Fight Aging! Newsletter, December 18th 2023
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- Exercise Beneficially Alters Polarization of Microglia in the Brain
- The NIA Interventions Testing Program Shows that Fisetin Does Not Extend Life in Mice
- Klotho Levels Decline with Age, But Are Unaffected by Physical Fitness at a Given Age
- Building Aging Clocks for Specific Organs from Circulating Protein Levels
- Changes in the Gut Microbiome Correlate with Aging and Renal Function
- Cellular Stress Signaling in the Development of Ventricular Fibrillation
- Toll-Like Receptors React to Molecular Damage to Contribute to the Inflammation of Aging
- Meta-Analysis Suggests Aspirin Use Reduces Risk of Cancer Mortality
- Aged Transplant Organs Cause Harm to Younger Recipients
- Thoughts on Air Pollution and Accelerated Aging
- Reviewing What is Known of Hair Aging
- HALD, a Human Aging and Longevity Knowledge Graph
- Age-Related Dysbiosis as a Contributing Cause of Delerium
- Looking for Evidence of Antagonistic Pleiotropy in Human Data
- Resolvin D2 Treatment Increases Monocyte Production and Slows Liver Aging in Mice
Exercise Beneficially Alters Polarization of Microglia in the Brain
https://www.fightaging.org/archives/2023/12/exercise-beneficially-alters-polarization-of-microglia-in-the-brain/
Regular moderate exercise remains one of the most beneficial interventions when it comes to slowing the progression of degenerative aging, if balancing effect size against volume of supporting data. This isn't where we'd like to be! Biotechnology is capable of so very much more, but progress is slow, and robust assessment of new therapies across large populations slower still. Exercise introduces sweeping changes in cellular biochemistry and the function of higher level systems in the body, which makes it an ongoing challenge for the research community to understand exactly how it produces benefits. As is usually the case, there is a disconnect between (a) the data that can be connected on cellular biochemistry and (b) an assessment of health parameters. Joining the dots between the high level and the low level is a sizable project with no end in sight.
Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body. Like macrophages, microglia adopt polarizations, defined packages of behaviors. An M1 microglia is pro-inflammatory, focused on chasing down pathogens. An M2 microglia is anti-inflammatory, focused on aiding in tissue regeneration and clearance of metabolic waste. Polarization is a useful concept, but the underlying range of behaviors across individual cells is more an analogue continuum from pro-inflammatory to anti-inflammatory, and the same for other behaviors, than a binary choice. Still, polarization can be influenced, and researchers are interested in finding ways to change microglia behavior in order to suppress inflammatory signaling and encourage tissue regeneration. As noted in today's open access paper, that exercise can affect polarization may lead to regulatory mechanisms that can be adjusted by other means.
Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia
Lifestyle changes including increased physical activity is an effective strategy for delaying the progression of neurodegenerative disease. Several studies have proposed a possible link between exercise training and cognitive improvement. We trained mice to run at increasing speed over 8 weeks which represents a typical in vivo model of physical activity. The principal findings of our study are 1) Exercise training can improve cognitive function in AlCl3/D-galactose-treated mice and aging mice by reducing neuronal loss and neuroinflammation, and 2) Elevated levels of lactate in the brain attenuate this neuroinflammation by acting as an "accelerator" for the "lactate timer" in microglia by promoting transition to a reparative phenotype through Histone H3 Kla. Our results provide an extension to the beneficial effects of exercise training beyond strengthening skeletal muscle, and further confirm that exercise training can improve cognitive function and reverses neuronal loss in the brain of AD-like mice.
Other studies have attributed the beneficial effects of exercise to lactate. For example, lactate partially mediates the effect of physical exercise on neurogenesis in a MCT2-dependent manner. Subcutaneous injection of lactate lead to an increase in blood lactate levels similar to exercise and increases brain VEGF protein. These studies provide a preliminary link between exercise, lactate, and cognitive function. Although studies demonstrated an important role of lactate in physiological function in neurons and astrocytes, there has been little empirical investigation on microglia. Over the past thirty years, microglia are traditionally described as two states, resting and activated. The reactive gliosis observed in Alzheimer's disease histopathology reflects an abnormal morphology and proliferation of microglia. Once overactivated microglia release a wide range of inflammatory and bioactive molecules which impose negative impacts on neurons. Extensive activation of microglia was detected in our AD mice and may contribute to the observed cognitive impairment.
Both running training and exogenous lactate treatment inhibited the hyperactivation of microglia in AD-like mice and increased the number of anti-inflammatory/reparative microglia. In vitro experiments in microglia confirmed that lactate treatment significantly increases the expression of repair genes, indicating that lactate may promote a shift in balance from damaging to reparative microglia.
The NIA Interventions Testing Program Shows that Fisetin Does Not Extend Life in Mice
https://www.fightaging.org/archives/2023/12/the-nia-interventions-testing-program-shows-that-fisetin-does-not-extend-life-in-mice/
The latest results from the NIA Interventions Testing Program (ITP) were recently published. The ITP conducts the most rigorous of animal life span studies, frequently demonstrating that earlier promising results were incorrect. The most interesting outcome from this batch of different interventions is that fisetin, demonstrated to clear senescent cells in mice and improve health measures, did not extend life. In contrast, dasatinib and quercetin, the most well-studied senolytic, has been shown by other groups to extend life in mice, by 36% in one study. This is puzzling!
We might theorize that either fisetin at the senolytic doses used in the ITP study (more frequent dosing for a longer period of time than I might have chosen) produces meaningful harmful side-effects in comparison to less frequent dasatinib and quercetin dosing, or that an ITP-run life span study for dasatinib and quercetin treatment would show no benefit to life span. The former sounds more plausible than the latter, but the data is the data. The ITP researchers consider that the issue may be differences between mouse strains used in various fisetin studies, and this is also interesting if the case, that senescent cell burden and type might be different enough in different strains to produce quite different outcomes.
Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used
In genetically heterogeneous (UM-HET3) mice, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12%, while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8%. Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± standard error (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant.
Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
Senescent cells have been reported as important mediators of the pathophysiology of aging, and senolytics like fisetin (Fis) may play important roles in mediating their effects. Past researchers treated naturally aged or progeroid mutant mice with Fis and found that it reduced cells with senescent markers; for example, C57BL/6 mice at 23 ± 1 months old were given Fis or vehicle for 5 days by oral gavage. Three days later, in inguinal fat, controls averaged 8% SA-β-gal+ cells, while Fis-treated fat had 2%. They also fed mice 500 ppm Fis from 19 months of age and found that the median lifespan was 27 months in controls and 30 months in Fis-treated, with 3 of 8 treated mice outliving all 8 controls.
We elected to use 600 ppm Fis, starting at 20 months of age, since senescent cells are present in potentially harmful quantities starting at that age in mice. We fed either continuously or for 3 days every 2 weeks. Fis, using the doses and route described here, did not significantly lower the amount of p16Ink4a mRNA in UM-HET3 mouse liver, kidney, or brain. p16Ink4a whole tissue mRNA is one marker of senescent cell burden, but it is not a fully sensitive marker of senescence, for example, it is also expressed in other cell types such as activated macrophages. We had hoped that Fis would deplete senescent cells and thus test the important idea that the removal of senescent cells would lead to longer lifespan, but the absence of an effect on p16Ink4a-positive cells and the lack of inflammatory p21Cip1+ cells in older UM-HET3 mice prevented us from addressing this question. Further studies to analyze the types and location of senescent cells that might increase with age in UM-HET3 mice and how they differ from other mouse models in regard to their upregulated senescent cell anti-apoptotic pathways (SCAPs), as well as the use of Fis and other senolytic agents by gavage, might help to clarify these issues.
Klotho Levels Decline with Age, But Are Unaffected by Physical Fitness at a Given Age
https://www.fightaging.org/archives/2023/12/klotho-levels-decline-with-age-but-are-unaffected-by-physical-fitness-at-a-given-age/
Klotho is a longevity-associated gene. Klotho functions within the cell, but a portion of the full protein is also released into the bloodstream. In humans, higher levels of circulating klotho correlate with lower incidence of age-related disease and mortality. In mice, interventions such as gene therapies that increase klotho levels have been shown to extend life, while reducing klotho levels shortens life. Klotho is thought to act within the kidney, where it is protective, slowing age-related decline of kidney function. Increased klotho levels produce cognitive improvement in mice and non-human primates, however, and higher levels in humans are associated with lesser degrees of cognitive decline in later life. This may be the case because kidney function is important to all organs, or it may be that klotho acts directly on the brain in some way yet to be rigorously determined. Some groups are pursuing delivery of klotho as a basis for therapies.
You might recall a recent discussion of circulating klotho protein in the bloodstream as a biomarker of the effectiveness of lifestyle interventions to modestly slow aging. Today's open access paper provides a counterpoint, in that it shows that while klotho levels and physical capabilities both decline with age, the degree of physical fitness at a given age doesn't appear to correlate with klotho levels. So, per these results, increasing one's physical fitness in later life wouldn't be expected to raise klotho levels. This is interesting, because circulating klotho has been shown to correlate with a number of parameters that one would expect to be helped by greater fitness. Levels of chronic inflammation, for example, are higher in people with less circulating klotho.
Relationship between klotho and physical function in healthy aging
Accumulating data suggests that the "anti-aging" protein Klotho may play a key role in the development of functional impairments. α-Klotho, hereby referred to as Klotho, is a large transmembrane glycoprotein that is predominantly expressed in the distal convoluted tubules of the kidneys. A landmark study found that Klotho-deficient mice exhibited a shortened lifespan and a premature aging phenotype that included functional impairments, such as severe muscle wasting, hypokinesis, an abnormal walking pattern, and decreased stride length. In support of these findings, experimental models have shown that Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, oxidative stress, and inflammation. Importantly, total circulating Klotho levels have been shown to decline with increasing age, and several epidemiological studies in older adults - all of which included those with chronic diseases - have revealed a strong association between lower Klotho levels and increased disability in activities of daily living, increased risk of frailty, lower performance in the short physical performance battery.
The majority of studies investigating the relationship between circulating Klotho and physical function focused solely on older adults and have included those with comorbidities. The problem is that it is currently unclear whether circulating levels of Klotho are associated with physical function in individuals without comorbidities, and whether they are also associated with impairments in physical function earlier in life. The present study therefore sought to examine the relationship between serum Klotho levels and physical function indices in a community-based cohort of healthy adults across various age categories. Elucidating this relationship enables us to examine the natural history of age-related declines in circulating Klotho and its relationship with physical function in the absence of any chronic disease. We hypothesized that serum Klotho levels are associated with higher measures of physical function in all age groups.
In this cross-sectional study, serum Klotho was measured in 80 adults. Participants (n = 20, 50% men per group) were chosen into four age groups: 20-34, 35-49, 50-64, and ≥ 65 years, and were further grouped based on performance (low vs. high) on grip strength and chair stand tests. Klotho levels were lower in the ≥ 65 years group and the 50-64 years group compared to 20-34 years. No differences were observed in Klotho between the low and high performers. The ≥ 65 years group walked a shorter distance during the 6-min walk test (6MWT) compared to 20-34 years. Klotho was correlated with age, body fat, and 6MWT distance. Klotho levels decline as early as the fifth decade of life, potentially before the onset of age-related impairment in exercise capacity.
Building Aging Clocks for Specific Organs from Circulating Protein Levels
https://www.fightaging.org/archives/2023/12/building-aging-clocks-for-specific-organs-from-circulating-protein-levels/
As illustrated by the last decade or so of research, any sufficiently complex set of biological data can be mined via machine learning to produce algorithms that report chronological age and incorporate some sensitivity to biological age. Biological data changes over time, and many of those changes are characteristic of age. The processes and dysfunctions of age touch on all mechanisms in the body, given time. The hypothetical perfect measure of biological age would accurately predict mortality risk, and be a comprehensive reflection of the burden of damage and dysfunction resulting from processes of aging. That may be impossible to achieve, but good enough clocks of biological aging will greatly speed progress towards therapies capable of treating aging.
Everyone suffers from the same processes of aging, and those processes tend to interact with one another, so if one pulls ahead, then it will make other accelerate as well. Nonetheless, the progression of aging is a stochastic process, a sequence of essentially random occurrences of damage, and random interactions between damaged components. There will be a distribution of outcomes even in identical bodies. Thus just as we see different people aging at different rates, we would expect that, in one individual, sometimes the state of dysfunction and damage will be worse in one tissue or organ, better in another.
In today's open access paper, researchers demonstrate that this is in fact the case. They do so by using data on circulating proteins that are generated by specific tissues, and which can be obtained from a blood sample. Given that data, machine learning approaches derive aging clock algorithms that are specific to those tissues. The results show that a fraction of people exhibit accelerated aging in one organ. As for all newly created clocks, it is entirely unclear as to which specific underlying processes of aging drive the observed changes and outcomes, but nonetheless one might hope that the existence of aging clocks will help to improve outcomes in research, medicine, and lifestyle choices.
Organ aging signatures in the plasma proteome track health and disease
While many methods to measure molecular aging in humans have been developed, most of them provide just a single measure of aging for the whole body. This is difficult to interpret given the complexity of human aging trajectories. Some recent methods have used clinical chemistry markers which include some markers of organ function. However, many of these markers have low organ specificity, making them difficult to interpret for organ-specific aging. Methods to measure brain aging have used MRI-based brain volume and functional connectivity measurements, which are costly and do not provide molecular insights, or have required tissue samples, which prevents their application in living persons. Building off the wealth of literature and clinical practice that uses certain organ-specific plasma proteins to noninvasively assess aspects of organ health, such as alanine transaminase for liver damage, we hypothesized that comprehensive quantification of organ-specific proteins in plasma could enable minimally invasive assessment and tracking of human aging for any organ.
Animal studies show aging varies between individuals as well as between organs within an individual, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan.
We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181, the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations, and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.
Changes in the Gut Microbiome Correlate with Aging and Renal Function
https://www.fightaging.org/archives/2023/12/changes-in-the-gut-microbiome-correlate-with-aging-and-renal-function/
The gut microbiome changes with age. Pro-inflammatory microbial populations grow in size at the expense of populations that produce beneficial metabolites. As researchers produce increasingly large databases of the composition of the gut microbiome across ages and populations, they are also mapping a growing number of specific connections between microbial species and aspects of aging. Some of this work shows causation, but most human data can only show correlations between aspects of the gut microbiome and aspects of aging. In today's open access paper, the authors focused on finding links between the gut microbiome and the function of the kidney. Declining kidney function is clearly important in degenerative aging, affecting organs throughout the body. If changes in the gut microbiome can accelerate kidney aging, then this will contribute to aging in much of the rest of the body as well.
Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging
Several cross-sectional studies have identified gut microbiota changes that occur with aging. Studies using 16S rRNA gene amplicon sequencing have indicated an association between diet-driven microbiota alterations and health decline in aging individuals and highlighted the presence of a core microbiota of prevalent, symbiotic bacterial taxa dominated by the families Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae, with a progressive reduction in the abundance of these core taxa with age. In recent years, deep shotgun sequencing studies have reported a trend toward an increase in the abundances of Escherichia and Streptococcus with age, while the abundances of Faecalibacterium and Ruminococcus were reported to exhibit a decreasing trend. Notably, compared to that in other age groups, the gut microbiota of healthy centenarians is enriched with bacteria with a potential for degradation of xenobiotics and biosynthesis of short-chain fatty acids. However, whether specific interactions between the serum metabolome and gut microbiota are related to an age-dependent decline in renal function remains largely unexplored.
Based on residents from a Chinese longevity county, with long-living individuals (nonagenarians and centenarians) as healthy aging controls, this study aimed to examine the possible relationship between renal function and age-associated alterations in the human gut microbiota and serum metabolome using an integrated omics approach. Our results indicated that the effect of the gut microbiota on serum metabolites increased with age and that many age-associated gut microbes (E. coli, O. splanchnicus, and D. piger in particular) and serum metabolites, including markers of impaired renal function and bile acids, were highly correlated. The relationships between renal functions, serum metabolites, and the gut microbiota further indicated a possible impact of the gut microbiota in the aging process. Through mediation analyses, we revealed putative causal relationships among the gut microbiota (E. coli, O. splanchnicus, and D. piger), markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and age.
Separately, feces of elderly individuals were transplanted into C57BL/6J mice. This fecal microbiota transplantation (FMT) experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Thus, this study not only revealed changes in the serum metabolome and the gut microbiota in the process of aging but also indicated a route by which the gut microbiota affects aging indirectly through its effect on renal function via the production of metabolites associated with impaired renal function.
Cellular Stress Signaling in the Development of Ventricular Fibrillation
https://www.fightaging.org/archives/2023/12/cellular-stress-signaling-in-the-development-of-ventricular-fibrillation/
Researchers here report on a mechanism by which increased cellular stress in heart tissue can disrupt the regulation of the heartbeat, thus leading to arrhythmia and potentially fibrillation. The accumulated molecular damage of aging, of course, provides increased contributions to cell stress, whether from inflammatory signaling, mitochondrial dysfunction, increased presence of molecular waste, or other causes. When researchers characterize more of the ways in which regulatory pathways in cells can produce maladaptive reactions to this damage, they tend to then search for means to alter the response, rather than means to repair the underlying damage. More focus should go towards damage repair in the research community, but that that is largely not the way in which research and development progresses.
Ventricular fibrillation is the most frequent cause of sudden cardiac death. Although aging is an established risk factor for the development of cardiac arrhythmia, the mechanisms underlying this connection have been hard to pin down, hindering progress toward the development of specific treatments. With the development of an arrhythmia, the cardiac cycle speeds up and becomes irregular, with potentially life threatening consequences.
Working with animal models, researchers discovered a connection between the development of ventricular fibrillation and the activation of two key signaling proteins, the stress kinases p38γ and p38δ. This discovery opens the way to new possible intervention strategies for this condition. When the scientists examined the hearts of old mice, they found that the activation of p38γ and p38δ was increased. A similar increase in the activity of these enzymes was also observed in the hearts of mice with a genetic or pharmacologically induced predisposition to developing ventricular arrhythmias. Together, these results suggest that stress signaling via p38γ and p38δ likely plays an important role in the development of this condition.
The scientists found that p38γ and p38δ phosphorylate a receptor called ryanodine receptor 2 and another protein called SAP97, resulting in a mislocalization of the potassium ion channel Kv4.3. These molecular changes lead to premature ventricular activation and an increased susceptibility to ventricular fibrillation. The study findings identify a promising therapeutic target for the development of new strategies to prevent sustained ventricular fibrillation and provide protection against this serious condition.
Toll-Like Receptors React to Molecular Damage to Contribute to the Inflammation of Aging
https://www.fightaging.org/archives/2023/12/toll-like-receptors-react-to-molecular-damage-to-contribute-to-the-inflammation-of-aging/
This review paper covers what is known of toll-like receptors in the development of age-related chronic inflammation, with a particular focus on toll-like receptor 4 (TLR4). A sizable number of researchers are focused on finding ways to suppress the constant overactivation of the immune system in later life by interfering in its regulation. Unfortunately, the sensing mechanisms involved are also required for normal immune function, so it is hard to envisage even sophisticated implementations of this strategy producing therapies that don't inhibit necessary immune functions, such as defense against pathogens and destruction of potentially cancerous cells. The better approach is to repair the underlying molecular damage and disarray that triggers toll-like sensors, such as the mitochondrial dysfunction that allows mislocalization of mitochondrial DNA into the cytoplasm where it is mistaken for bacterial DNA. This is not a sizable focus in the research and development community, alas.
Toll-like receptor (TLR) is a type of pattern recognition receptor (PRR) that plays a crucial role in the immune system. PRRs, predominantly expressed by innate immune cells such as dendritic cells, macrophages, monocytes, neutrophils, and epithelial cells, serve as sentinels of the body's defenses. They become activated upon detecting pathogen-associated molecular patterns (PAMPs), which are molecular signatures unique to external pathogens and distinct from host components, as well as damage-associated molecular patterns (DAMPs), encompassing molecules like heat shock proteins (HSPs) and plasma membrane components released due to cellular damage or death. PRR is a major factor in innate immunity and also plays a role initiating adaptive immunity through induce the maturation of dendritic cells and the release of inflammatory cytokines.
TLR activation serves as a defense mechanism for the host against infections and tissue damage, initiating a signaling cascade that leads to the secretion of various inflammatory cytokines and the activation of immune cells. Notably, TLR4, a pivotal member of the innate immune response, becomes activated by diverse ligands classified as PAMPs and DAMPs. However, excessive TLR4 activation disrupts immune homeostasis by sustaining pro-inflammatory cytokine and chemokine production, thus contributing to the onset and progression of various diseases, including Alzheimer's disease, cancer, osteoarthritis, and sepsis.
The aging process significantly impacts the immune system, fostering a bidirectional influence termed 'immunosenescence'. Cellular senescence triggers the release of senescence-associated secretory phenotype (SASP), which can induce inflammation, subsequently promoting the generation of damage-associated molecular patterns (DAMPs), and escalating the exposure and circulation of externally infiltrated pathogen-associated molecular patterns (PAMPs) due to barrier deterioration. Diverse factors heightened by the aging process result in aberrant immune system regulation through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), consequently affecting cardiovascular, metabolic, and age-related degenerative diseases. In this review, we delineate the role of TLR4, a pivotal component of the immune system, and its association with aging-related diseases, thereby shedding light on the significance of TLR4 signaling in disease research.
Meta-Analysis Suggests Aspirin Use Reduces Risk of Cancer Mortality
https://www.fightaging.org/archives/2023/12/meta-analysis-suggests-aspirin-use-reduces-risk-of-cancer-mortality/
Aspirin is probably a candidate for most well-studied drug in human patients, going by number of participants and sheer volume of data generated by studies. It is also a cautionary tale for those who expect clear answers to result from studies of modest, long-term effects in humans. The long-term benefits of aspirin, like most small molecule approaches to manipulation of metabolism, tend to appear in some studies and vanish in others. Effects may be positive in some classes of individual, negative in others, and it is not well understood how to differentiate between those groups. The meta-analysis here stands in opposition to the ASPREE study, for example, in which modestly increased mortality was found to correlate with aspirin use.
Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence 'for' and 'against' the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients
Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.
Aged Transplant Organs Cause Harm to Younger Recipients
https://www.fightaging.org/archives/2023/12/aged-transplant-organs-cause-harm-to-younger-recipients/
Old tissues are dysfunctional in ways that young tissues are not. This has always been known in the context of organ transplants, but absent measures of aging and means to treat aging, there was little to be done about it and arguably more pressing logistical issues to focus on. Times change, however. A growing appreciation of the role of senescent cells in degenerative aging, and the ability to clear some fraction of these cells via senolytic therapies such as the dasatinib and quercetin combination, has given the research, medical, and industry communities involved in organ transplant a novel approach to improve the quality of transplanted organs and outcomes for patients.
Most organ transplantations involve supply from older donors to younger recipients. Aging cells can become senescent, a condition in which they stop multiplying and secrete chemicals that negatively affect neighboring cells. Senescent cells accumulate in older donor organs, and have the potential to compromise transplant outcomes.
A study found that in preclinical animal models, transplanting older organs can trigger senescence in younger recipients. They observed that young and middle-aged mice that received heart transplants from older mice had impaired physical capacity, with reduced running times and grip strengths. Middle-aged mice who received older hearts also showed increased anxiety-related behavior, impaired memory, and poorer learning performances.
Researchers found that these accelerated aging-related effects in younger recipients were driven by the release of senescence-associated factors and mitochondrial DNA from older transplants. Treating older donor mice with senolytics, or senescence-inhibiting drugs, before organ extraction reduced symptoms of senescence in the recipient mice.
Thoughts on Air Pollution and Accelerated Aging
https://www.fightaging.org/archives/2023/12/thoughts-on-air-pollution-and-accelerated-aging/
A number of large epidemiological studies demonstrate that particulate air pollution correlates with mortality and incidence of age-related disease, likely via mechanisms that involve increased inflammation that results from the interaction of particulates with lung tissue. While socioeconomic status interacts with both exposure to air pollution and life expectancy, it is nonetheless possible to disentangle these effects in some population studies. While the long-term trend is towards reduced air pollution, it seems likely that chronic inflammation will be controlled and its effects on tissues reversed via novel therapeutics on much the same timescale as meaningful control over particulate levels could be achieved.
Air pollution (AirPoll) accelerates human aging, as assessed by increased adult mortality and earlier onset of cardiovascular diseases, and dementia. Socio-economic strata (SES) of wealth and education have parallel differences of mortality and these diseases. Children from impoverished homes differ in brain development at birth and in risk of early fat excess and hypertension. To further enhance the healthspan, biogerontologists may consider a wider range of environmental exposures from gestation through later life morbidity that comprise the Gero-Exposome.
Experimental studies with rodents and nematodes document shared transcriptional responses to AirPoll. In rodents, AirPoll exposure activates gene systems for body-wide detoxification through Nrf2 and NFkB transcription factors that mediate multiple aging processes. Gestational environmental factors include maternal diet and exposure to AirPoll and cigarette smoke. Correspondingly, gestational exposure of mice to AirPoll increased adult body fat, impaired glucose clearance, and decreased adult neurogenesis in the hippocampus, a brain region damaged in dementia. Nematode larvae also respond to AirPoll with Alzheimer's relevant responses. These experimental approaches could identify interventions for expanded human health and longevity across SES gradients.
Reviewing What is Known of Hair Aging
https://www.fightaging.org/archives/2023/12/reviewing-what-is-known-of-hair-aging/
The aging of hair is a priority for many, but in the grand scheme of things we might perhaps want to suffer that loss in preference to the decline of other bodily systems more essential to life. If that choice in priority of research and development is offered, at least. In fact, while a sizable and vocal industry focuses on the little that can be done today to satisfy the demand for an end to the aging of hair, research and development does occur, but not to the degree one might imagine, and is moving very slowly. The age-related disruption of hair growth and coloration processes is complex and incompletely understood. Even non-age-related conditions of alopecia have yet to be deciphered.
Hair follicles (HFs) are constituted by different cell types, including hair follicle stem cells (HFSCs), non-HFSC epithelial cells, immune cells, neurons, mesenchymal cells, adipocytes, and melanocytes. Other structures, such as sebaceous glands (SGs), blood vasculature, and arrector pili muscle (APM), are also important HF components. Generally, HF status depends on the hair cycle, which can be roughly divided into three stages, including anagen (the growing phase), catagen (the transition phase), and telogen (the resting phase). These phases are modulated by genes, age, microenvironment, diet, and psychological factors. HF homeostasis is disrupted due to aging, gene mutations, nutritional imbalance, hormonal dysregulation, the inflammatory microenvironment, etc., which will lead to various HF disorders such as hair aging. Although hair-related diseases are not life-threatening, they can significantly influence people's social activities and psychological wellbeing. Among these disorders, hair aging is manifested by hair graying, hair loss, hair thinning, hair follicle miniaturization (HFM), structural changes, lipid composition change, and curvature in the hair fiber. There are multiple causes of hair aging, including genetic defects, systemic diseases, ultraviolet (UV) radiation, nutritional imbalance, environmental pollution, and physical damage.
Hair aging is often accompanied by hair graying, hair loss, and hair thinning. The hair pigmentation process starts with melanocyte stem cells (McSCs), which differentiate into melanocytes to produce pigmentation units. During anagen, melanocytes go through mitosis and are activated, manifested by increasing dendricity. Through the dendrites, they can transfer melanosomes, which contain melanin. Hair graying happens when the pigmentation process is disrupted. For example, it was recently reported that McSCs could switch between transit-amplifying status and quiescence status and reside in a dynamic niche, indicating a potential role of McSC mobility in regulating cell stemness and hair graying. Hair loss, however, is mostly related to HFSC dysfunction and depletion. Physiologically, HFSCs are activated at anagen and stay quiescent at telogen. Whereas, in alopecia, HFSCs are depleted or remain in a quiescent status, leading to irreversible or reversible hair loss, respectively. HFSCs are regulated by intrinsic and extrinsic cues, such as Wnt and bone morphogenetic protein (BMP) signaling, as well as skin wounding. Hair thinning can be a transitional status before hair loss, frequently occurring with HFM, which is manifested by the reduction of the diameter of HFs and hair shaft.
Numerous theories exist about the primary mechanism underlying hair aging. The most well-known one is the thesis of oxidative stress, which accounts for multiple kinds of cell dysfunction such as mitochondrial damage and upregulated inflammatory signaling. Additionally, extensive research is being done on other possibilities, including hormone-induced premature hair aging, inflammation-predominant hair aging, and DNA damage-driven hair aging. The following sections will give detailed depictions of these concepts. In this review, we try to outline and update the signaling pathway underlying these hair aging hypotheses and provide insights into the current progress and limitations of hair aging research.
HALD, a Human Aging and Longevity Knowledge Graph
https://www.fightaging.org/archives/2023/12/hald-a-human-aging-and-longevity-knowledge-graph/
For those who find use in such things, HALD is an interesting tool for exploration of the literature surrounding particular genes, proteins, lipids, and other molecules. The authors mined the literature and determined relationships between these various items, as well as their roles as biomarkers. At the high level, the life sciences find themselves afloat on a sea of data. It costs little to generate ever more data, and much more to try to analyze it, so the pace at which databases grow is somewhat faster than the pace at which various groups are organizing, analyzing, and obtaining useful insights from that data.
Human aging is a natural and inevitable biological process that leads to an increased risk of aging-related diseases. Developing anti-aging therapies for aging-related diseases requires a comprehensive understanding of the mechanisms and effects of aging and longevity from a multi-modal and multi-faceted perspective. However, most of the relevant knowledge is scattered in the biomedical literature, the volume of which reached 36 million in PubMed.
Currently, there are some publicly online databases related to human aging and longevity. However, to the best of our knowledge, these databases are all manually curated, making it difficult to incorporate comprehensive knowledge of human aging and longevity. It is also difficult to obtain the latest biomedical knowledge from manually curated databases as their services are out of maintenance or not updated in time. In addition, although human nucleic acids information is generally involved in these studies, knowledge of other important organic compounds like carbohydrates, lipids, and proteins is not yet fully integrated.
Here, we presented HALD, a text mining-based human aging and longevity dataset of the biomedical knowledge graph from all published literature related to human aging and longevity in PubMed. HALD integrated multiple state-of-the-art natural language processing (NLP) techniques to improve the accuracy and coverage of the knowledge graph for precision gerontology and geroscience analyses. Up to September 2023, HALD had contained 12,227 entities in 10 types (gene, RNA, protein, carbohydrate, lipid, peptide, pharmaceutical preparations, toxin, mutation, and disease), 115,522 relations, 1,855 aging biomarkers, and 525 longevity biomarkers from 339,918 biomedical articles in PubMed.
Age-Related Dysbiosis as a Contributing Cause of Delerium
https://www.fightaging.org/archives/2023/12/age-related-dysbiosis-as-a-contributing-cause-of-delerium/
Delerium is not an often discussed topic in the context of aging research, but it is an age-related occurrence, usually presenting in the old, particularly those suffering neurodegenerative conditions. Researchers here argue that the aged gut microbiome contributes meaningfully to risk of episodes of delerium. The balance of populations in the gut microbiome changes with age in detrimental ways, such as an increase in pro-inflammatory microbial species and a loss of those microbes that generate beneficial metabolites. It is now known that Alzheimer's and Parkinson's patients exhibit a distinctly different gut microbiome from similarly aged individuals without evident neurodegenerative conditions.
Delirium is a clinical syndrome characterized by an acute change in attention, awareness, and cognition with fluctuating course, frequently observed in older patients during hospitalization for acute medical illness or after surgery. Its pathogenesis is multifactorial and still not completely understood, but there is general consensus on the fact that it results from the interaction between an underlying predisposition, such as neurodegenerative diseases, and an acute stressor acting as a trigger, such as infection or anesthesia.
Alterations in brain insulin sensitivity and metabolic function, increased blood-brain barrier permeability, neurotransmitter imbalances, abnormal microglial activation and neuroinflammation have all been involved in the pathophysiology of delirium. Interestingly, all these mechanisms can be regulated by the gut microbiota, as demonstrated in experimental studies investigating the microbiota-gut-brain axis in dementia. Aging is also associated with profound changes in gut microbiota composition and functions, which can influence several aspects of disease pathophysiology in the host. This review provides an overview of the emerging evidence linking age-related gut microbiota dysbiosis with delirium, opening new perspectives for the microbiota as a possible target of interventions aimed at delirium prevention and treatment.
Looking for Evidence of Antagonistic Pleiotropy in Human Data
https://www.fightaging.org/archives/2023/12/looking-for-evidence-of-antagonistic-pleiotropy-in-human-data/
The dominant view of the evolution of aging is that it emerges from what is known as antagonistic pleiotropy, a term used to describe a mechanism that is initially helpful but later harmful. Mutations that help early life reproductive fitness will be selected even if they cause later harm, as a greater chance of earlier reproduction tends to win out over a greater chance of sustained reproduction over time. Natural selection thus tends to produce biological systems that invest little in long-term maintenance and sustainability. Aging is the result.
In 1957, evolutionary biologist George Williams proposed that genetic mutations that contribute to aging could be favored by natural selection if they are advantageous early in life in promoting earlier reproduction or the production of more offspring. Researchers have now tested the Williams hypothesis using genetic, reproductive, and death-registry information from 276,406 participants in the UK Biobank database. They found reproduction and lifespan to be genetically strongly negatively correlated, meaning that genetic mutations that promote reproduction tend to shorten lifespan.
In addition, individuals carrying mutations that predispose them to relatively high reproductive rates have lower probabilities of living to age 76 than those carrying mutations that predispose them to relatively low reproductive rates, according to the study. However, the authors caution that reproduction and lifespan are affected by both genes and the environment. And compared with environmental factors - including the impacts of contraception and abortion on reproduction and medical advances on lifespan - the genetic factors discussed in the study play a relatively minor role, according to the authors. "These results provide strong support for the Williams hypothesis that aging arises as a byproduct of natural selection for earlier and more reproduction. Natural selection cares little about how long we live after the completion of reproduction, because our fitness is largely set by the end of reproduction."
Resolvin D2 Treatment Increases Monocyte Production and Slows Liver Aging in Mice
https://www.fightaging.org/archives/2023/12/resolvin-d2-treatment-increases-monocyte-production-and-slows-liver-aging-in-mice/
Researchers here report on their exploration of a way to adjust the production of monocytes in the bone marrow, cells that become macrophages of the innate immune system. This is chiefly interesting for the lasting effect that a single treatment appears to have on the progression of liver aging in mice, leading to reduced pathology connected to inflammation, such as fibrosis. Also interesting is that providing aged bone marrow to young mice accelerates this liver pathology, by altering the generation of macrophages in the direction that induces liver pathology. Fibrosis is the excessive generation of collagen structures in the extracellular matrix, disruptive to tissue structure and function, and presently hard to treat.
Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein-coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice.
MA mice that lacked GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, increased monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly on the bone marrow to increase monocyte-macrophage progenitors.
A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice. Transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.