster (HR 2.00) in women and in the diabetes and hypertension cluster (HR 2.24) and coronary heart disease, hypertension, and stroke cluster (HR 1.94) in men, compared with no multimorbidity. The associations between multimorbidity and dementia were greater in those with a lower genetic risk of dementia (HR 1.96) than in those with a higher genetic risk of dementia (HR 1.39). Similar findings were observed when stratifying diseases clusters by genetic risk for dementia.

More On Depletion of Soluble Amyloid-β in Alzheimer's Disease
https://www.fightaging.org/archives/2022/10/more-on-depletion-of-soluble-amyloid-%ce%b2-in-alzheimers-disease/

If slow amyloid-β aggregation over years is the cause of Alzheimer's disease, then how to explain the older individuals who have high levels of amyloid-β in the brain, but do not suffer from Alzheimer's disease? Further, how to explain the failure of amyloid-β clearance via immunotherapy in clinical trials? Amyloid-β is successfully cleared from the brain, but patient outcomes do not improve meaningfully. This line of thinking led to the hypothesis, with supporting evidence, that amyloid-β aggregation is pathological only because it depletes levels of soluble amyloid-β. It doesn't cause that issue to the same degree in every older individual, however, and individuals who manage to maintain high levels of soluble amyloid-β avoid Alzheimer's disease even when they have a large burden of amyloid-β aggregates.

Key support for the toxic amyloid hypothesis comes from the observation that mutations in any of three genes (APP, PSEN1, and PSEN2) lead to Alzheimer's disease (AD). The genetic evidence causally implicates the fibrillogenic 42-amino acid amyloid-β peptide (Aβ42). However, the disease pathogenesis may arise from either of two ends of the protein aggregation process: the increase in insoluble amyloid plaques or the depletion of the soluble Aβ42 peptide, which has important functions. While insoluble amyloid plaques can be present in normal individuals, low soluble levels of Aβ42 are an invariable feature of AD.

The hypothesis of Aβ toxicity has traditionally been supported by the notion that AD-causing mutation carriers must have high levels of soluble Aβ42 relative to non-mutation populations. In fact, mutation carriers have lower Aβ42 levels compared to non-mutation populations. The reduction in soluble Aβ42 levels among mutation carriers begins as many as 25 years before the onset of cognitive symptoms. Therefore, the toxicity in the process of accelerated protein aggregation among mutation carriers may conceivably be due to the depletion in soluble Aβ42 to a greater extent than the corresponding increase in amyloid. This alternative hypothesis offers an explanation for the failures in translating amyloid reduction into cognitive improvement, even among mutation carriers, and for the paradoxes posed by the large proportion of amyloid-positive individuals without dementia and even of centenarians without history of cognitive abnormalities, half of whom have autopsy-confirmed AD pathology.

We recently observed that among amyloid positron emission tomography (PET)-positive individuals, higher levels of soluble Aβ42 were associated with normal cognition and brain volumes in all tertiles of brain amyloidosis, with an effect size greater than that of increases in brain amyloid burden.

Is Blood-Brain Barrier Dysfunction Cause or Consequence in Alzheimer's Disease Pathology?
https://www.fightaging.org/archives/2022/10/is-blood-brain-barrier-dysfunction-cause-or-consequence-in-alzheimers-disease-pathology/

The blood-brain barrier is a layer of specialized cells wrapping blood vessels in the central nervous system, isolating the brain from the rest of the body by allowing on some cells and molecules to pass. The blood-brain barrier becomes leaky with age, however, as vascular dysfunction progresses. This allows inappropriate molecules into the brain to provoke inflammatory responses from brain-resident immune cells, and no doubt produces other detrimental consequences as well. Researchers do not consider it settled that blood-brain barrier dysfunction is a deeper cause of neurodegeneration, however. It may be at least in part a consequence of other aspects of neurodegenerative aging that take place in brain tissue.

Alzheimer's disease (AD) is a complex disorder that is clinically characterized by the progressive decline in cognition, and pathologically characterized by the accumulation of amyloid-β (Aβ) and phosphorylated tau (P-tau) in the brain. In recent years, a series of studies have demonstrated that AD is linked to blood brain barrier (BBB) dysfunction. BBB dysfunction has been identified in the early stage of AD. The BBB is a continuous membrane formed by a tightly sealed monolayer of endothelial cells. The main function of the BBB is maintenance of the brain health micro-environment by keeping neurotoxic components, pathogens, and circulating blood out of the brain.

The first clues regarding BBB dysfunction came from studies performed in AD genetic animal models with Aβ or tau pathology. Therefore, at that time, it was believed that BBB dysfunction was associated with Aβ or tau pathology. However, BBB breakdown and vascular dysregulation were also determined in preclinical and early-stage AD patients before cognitive decline or positive Aβ and tau pathology. These results suggested that the BBB breakdown that appeared in the early stage of AD could not be fully explained by the consequence of Aβ and/or tau pathology (the forms of plaques, tangles, and oligomers).

In recent years, emerging evidence has supported the contributions of neuroinflammation to AD pathogenesis. The associations between BBB breakdown and neuroinflammation have been explored in several studies. An injured BBB was associated with neuroinflammation such as microglial activation and elevated inflammatory cytokines release. However, the exact role of BBB dysfunction in AD pathogenesis is still unknown. It remains elusive whether BBB dysfunction is a consequence or a cause of Aβ pathology, tau pathology, neuroinflammation, or other conditions.

Cellular Senescence and Abdominal Aortic Aneurysm
https://www.fightaging.org/archives/2022/10/cellular-senescence-and-abdominal-aortic-aneurysm/

In recent years, researchers have presented evidence for the age-related accumulation of senescent cells to be a meaningful contributing cause of aneurysm, the formation of a bulging weak spot in a blood vessel, vulnerable to bursting. Relatedly, pro-inflammatory immune cells are also implicated. The commonality here is inflammatory signaling, disruptive to tissue function. Here researchers review the mechanisms likely involved, and the high points of existing evidence for a relationship between the presence of senescent cells and formation of aneurysms.

Abdominal aortic aneurysm (AAA) is locally weak and aneurysm-like dilatation of the abdominal aorta, with a diameter of 3 cm or more, more than 1.5 times the normal diameter AAA is a common disease among the elderly, and the incidence of AAA increases with age. Most AAA patients are asymptomatic and are discovered accidentally during a physical exam or ultrasound screening. However, rupture or precursor rupture may occur when patients present with symptoms such as lumbago and abdominal pain. The in-hospital mortality rate of rupture is about 40%, while the out-of-hospital mortality rate can be as high as 90%, resulting in about 150,000-200,000 deaths globally per year.

The threat of AAA mainly in elderly patients is becoming more and more serious. Currently there is no effective method to inhibit AAA progress via treatment with clinical drug. Thus it is of great clinical significance to study the pathogenesis of AAA and explore potential therapeutic targets. The purpose of this paper is to analyze the pathogenesis of AAA from the perspective of cellular senescence: on the basis of clear evidence of cellular senescence in aneurysm wall, we actively elucidate specific molecular and regulatory pathways, and to explore the targeted drugs related to senescence and senescent cell elimination measures, eventually improve the health of patients with AAA and prolong the life of human beings.

Centrophenoxine Is Not That Interesting
https://www.fightaging.org/archives/2022/10/centrophenoxine-is-not-that-interesting/

The Forever Healthy Foundation publishes, intermittently, a series of rigorous literature reviews for presently available treatments that are alleged to help with mechanisms of aging. The viewpoint is conservative; the authors are less convinced by the evidence for the utility of early senolytics than I am, for example. Their latest publication covers centrophenoxine, not a treatment I am familiar with, but by the sound of it I'm not missing out on anything. The data is emblematic of much of what is marketed under the "anti-aging" banner; unconvincing, mixed, marginal.

Centrophenoxine (CPH) is a compound consisting of dimethylaminoethanol (DMAE) and para-chlorophenoxyacetic acid (pCPA), joined by a chemical bond. DMAE can be converted by cells into choline, which is a precursor of membrane phospholipids, neurotransmitters, and other important biomolecules. The pCPA component enhances the penetration of CPH across the blood-brain barrier. CPH supplementation is hypothesized to increase brain acetylcholine levels, protect neurons from oxidative damage, improve cognitive function, and reduce age-related lipofuscin accumulation.

There is moderate evidence that centrophenoxine may benefit patients hospitalized for injury to the brain from either vascular or traumatic origin, especially in acute cerebral hemorrhage. However, despite several decades of use since it was first synthesized, the clinical utility of centrophenoxine in healthy individuals remains unclear, primarily because the vast majority of published trials test the efficacy of centrophenoxine in treating study populations with specific diseases.

Centrophenoxine is marketed as a general anti-aging supplement, however, we found no evidence in humans to support this purported benefit. Preclinical studies on the effect of centrophenoxine on longevity in animals are also scant. The evidence regarding the use of centrophenoxine as a cognitive enhancer is inconsistent. Many studies employed a wide battery of tests, often reporting a narrow but significant positive result among many assessments that did not change, or occasionally worsened. Most studies were small, less than 30 participants, conducted in older adults with significant cognitive impairment, often in frail clinical condition, and suffered from high dropout rates.

Although low doses are unlikely to cause harm, we conclude that, in the healthy population, the evidence for any benefits of centrophenoxine supplementation is not sufficiently compelling to overcome the precautionary principle.

Cancers Force T Cells into Senescence
https://www.fightaging.org/archives/2022/10/cancers-force-t-cells-into-senescence/

Established cancers aggressively manipulate the immune system to their advantage, co-opting innate and adaptive immune cells to support rather than attack a tumor. Researchers here note a mechanism by which cancerous tissue forces T cells into a senescent state. Inhibiting this transition makes the immune system more effective at attacking the cancer, where fired up by a suitable immunotherapy that overcomes other barriers that the cancer puts in place to suppress the immune response.

It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.

We report that both mouse malignant tumor cells and regulatory T cells (Tregs) can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer, and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling.

Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.

A Complex Systems View of the Biology of Aging
https://www.fightaging.org/archives/2022/10/a-complex-systems-view-of-the-biology-of-aging/

The study of complex systems, made up of many interacting parts, is a well-developed area of research and development, spanning many distinct disciplines of science and engineering. Any particular subset of cellular biology can be considered a complex system, and the tools developed in other disciplines can be adapted to use in the life sciences. Here, researchers discuss how to apply complex systems frameworks to the study of aging. This approach to develop means of intervention embraces the complexity of our biology. It is the polar opposite of, say, the SENS approach to rejuvenation, which seeks to work around that complexity (and the amount of work needed to understand it) by focusing on the comparatively narrow domain of the root causes of aging. If addressing causes, we do not need to fully understand all of the consequences of those causative mechanisms in detail, we just need to fix those causes.

The goals of aging biology research are broad and ambitious - to understand how a multitude of genes, pathways, and mechanisms at multiple scales contribute to declines in function, health and lifespan in ways that can vary across populations, environments and species. Enormous progress has been made identifying individual genes, pathways, molecules and their connection in mechanisms that modulate aging. However, there has been limited progress in our understanding of how these factors interact to produce a global set of aging processes, or in how these processes combine to produce functional phenotypes of aging such as frailty, or demographic patterns such as the Gompertz mortality curves found across the tree of life.

Accordingly, research is increasingly focusing on understanding how mechanisms and pathways integrate, drawing on concepts of complex systems such as resilience, homeostasis, networks, and interactions. This transition to a complex systems view of aging has been happening piecemeal and is only sometimes explicitly acknowledged; many of the core concepts and methods are unfamiliar to biologists and may be defined in various ways. Here, we provide a theoretical framework and introduction to the key concepts of complex systems theory as applied to aging, as a primer to orient researchers new to the field and in the attempt to offer a unifying vision for how a complex systems approach could be transformative in aging biology research.

Cognitively Healthy Centenarians are Resistant to Age-Related Brain Pathology
https://www.fightaging.org/archives/2022/10/cognitively-healthy-centenarians-are-resistant-to-age-related-brain-pathology/

The article here notes that researchers find cognitively healthy centenarians exhibit levels of protein aggregation and other brain lesions typical of people showing symptoms of neurodegenerative diseases. They are in some way more resistant, but why this is the case is a continuing research project. It is possible to identify specific gene variants and more youthful gene expression for some genes in cognitively healthy older individuals, but it is long trek from that data to an understanding of the mechanisms involved.

Researchers initially aimed to recruit 500 cognitively healthy centenarians. As of June 2021, 406 had signed up. Their average age when they joined was 101; the oldest is now 107. Seventy percent are women; 43 percent still live independently. About 30 percent have agreed to donate their brains after death and, to date, 95 of them have passed away. Researchers have presented the neuropathology findings from 85 of those.

At autopsy, some of these centenarians were found to have had pathologies typical of people with Alzheimer's disease (AD). Many had been in stage 2 or 3 amyloidosis when they died, as judged by NIA criteria, and had accumulated stage 2 or even stage 3 neuritic plaques per CERAD scores. All were in at least Braak stage I for neurofibrillary tangles, though the majority were at stage III or higher. The brains weighed about as much as those from people who had had AD dementia, but neither plaques nor tangles correlated with cognitive assessments.

The same was true for a host of other age-related pathologies, including cerebral amyloid angiopathy, TDP-43 proteinopathy, Lewy bodies, hippocampal sclerosis, granulovacuolar degeneration, atherosclerosis, and vascular infarcts. Many centenarians had at least one of these. Across all of these pathologies, increased levels in the postmortem brain generally came with lower cognitive scores before death, but the associations were weak. Of all neuropathological substrates tested, tangles correlated most robustly with lower performance, but these healthy centenarians seemed surprisingly resistant even to the effects of high levels of tangles.

Scientists compared the centenarians' proteomes to those from 50- to 95-year-old people with AD and to 50- to 90-year-old healthy controls. They found that, while concentrations of about two dozen proteins fall with age, in centenarians, these protein levels were higher than expected for their age. For four other proteins that normally tick up with age, levels remained steady in the centenarians. The proteins that bucked these trends included those involved in microtubule and intermediate filament biology, myelination, the immune system, basic metabolism, and protein transport. "In a nutshell, these centenarians have younger-looking brains."

High Allostatic Load Correlates with Greater Risk of Cancer Mortality
https://www.fightaging.org/archives/2022/10/high-allostatic-load-correlates-with-greater-risk-of-cancer-mortality/

Allostatic load is a compound measure of stress on the body, usually including an emphasis on inflammatory activity in the immune system. The measures making up allostatic load are raised by psychological stress, chronic exposure to pathogens or pollutants, and similar circumstances. Researchers here note that this, perhaps unsurprisingly, correlates with increased cancer mortality. Greater inflammation produces a more hospitable environment for cancer to occur and then grow, and the relationship between allostatic load and cancer may indeed be largely determined by the state of the immune system.

Allostatic load attempts to quantify physiological stress by measuring biomarkers across cardiovascular, immune, and metabolic systems. It has been defined using varying configurations, although most incorporate biomarker measures from these three different categories of physiologic functioning. While there is no consensus definition, we elected to define allostatic load using components including body mass index (BMI), diastolic blood pressure (DBP), glycohemoglobin (hemoglobin A1c), systolic blood pressure (SBP), total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein (CRP).

Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, causing the release of corticosteroids and catecholamines respectively. Frequent exposure to these compounds have been linked to the development of cancer by DNA damage, inhibition of p53, and promoting a microenvironment favoring tumorigenesis. Chronic stress has also been shown to modulate the immune system in favor of conditions for cancer progression. In the innate immune system chronic stress and associated hormones increase pro-inflammatory cytokines. Long term pro-inflammation can influence all stages of cancer development through manipulation of tumor microenvironment, genetic mutation, and epigenetic modifications.

In fully adjusted models, high allostatic load was associated with a 14% increased risk of cancer death among all participants and a 18% increased risk of cancer death among Non-Hispanic White (NH-White) adults. When further stratified by age (participants aged less than 40 years), high allostatic load was associated with a 80% increased risk among all participants; a 95% increased risk among NH-White adults; a 2-fold increased risk among Non-Hispanic Black (NH-Black) adults; and a 36% increased risk among Hispanic adults.