Fight Aging! Newsletter, September 25th 2023

A decade ago, five indisputably mainstream luminaries of geroscience published a paper that remains, by far, the most highly-cited publication in the entire field this century: "The Hallmarks of Aging". It had its roots in a paper that I and my collaborators published more than a decade earlier: "Time to talk SENS: Critiquing the Immutability of Human Aging", and laid to rest the debate as to whether the divide-and-conquer, damage-repair approach that the earlier paper introduced was feasible. What remained was to implement it.

Inevitably, some of the component interventions in the SENS rejuvenation biotechnology program are much more challenging to implement than others. That is why, while the field has mostly focused on the lower-hanging fruit, SENS Research Foundation has focused on filling that vacuum by targeting the hardest types of damage to repair, since no divide-and-conquer approach can succeed otherwise.

Now, however, the field has reached a new phase of implementing the SENS program. While the themes that SRF have pursued remain relevant, and are now much better funded as a result of Richard Heart's admirable initiative of 2021 that added 27 million to SRF coffers, it has also become possible to move to the final phase of the implementation of divide-and-conquer, namely the combining - in mice, for now - of interventions that individually show considerable promise.

That is why my new organisation, LEV Foundation, is focusing on combination studies as its flagship research program. I continue to provide regular updates on social media regarding the first such study, which we at LEVF are terming "Robust Mouse Rejuvenation 1", as the study progresses towards the point at which interesting differences emerge in the mortality of the cohorts.

Importantly, there is a long list of promising interventions not included in our current study, and which I and the LEVF team are eager to incorporate into a second study: Robust Mouse Rejuvenation 2. We are now focused on raising the funds for this new project, which like our first study will continue to identify the best combinations, antagonistic interactions, and sex and age differences in the degree to which each intervention can impact aging.

The specifics of the second study are being finalized, and we have conducted extensive work to narrow the options down, as I outlined in my presentation at LEVF's Dublin conference. Many of the remaining decisions, both between these options and concerning their details, come down to cost. Thus it continues to be the nature of our work that every offer of financial support counts. We are immensely grateful to those who have made our past work possible, and those who continue to make our future plans possible. Please reach out if you can help to make a difference!

Aging is a natural process associated with decreased physiologic function in all organs, i.e. it not only affects our immune system, but also affects all tissues and cells, resulting in increased risk of several chronic diseases and vulnerability to death. The gut microbiome is now recognized as one of the key elements to maintaining host health1 and contributing to disease progressions such as high abundance of pathogenic bacteria (such as Escherichia coli, Staphylococcus aureus, and Clostridium difficile) and low abundance of short-chain fatty acid producing bacteria such as Bifidobacterium, Faecalibacterium, Roseburia. Several studies over the past few years revealed that the gut microbiome and its composition changes with age which could have significant implications on overall health during aging, however, the mechanisms by which it impacts the biology of aging remain largely unknown.

The microbiome is composed of diverse microbes i.e., bacteria, archaea, viruses, eukaryotic microbes, and fungi, that have lived in and around our body since birth. The gut and skin are the most extensively colonized regions of our body, while other areas including the mouth, eyes, ears, and reproductive organs also harbor dense populations of specific microbes. These microbes establish a symbiotic relationship with the host, playing a crucial role in regulating essential functions such as protection against pathogens, immunomodulation, and maintaining the structural integrity of the gut mucosal barrier, indicating a strong association between abnormalities in gut microbiota and the development of a wide range of diseases including autoimmune disorders, depression, and neurodegenerative diseases such as Alzheimer's disease and metabolic disorders.

However, the mechanisms by which the microbiome contributes to the development of these diseases are unclear. There can be several mechanisms but inflammation is a key suspect. Low-grade inflammation is often higher in older adults but the source of inflammation remains largely elusive. Growing evidence indicates that gut dysbiosis, characterized by an imbalance in gut microbial composition, tends to escalate with age. This dysbiosis, in turn, contributes to increased gut permeability, often referred to as "leaky gut". This heightened permeability facilitates the passage of pro-inflammatory substances such as bacterial toxins and lipopolysaccharide (LPS) from the gut lumen into the bloodstream or mucosal immune system, thereby triggering inflammation. Elevated inflammation is also known to increase the permeability of other epithelial and endothelial barriers such as intestinal epithelia (leaky gut), blood vessel endothelia (leaky vessels), blood-brain barrier (BBB) (leaky brain), and others, and collectively called "leaky syndrome". The link between leaky syndrome with chronic inflammation and microbiome dysbiosis in aging biology remains poorly understood.

The field of aging is at a precipice. Attention and funding are increasingly focused on this area, and exciting, fundamentally important findings are being reported literally every day. As the great promise of targeting aging comes into sharper focus, we are rapidly approaching the point where we must face the elephant in the room: We lack any semblance of a consensus on the nature of aging or, more fundamentally, on the essence of this process. Taking steps to resolve these foundational issues in aging biology will enable us to advance this field to the next level.

As a field, we claim to study aging - but what, in essence, do we study? What is that most basic, fundamental feature of the process that we call aging? Is it functional decline, damage accumulation, increased mortality rate, continuation of development, increased biological age, decrease in the strength of natural selection, the totality of age-related changes, loss of homeostasis, loss of information, their combination, or something else? After organisms reach adulthood, all of these features seemingly go hand in hand, but their coordination is not perfect, and there must be one underlying, explanatory feature that leads to the others. What is it, and can we truly advance the field without identifying it?

Aging biology is exponentially growing as a field, and talented scientists are designing and carrying out many elegant studies. However, in many ways, we are attempting to construct a building without a foundation. One can see this by the lack of clear answers to some of the most basic questions: When does aging begin? To what extent, if any, is biological age dynamic and potentially reversible? Which biomarkers are most appropriate to measure biological age, and do any of them actually measure aging directly?

To begin answering these questions and ensuring the future success of this field, we propose two critical concepts on which aging biologists can actively focus their collective attention: the essence of aging and the nature of aging. To be clear, we are not suggesting that either a formal definition or a unified theory of aging is an immediate need for the field. The essence and nature of aging represent more fundamental concepts, from which we envision that a consensus definition and theory of aging may proceed in the future. In the immediate term, these concepts may serve as building blocks to form the basis of our understanding of aging biology.

We define the "essence of aging" as the most basic, essential, explanatory, and causative feature of biological aging. It is the underlying driving force of the manifestations of advanced age, such as frailty, loss of function, and age-related diseases. Identifying the essence of aging is critical if we wish to study and target aging itself, rather than its later-stage manifestations. Many aging biologists invoke the hallmarks or pillars of aging as a basic starting point for conceptually framing aging biology. However, the essence of aging, in our minds, represents a more fundamental concept underlying these and other characteristics of aging. In the same way that the Hallmarks of Cancer can be reduced to a single essence - mutations - we should be able to, and should strive to, distill a single essence of aging that drives all of the hallmarks/pillars and higher-level manifestations of aging.

We define the "nature of aging" as the inherent properties and dynamics that characterize aging as a biological phenomenon. The nature of aging is conceptually related to critical outstanding questions in the field, such as the behavior of biological age over the life course; the point at which aging begins; and the extent to which aging of a subset of cells or tissues impacts the aging of surrounding or distant cells/tissues. The nature of aging is a much broader concept than the essence of aging, but understanding the nature of aging is no less critical to our ability to target this process.

The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. This study assessed the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (older than 60 years) with dementia. Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries. Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables.

The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group.

The analysis included 17 studies with 34,519 community dwelling older adults (58.4% female) with a mean age of 72.5 ± 7.5 years and a mean follow-up of 4.3 ± 4.3 years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio 1.42) and 26% increased risk compared with individuals with treated hypertension (hazard ratio 1.26). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls. The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses.

In conclusion, this individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

In an earlier five-part series, I laid out the reasons to be skeptical that metformin would pan out as a longevity therapeutic. The centerpiece of the second post in the metformin series was a 2014 observational study, which is the one study that is most often cited as evidence that metformin slows aging in humans. A press release that accompanied the Bannister paper wrongly stated that it showed that "Type 2 diabetics can live longer than people without the disease" if they take metformin.

But as other scientists had pointed out before me, the study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients whose blood sugar was harder to get under control (those on second-line diabetes medications) as well as to a random assortment of the nondiabetic population. Their study design then unwittingly but systematically pushed subjects who were taking metformin "off the books" as soon as their diabetes got worse. This methodological artifact created the illusion that metformin users lived longer lives than nondiabetics, because it meant that the study would only count metformin users as metformin users if they managed to stay healthy.

In the months since I wrote the original blog post explaining this, I've become aware of two other studies asking the same core question but using different methods - and they both find that, as you would expect, people on metformin for diabetes are shorter-lived than people without diabetes. Because these studies address this question more directly than any of the studies discussed in that blog post, we'll review them here. In summary, the metformin users were clearly dying more often than the nondiabetic population. The long-term effect on metformin was better than going untreated as a diabetic, but its benefits were clearly not even enough to get them back on the miserable course of "normal" aging, let alone to have a real anti-aging effect.

We shouldn't stop looking for hidden benefits in common medications - and if we find good evidence that such a drug might slow something as terrible as degenerative aging, it may be worth it to follow that signal up with clinical trials. But with metformin, a story that emerged in cell culture and some poorly-designed animal and human observational studies have led many smart people astray. And even if metformin had turned out to be as effective as it seemed to be in some of the early studies of metformin in abnormally short-lived animals, the implied potential benefits for aging humans would have been pretty modest. It would garner an aging humanity a far greater gain if the media, many advocates, and scientists would redirect the resources and attention that have gone into metformin into developing therapies that directly repair the damage in aging tissues.

Optimal blood pressure (BP) management strategy among the elderly remains controversial, with insufficient consideration of long-term BP trajectory. In this study, we included 11,181 participants older than 60 at baseline (mean age, 80.98 ± 10.71) with 42,871 routine BP measurements from the Chinese Longitudinal Healthy Longevity Survey. Latent class trajectory analysis and Cox proportional hazard model were conducted to identify trajectory patterns and their associations with mortality. Furthermore, we also applied mixed-effects model to identify terminal BP trajectories among the elderly.

Compared with stable at normal high level trajectory, excess systolic BP (SBP) trajectory with decreasing trend was associated with a 34% (hazard ratio, HR = 1.34) higher risk of all-cause mortality. Considering the competing risk of non-CVD death, excess BP trajectory with decreasing trend had a more pronounced effect on cardiovascular disease (CVD) mortality, in which HR was 1.67. Similar results were also found in diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) trajectories. We further conducted a mixed-effects model and observed that SBP and PP trajectories first increased and began to decline slightly six years before death. In contrast, DBP and MAP showed continuous decline 15 years before death.

In conclusion, long-term BP trajectory was associated with all-cause mortality, especially CVD mortality. Keeping a stable BP over time may be an important way for CVD prevention among the elderly.

Even during physiologic aging, the kidney experiences a loss of mass and a progressive functional decline. This is clinically relevant as it leads to an increased risk of acute and chronic kidney disease. The kidney tubular system plays an important role in the underlying aging process, but the involved cellular mechanisms remain largely elusive. Kidneys of 3-, 12- and 24-month-old male C57BL/6J mice were used for RNA sequencing, histological examination, immunostaining, and RNA-in-situ-hybridization. Single cell RNA sequencing data of differentially aged murine and human kidneys was analyzed to identify age-dependent expression patterns in tubular epithelial cells. Senescent and non-senescent primary tubular epithelial cells from mouse kidney were used for in vitro experiments.

During normal kidney aging, tubular cells adopt an inflammatory phenotype, characterized by the expression of MHC class II related genes. In our analysis of bulk and single cell transcriptional data we found that subsets of tubular cells show an age-related expression of Cd74, H2-Eb1 and H2-Ab1 in mice and CD74, HLA-DQB1 and HLADRB1 in humans. Expression of MHC class II related genes was associated with a phenotype of tubular cell senescence, and the selective elimination of senescent cells reversed the phenotype. Exposure to the Cd74 ligand MIF promoted a prosenescent phenotype in tubular cell cultures.

Together, these data suggest that during normal renal aging tubular cells activate a program of 'tubuloinflammaging', which might contribute to age-related phenotypical changes and to increased disease susceptibility.

Chronic pain is one of the most common, costly, and potentially debilitating health issues facing older adults, with attributable costs exceeding 600 billion annually. The prevalence of pain in humans increases with advancing age. Yet, the contributions of sex differences, age-related chronic inflammation, and changes in neuroplasticity to the overall experience of pain are less clear, given that opposing processes in aging interact.

This review article examines and summarizes pre-clinical research and clinical data on chronic pain among older adults to identify knowledge gaps and provide the base for future research and clinical practice. We provide evidence to suggest that neurodegenerative conditions engender a loss of neural plasticity involved in pain response, whereas low-grade inflammation in aging increases central nervous system sensitization but decreases peripheral nervous system sensitivity. Insights from preclinical studies are needed to answer mechanistic questions. However, the selection of appropriate aging models presents a challenge that has resulted in conflicting data regarding pain processing and behavioral outcomes that is difficult to translate to humans.

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long-lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti-immunosenescence, we first built high-quality reference genome for a long-lived myotis bat, and then compared three long-lived mammals (i.e., bat, naked mole rat, and human) versus the short-lived mammal, mouse, in splenic immune cells at single-cell resolution.

A close relationship between B-cell:T-cell ratio and immunosenescence was detected, as B-cell:T-cell ratio was much higher in mouse than long-lived mammals and significantly increased during aging. Importantly, we identified several iron-related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long-lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of reactive oxygen species (ROS)-induced damage in mouse.

PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti-immunosenescence, and provide unique insight for improving human healthspan.

When biomes turn unhealthy, either by invasion of outside pathogens, or a major change in the relative numbers of the microbial species present, a dysbiosis, or imbalance in the microbiota, occurs. This dysbiosis can alter human metabolism and cause inflammation, which has been linked to the tissue damage seen in ulcerative colitis, rheumatoid arthritis, and many other chronic inflammatory diseases. Studying 130 samples from the donated brains of 32 people - 16 with Alzheimer's and 16 age-matched controls without the disease, researchers found bacterial flora in all the brains- but the Alzheimer's brains showed profoundly different bacterial profiles when compared to their age-matched controls.

The group used full-length 16s ribosomal RNA gene sequencing, a technique that can detect any and all bacterial species present in a sample. In this process, the researchers pinpointed disease-specific sets of bacteria in almost all of the Alzheimer's-affected brains, suggesting these groups of bacteria are strong predictors of the disease. The authors detected five brain microbiomes, four that are hypothesized to be present at different times in the evolution of the Alzheimer's-afflicted brains. The authors said it is likely that the observed Alzheimer's microbiomes evolve to become more pathogenic as the disease progresses with the later stages characterized as a pathobiome. The authors hypothesize that the brain begins with a healthy biome, but as the disease develops, the healthy biome is supplanted as a new set of microbes replace the original healthy ones with the eventual emergence of the Alzheimer's pathobiome.

Samples from both sets of brain samples were drawn from the frontal and temporal lobes and entorhinal cortex. Based on the random distribution of microbiomes requiring delivery all over the brain, the results were consistent with failure in one or more of the brain's networks; however it too soon to tell if the observed distribution patterns result from a leaky blood-brain barrier, the brain's glymphatic system, or synaptonemal transmission that allowed bacteria, including Cutibacterium acnes (formerly called Proprionibacterium acnes), Methylobacterium, Bacillus, Caulobacter, Delftia, and Variovora to enter the brain. In Alzheimer's brain samples, the researchers noted, these pathogenic bacteria appeared to have overpowered and replaced Comamonas sp. bacteria, which are associated with a dementia-free brain.

Researchers interested in the biology of aging, and its potential modification by antiaging drugs, have devoted a substantial amount of community effort to the search for possible biomarkers of aging, conceived as quantifiable traits that can reveal the biological age of an individual animal. The central framework here is that such biomarkers might change monotonically through some relevant portion of adult life, might discriminate younger from older adults, might predict mortality risk at some useful distance from ultimate date of death, and, crucially, might serve, individually or collectively, as surrogate endpoints for studies of putative antiaging diets, drugs, or polymorphic alleles. Like an odometer in a car, biomarkers or weighted combinations of biomarkers might in principle reveal how far along the aging trajectory an individual organism has already proceeded. Odometers do not reveal the speed at which a car is currently traveling. A low-mileage or high-mileage car might be going quickly or slowly. Speed and distance traveled are independent and unconnected measures of a vehicle's state.

This essay presents the concept of aging rate indicators (ARIs) as speedometers for aging research. In principle, an ARI is a quantitative trait or measurement, an endpoint, which discriminates slow-aging mice from normal mice; it measures how quickly the aging process is proceeding in an individual organism. (The definition carefully takes no position on whether ARIs might also discriminate fast-aging animals from normal ones, a topic that will be deferred for another occasion). An ideal ARI would make this discrimination regardless of the age at which it is measured, at least within the portion of adult life where serious diseases are rare and mortality risk is minimal. The critical feature of an idealized ARI, the critical test of a candidate ARI, is that it should be modulated, in the same direction, by antiaging perturbations, whether the slowed aging and extended lifespan are caused by genetic factors, by dietary intervention, or by lifespan-increasing drugs.

It is helpful to consider the differences between ARIs and the more familiar biomarkers of aging. If a measurement - an estimate of collagen cross-linking, a score of visual acuity, or reflex speed, an index combining levels of DNA methylation at several sites, a T cell subset ratio, and so on - is proposed as a biomarker of aging, it is expected to show age-related change in adults, that is, to distinguish young, middle-aged, and older adults. Evaluation of an endpoint as a candidate ARI involves an entirely different set of criteria. Evidence that a candidate ARI changes with age is quite beside the point, because ARIs are taken to be measures of the pace or speed at which aging is currently occurring, and not as indices of how much a given subject has already aged, in the past. In such a framework, estimates of ARIs made in young adults are expected to be highly informative, because these individuals may actually be aging at different rates; for example, one might be on a calorie-restricted (CR) diet, or carry a mutant growth hormone receptor (GHR) allele, or be in a rapamycin treatment cohort. The key criterion for a putative ARI is that it should be modified, in a consistent direction, by most or all genes, diets, and drugs that are known, on independent evidence, to slow the signs of aging, postpone late-life illnesses, and increase lifespan.

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson's. But the new study suggests that a dysfunction in the neuron's synapses - the tiny gap across which a neuron can send an impulse to another neuron - leads to deficits in dopamine and precedes the neurodegeneration. The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans.

Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of. It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of ineffective mitophagy.

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson's disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48. The reason for the disparity led to an important new discovery. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson's.

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal - unrelated to its recycling work - where it controls dopamine release. With this new understanding of what went wrong for the sister, scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons. "We discovered a new mechanism to activate Parkin in patient neurons. Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson's."

Two weeks ago, longevity biotech startup Clock.bio emerged from stealth with 4 million in funding, and setting itself an ambitious goal to be in a Phase 3 trial for a healthspan-extending intervention by the end of the decade. With the clock ticking, the company is already working to map rejuvenation biology across the entire human genome over the next 12 months. Having completed an initial screen of around 1,000 genes, Clock.bio says it has already identified several new potential rejuvenation targets.

The company is based on the idea of triggering the self-rejuvenation mechanism of pluripotent stem cells to gain insight into the cellular drivers of aging and rejuvenation. Crucially, Clock.bio has found a way to shortcut the screening process required to identify rejuvenation drivers across the entire human genome. "We have been able to create a paradigm in the lab, where we override the repair programs, and force-age the stem cells, so that their rejuvenation capabilities kick in again." The company uses unbiased CRISPR screens on large samples of stem cells to identify gene candidates that are causally relevant for cell rejuvenation.

Clock.bio then identified some existing, approved drugs that could potentially be used against the targets identified in the first screen. "We looked at whether these drugs could beneficially modulate aged neurons - we found that they did, and if we combined them the results got even better. So, now we have this end-to-end validation in vitro - from being able to identify rejuvenation genes, which are essentially controlling repair processes, through to activating those repair processes in aged cells. It's a completely unbiased way to understand every process that's involved in restoring the aging hallmarks."

Atherosclerosis is chronic arterial inflammation caused by both conventional and unconventional risk factors that result in plaque development in the vascular intima. Inflammation starts with the activation of NLRP3 inflammasomes, which results in the production of proinflammatory cytokines IL-1 and IL-18, acting via the autocrine, paracrine, or endocrine pathways. IL-1 has been demonstrated to promote its own gene expression in a variety of cell types through an amplification loop known as autoinduction. IL-1 increases endothelial dysfunction, leukocyte-endothelial cell adhesion, procoagulant activity, and neutrophil recruitment, all of which contribute to atherogenesis and plaque ruptures.

Aging is one of the strongest risk factors for atherosclerosis which increases the morbidity and mortality of patients. Understanding the mechanisms of the age-related increase in atherosclerotic diseases can better guide prevention and therapy in this risk group, since it is unclear whether aging itself increases the susceptibility to atherosclerotic diseases and their severity. In this review, we present two main areas in which aging promotes atherosclerosis. The first group of factors is those outside of the vascular system, such as the impact of age on the clonal hematopoiesis of indeterminate potential (CHIP) differentiation of hematopoietic cells in the myeloid cell lineages. The second group of factors is the vascular intrinsic ones, such as the effect of aging on vascular bioenergetics due to impairment of mitochondrial function, mitophagy (removal of damaged mitochondria), and an impact on inflammation in vessels. In addition, mitochondrial DNA damage, which is an early event of atherogenesis in apolipoprotein deficient (ApoE) mice, can result in mitochondrial dysfunction, leading to proatherogenic processes such as inflammation and apoptosis.

The vascular endothelium, as an integral component of the cardiovascular system intimately interfacing with the blood, plays a crucial role in maintaining systemic homeostasis. It acts as a lining of the cardiovascular system, forming a particular barrier to various molecules. It assumes multifaceted functions within the human body, being intricately responsive to a myriad of external stimuli present in the surrounding environment. The vascular endothelium plays a regulatory role in vascular muscle contraction, relaxation, smooth muscle proliferation, and the expression of adhesion molecules or chemotactic factors. These factors are responsible for the adhesion, activation, or migration of inflammatory cells, as well as platelet adhesion and aggregation. Additionally, the vascular endothelium influences the coagulation and fibrinolysis processes. Disruption of these processes underpins the mechanism of atherosclerosis of the blood vessels.

The adaptation-maladaptation framework of aging posits that a cornerstone of aging is a decrease in the ratio of beneficial adaptation (Ab) to harmful adaptation (Ah) at several organizational levels of the organism, from cells to cell networks to the whole body. Decreases in Ab lead to lowered capacities in physiological adaptation functions such as learning and memory, immune system plasticity, and muscle anabolism, whereas increases in Ah promote dysfunctional metabolic remodeling, cancer, autoimmunity, and pathological cardiovascular remodeling, among others.

Certain adaptation mechanisms such as adaptive transcription can be involved in protection against aging as well as driving aging-related pathologies. Thus, aging-related decline might be inevitable but not necessarily due to random accumulation of damage over time but because adaptive mechanisms will, one way or the other, lead to progressive dysfunction (e.g., either through "directed" damage as part of adaptation or through maladaptation). Because aging is at least partly an active process, it might be possible to counteract it if we understand how biological goal states can be influenced and how adaptation mechanisms can be directed. To do so, we need to study the underlying molecular signaling dynamics in greater detail beyond mere upregulation or downregulation and beyond simple association studies.

Studying aging from the perspective of the adaptation-maladaptation dilemma with the central phenotype of a reduction in Ab/Ah opens up new experimental and theoretical approaches to study longevity mechanisms.