Fight Aging!

This open access paper could serve as an introduction to aging clocks for someone who has previously given little attention to the ongoing attempts to build ways to quickly and cost-effectively measure biological age. Near every complex set of biological data obtained from an individual can be used to build clocks that estimate age. The present major challenge is the inability to trust the results of any specific clock for any specific scenario involving the use of therapies to treat aging. There is next to no understanding of how in detail the clock data is driven by mechanisms and dysfunctions of aging, and thus no ability to predict ahead of time whether a clock will give useful answers for any given therapy targeting a mechanism of aging. Clocks must be calibrated to their uses, and this is a slow and expensive process.

Aging research has delineated the aging process by classifying two separate but interconnected mechanisms: intrinsic and extrinsic aging. Intrinsic aging describes changes in biological hallmarks including cellular and molecular changes, genetics, and hormonal changes that have been described to occur naturally over time. Extrinsic aging, however, is regulated by exposure to environmental stressors, dietary habits, oxidative stress, and other factors that accelerate physiologic aging. Traditionally, aging has been quantified by chronological age, which is the exact number of years an individual has lived. However, chronological age does not fully capture the heterogeneity of the aging process, excluding many extrinsic factors that contribute to aging.

Subsequently, the calculation of biological age, which aims to account for interindividual variations in aging rate, has become a topic of interest in aging research. Aging clock models are tools that utilize various modeling approaches to estimate chronological or biological age. Moreover, aging clock models can estimate the rate of aging (ΔAge), otherwise known as the difference between model-predicted biological age and chronological age. Positive differences between model-predicted biological age and chronological age indicate accelerated aging whereas a negative difference indicates decelerated aging. If the calculated ΔAge exceeds the mean absolute error (MAE) of the aging rate estimation, these individuals can be determined to be fast or slow agers.

Aging clocks models may utilize any hallmark changes that occur because of aging, and these may include epigenetic changes, telomere length, genomic stability, altered intercellular communication, chronic inflammation, and gut microbiome dysbiosis, among others. Notably, some of the first aging clock models include the Horvath clock (2013) and Hannum clock (2013), which are both epigenetic clocks modeled after changes in DNA methylation patterns and varying cytosine phosphate guanine (CpG) sites across the genome. Several aging clock models have emerged since then, varying from microbiome-based clocks to proteomic clocks.

Link: https://doi.org/10.3389/fragi.2024.1487260

To what degree is it possible to slow or regress atherosclerosis by clearing senescent cells from plaque and artery walls? A few lines of evidence from animal studies suggest that slowing plaque growth is possible. These include efforts to clear senescent macrophages that have become foam cells in plaque using small molecule senolytics, or Bitterroot Bio's targeting of CD47 to achieve a similar outcome. This does not appear to produce plaque regression, however, most likely because it doesn't address the toxic cholesterol that makes up a plaque. That cholesterol will continue to attract new cells and drive those cells into dysfunction and senescence for so long as it is present.

CDKN2A/p16INK4a, a key marker of cellular senescence, is substantially upregulated during cell senescence. The elevated expression of CDKN2A inhibits the activation of CDK4 and CDK6, decreases Rb phosphorylation and blocks the G1/S transition of the mitotic cell cycle. The expression of CDKN2A increases significantly with age driven by oxidative stress and reactive oxygen species (ROS) accumulation in endothelial progenitor cells and modulates age-dependent senescence of these cells. Elimination of CDKN2A/p16INK4a-positive senescent cells has proved to be effective to attenuate age-dependent changes in several organs including kidney and heart. Therefore, CDKN2A appears to play a critical role on the onset and progression of cellular senescence. Control of CDKN2A expression is therefore a crucial mechanism for suppressing cellular senescence. To date, no studies investigated whether preventing the activation of CDKN2A and CDK4 and CDK6 pathway ameliorates vascular cellular senescence and atherogenesis in vivo and in vitro.

In our studies, β-galactosidase activity and ROS production were significantly elevated in human and mice atherosclerotic lesions. β-galactosidase, co-localized with CD31, was obviously upregulated in atherosclerotic lesions, indicating endothelial cellular senescence in vivo. CDKN2A, co-localized with CD31, was markedly increased in atherosclerotic lesions. Colocalization of CDKN2A with CDK4 and CDK6 revealed the potential connection in vivo.

Knockdown of CDKN2A counteracts endothelial cell senescence induced by oxidized LDL. CDK4 and CDK6 inhibitor palbociclib, a potent anti-proliferative agent for the treatment of breast cancer, is demonstrated to accelerate endothelial cell senescence in vitro and deteriorate atherogenesis in vivo. Our findings suggest that by ameliorating endothelial cell senescence, modulating CDKN2A and CDK4 and CDK6 pathway may represent a new highly promising strategy for the treatment of atherosclerosis.

Link: https://doi.org/10.1016/j.bcp.2025.116916

Proteins make up most of the cogs, wheels, and switches of the intricate machinery of the cell. Their assemblies and interactions depend on the proteins involved having the correct structure. A protein is a complicated molecule and assembly alone, by joining amino acids together in a ribosome according to the blueprint provided by a messenger RNA molecule, doesn't guarantee that the resulting protein ends up folded into the right shape. Chaperone molecules exist to guide protein folding, but one of the forms of stress that a cell can suffer is the accumulation of unfolded or incorrectly folded proteins. Too much of this and the cell behavior changes to become problematic, or the cell dies.

Cells respond to this form of stress with what is known as an unfolded protein response, which can focus on the endoplasmic reticulum where most proteins are folded, those encoded in the nuclear genome, or it can focus on mitochondria. As the descendants of ancient symbiotic bacteria, mitochondria have their own small genome and can manufacture their own proteins independently of the rest of the cell. Thus they can also suffer unfolded protein stress, and can mount a response against it.

As researchers point out in today's open access review, the generally beneficial consequences of the mitochondrial unfolded protein response are not limited to the mitochondria, but have important effects on other parts of the cell, other cells, and even other tissues in the body. In part this is because most formerly mitochondrial genes have migrated to the cell nucleus over evolutionary time, but producing distant benefits is generally a characteristic of cell stress responses, as illustrated by the response to calorie restriction, heat shock, and so forth.

The mitochondrial unfolded protein response: acting near and far

The paramount importance of maintaining a healthy protein pool is highlighted by the significant fraction of the proteome that is devoted to protein surveillance across species. An extensive plexus of chaperones and the proteolytic degradation machinery, coordinated by stress response pathways, collectively referred to as the proteostasis network (PN), safeguards proteostasis. Notably, the efficacy of the PN declines with age, leading to the accumulation of misfolded proteins, toxic oligomers, and protein aggregates, culminating in proteotoxicity. Post-mitotic cells, such as neurons, are particularly susceptible to protein aggregation and PN dysfunction. Intensive scientific efforts have been focused on slowing PN decline to mitigate late-onset neurological disorders.

Mitochondria are the result of endosymbiotic events between ancestral eukaryotic cells and free-living proteobacteria. They are central to cellular metabolism, producing ATP via oxidative phosphorylation (OXPHOS) and being involved in processes such as the TCA cycle and the beta-oxidation of fatty acids, but are also critical for the production of essential cofactors and regulatory metabolites. Mitochondrial dysfunction is a key hallmark of aging and is associated with the manifestation of a wide spectrum of human pathologies affecting the muscular, neuronal and immune systems. Sophisticated quality control and protein turnover mechanisms (i.e. chaperones, proteases, mitochondrial-associated degradation) maintain protein integrity in various mitochondrial compartments, while others ensure that irreversibly damaged or superfluous mitochondria are removed by autophagic degradation (i.e. mitophagy). The vast majority (more than 99%) of mitochondrial proteins are encoded by the nuclear genome, translated by cytosolic ribosomes and then imported into the mitochondria. Therefore, any change in the mitochondrial status should be communicated to the nucleus so that the mitochondrial network can successfully adapts to ever-changing physiological demands and functionally recover from stress.

To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as the mitochondrial unfolded protein response (UPRmt) is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.

Epidemiological evidence for improved health and reduced late life mortality in vegans and vegetarians is both extensive and much debated at the detail level. The study noted here is an interesting addition to this body of work, the researchers having found a sizable population with a long-standing practice of cycling between periods of vegan and omnivorous diets. This produces a more compelling picture of beneficial metabolic changes that take place when animal products are eliminated from the diet. It remains a question as to how much of this is due to a reduced calorie intake in a vegan diet versus other mechanisms.

Dietary interventions constitute powerful approaches for disease prevention and treatment. However, the molecular mechanisms through which diet affects health remain underexplored in humans. Here, we compare plasma metabolomic and proteomic profiles between dietary states for a unique group of individuals who alternate between omnivory and restriction of animal products for religious reasons. We find that short-term restriction drives reductions in levels of lipid classes and of branched-chain amino acids, not detected in a control group of individuals, and results in metabolic profiles associated with decreased risk for all-cause mortality.

We show that 23% of proteins whose levels are affected by dietary restriction are druggable targets and reveal that pro-longevity hormone FGF21 and seven additional proteins (FOLR2, SUMF2, HAVCR1, PLA2G1B, OXT, SPP1, HPGDS) display the greatest magnitude of change. Through Mendelian randomization we demonstrate potentially causal effects of FGF21 and HAVCR1 on risk for type 2 diabetes, of HPGDS on BMI, and of OXT on risk for lacunar stroke. Collectively, we find that restriction-associated reprogramming improves metabolic health and emphasise high-value targets for pharmacological intervention.

Link: https://doi.org/10.1038/s44324-025-00057-2

One of the primary ways in which the beneficial, age-slowing response to calorie restriction is regulated is via sensing of methionine levels. Methionine is an essential amino acid, used in all protein synthesis, but not manufactured in the body. It must come from the diet. There is plenty of evidence for methionine restriction, meaning to construct a diet that is low in methionine without reducing calorie intake, to slow aging in rodents. Researchers here demonstrate that it remains beneficial when started in old age in mice. Interestingly, they also find that it doesn't affect epigenetic age, which is an intriguing outcome akin to the insensitivity of early epigenetic clocks to physical fitness.

We and others previously demonstrated that both steady-state levels of methionine and methionine flux are altered during aging using Drosophila as a model system. Moreover, targeting methionine metabolism via dietary manipulations of fly food, enzymatic degradation, or manipulation of enzymes either directly involved in methionine metabolism or those that affect the levels of methionine metabolism metabolites extend health- and lifespan. In addition to results seen in Drosophila, methionine restriction (MetR) extends lifespan in yeast, rodents, and human diploid fibroblasts.

Here, we determine whether targeting either methionine metabolism with dietary MetR started late in life in 18-month-old male and female C57BL/6J mice for 6 months affects various aspects of aging-related phenotypes. Dietary MetR does not affect mouse epigenetic clocks despite multiple improvements in different parameters of metabolic health, neuromuscular function, lung function, and frailty index. Similarly, we did not observe any effects of dietary MetR on human epigenetic clocks.

Using single-nucleus RNA sequencing (snRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on the muscle tissues, we identified several subtype-specific processes and transcription factors (TFs) activated by dietary MetR that indicates a cell type-specific response to MetR. In addition, we confirm the beneficial effects of dietary MetR on neuromuscular function in a separate disease cohort using the Alzheimer's disease 5XFAD mouse model. Based on these mouse studies, targeting methionine metabolism holds great promise as an antiaging intervention in humans.

Link: https://doi.org/10.1126/sciadv.ads1532

Navigating a pharma or biotech startup company from preclinical proof of concept of some new and potentially useful technology to the stage of running clinical trials is hard at the best of times. To a first approximation, institutional investors, those with deep enough pockets to fund the enormous regulatory costs imposed upon drug manufacture and clinical trials, do not fund new directions, new mechanisms, truly novel therapies. We can debate whether those at fault are more the venture capitalists who run the funds or the limited partners who hold the purse strings, but the end result is a strong aversion to well understood risks - such as anything that is new. Investors like small tweaks on proven existing drugs, which is how we end up with overinvestment in strategies for lowering LDL cholesterol, despite the fact that none of these drugs is capable even in principle of reliably reversing cardiovascular disease.

On top of that, most of the last decade has been a decided gloomy market environment for drug development. Good technologies have fallen to the wayside. The latest to succumb is Covalent Biosciences, developer of catalytic antibodies. They are shutting down, preparing some scientific publications to explain the aspects of their platform and research not already published, and in a few years their patents will expire. Catalytic antibodies are in principle vastly more effective than normal antibodies, as the catalytic antibody can interact with countless target molecules rather than just one. The Covalent Biosciences team sought to apply this technology to transthyretin amyloidosis and Alzheimer's disease, among other targets.

If we want to speculate as to the reasons why Covalent Biosciences failed to attract the necessary funding to run clinical trials, one might think that it was because they couldn't have picked a worse period of years to work on transthyretin amyloidosis and Alzheimer's disease. In the former case, therapies based on stabilizing transthryretin to prevent misfolding emerged to prove effective enough to give investors pause on funding other approaches yet to reach the clinic. In the latter case, amyloid-targeting immunotherapies deployed by large pharmaceutical companies have had their moment of success in recent years, eclipsing any alternative path to amyloid clearance for now.

Secondly, investors care about remaining patent life span, how much is left of the 20 years since the filing date. The high valuation of a drug development company derives from the legal monopoly over its technology given by a patent. Without that high valuation, a company cannot raise the enormous funds required by regulators set up manufacturing and run clinical trials. If a company goes too long without having successfully made the leap to the clinic, then its present and potential future value falters in the eyes of investors. Covalent Biosciences was working with core patents that were already well advanced in years.

One can hope that, once in the public domain, someone will advance the catalytic antibody platform and find uses for it. By the way that the biotech industry works, that will necessarily mean establishing some novel antibody or approach to catalytic antibodies in order to generate novel patents and start the clock ticking once more. Looking at what has happened elsewhere, this might take a decade or more to come to pass - look at how long it took for a company to emerge to pick up work on the DRACO antiviral approach. What we most likely won't see is a company making use of the existing advances and drug candidates, for the reasons of valuation and funding noted above; off-patent technologies do not attract funding, but still have the same regulatory costs. This is the same reason that generic drugs and supplements are largely ignored by the clinical industry, even if they might be very useful, such as the dasatinib and quercetin combination to clear senescent cells. If you think that there really should be a better way to run medical research and development, well, you are not the only one!

The balance of microbial species making up the gut microbiome has been shown to change with age. Inflammatory microbes grow in number at the expense of species that generate beneficial metabolites such as butyrate. Patients with neurodegenerative conditions, diseases that are characterized by chronic inflammation and immune dysfunction, have been shown to exhibit a distinctly dysfunctional gut microbiome. In human populations, there remain the questions on direction of causation, but in animal models researchers can quite readily demonstrate that transplanting a young gut microbiome into an old animal improves health, while the reverse happens when an old gut microbiome is transplated into a young animal.

Gut microbiota alteration during the aging process serves as a causative factor for aging-related cognitive decline, which is characterized by the early hallmark of hippocampal synaptic loss. However, the impact and mechanistic role of gut microbiota in hippocampal synapse loss during aging remains unclear. Here, we observed that the fecal microbiota of naturally aged mice successfully transferred cognitive impairment and hippocampal synapse loss to young mouse recipients. Multi-omics analysis revealed that aged gut microbiota was characterized with obvious change in Bifidobacterium pseudolongum (B.p) and indoleacetic acid (IAA), a metabolite of tryptophan, in the periphery and brain. These features were also reproduced in young mouse recipients that were transplanted with aged gut microbiota.

In human patients, fecal B.p abundance was reduced in patients with cognitive impairment compared to healthy subjects and showed a positive correlation with cognitive scores. Microbiota transplantation from human patients who had fewer B.p abundances into mice yielded worse cognitive behavior in the mice than transplants from human patients with higher B.p abundances.

Supplementation of B.p was capable of producing IAA and enhancing peripheral and brain IAA bioavailability, as well as improving cognitive behaviors and microglia-mediated synapse loss in 5xFAD transgenic mice. IAA produced from B.p was shown to prevent microglia engulfment of synapses in an aryl hydrocarbon receptor-dependent manner. This study reveals that aged gut microbiota induced cognitive decline and microglia-mediated synapse loss that is, at least partially, due to the deficiency in B.p and its metabolite, IAA. It provides a proof-of-concept strategy for preventing neurodegenerative diseases by modulating gut microbiome and their tryptophan metabolites.

Link: https://doi.org/10.1111/acel.70064

Epigenetic clocks of various sorts have become quite diverse in recent years, and it is worth noting that more recent clocks do not exhibit the insensitivity to physical fitness that was a characteristic of the earliest clocks. We should assume that any clock will have quirks, even those that do well with exercise. Since the relationships between specific causes and dysfunctions in aging and the specific epigenetic marks used in epigenetic clocks remain almost entirely unknown, a clock cannot be trusted to correctly assess the impact of any specific intervention on aging. The clock has to be calibrated against that intervention. This defeats the whole point of the exercise, which is to find ways to quickly assess the merits of potential novel rejuvenation therapies, without having to run lengthy studies to assess life span and mortality.

Epigenetic clocks include several specific measures such as HorvathAge, HannumAge, SkinBloodAge, LinAge, WeidnerAge, VidalBraloAge, ZhangAge, and PhenoAge. Ageing research increasingly focuses on understanding the biological mechanisms that contribute to ageing and how lifestyle factors, such as physical activity (PA), can influence these processes. The above epigenetic ageing indicators represent different approaches to estimating biological age and have been associated with various health outcomes. Recent studies have highlighted the stronger and more consistent associations between PA and epigenetic aging, especially with GrimAge.

This study investigates the relationship between physical activity (PA) levels and DNA methylation (DNAm)-predicted epigenetic clocks in a U.S. population sample (n = 948, mean age 62, 49% female). The eight above mentioned epigenetic clocks were analyzed, revealing that higher PA levels were significantly associated with younger biological ages across all indicators, with the strongest effects observed for SkinBloodAge and LinAge. Subgroup analyses indicated that these associations were more pronounced among non-Hispanic whites, individuals with a BMI of 25-30, and former smokers, suggesting that the impact of PA varies across different groups. These findings emphasize the role of PA in slowing biological ageing and reducing age-related health risks.

Link: https://doi.org/10.1038/s41514-025-00217-0

A great many studies have used large human population data sets to show statistical relationships between specific gene variants or specific protein levels on the one hand and age-related disease and mortality on the other. Near all of these relationships represent a small effect size, and further fail to replicate in different study populations. Still, researchers keep trying. Some successful replications have been achieved, and a few genes and proteins are generally accepted as being longevity-associated in humans. It remains unclear as to whether they are of any great practical relevance to extending the healthy human life span, however. Some, such as klotho and APOE, are the subject of programs to develop treatments to improve late-life health or treat specific age-related diseases.

Today's open access paper is an interesting example of establishing a protein association with increased mortality and accelerated aging, and then tracing it back to a relationship with lifestyle factors, cancer incidence, and mechanisms relating to cellular senescence. Senescent cells accumulate with age and are an important contributing factor in age-related disease and loss of function. The research focuses on PDAP1, a protein that appears to be upregulated in stressed and senescent cells, and also acts to induce senescence in bystander cells. One would imagine that the next step here is to run studies of PDAP1 inhibition in aged mice, to see whether long term health and mortality are improved.

Identifying PDAP1 as a Biological Target on Human Longevity: Integration of Mendelian Randomization, Cohort, and Cell Experiments Validation Study

Identifying factors affecting lifespan, including genes or proteins, enables effective interventions. We prioritized potential drug targets and provided insights into biological pathways for healthy longevity by integrating Mendelian randomization, cohort, and experimental studies. We identified causal effects of tissue-specific genetic transcripts and serum protein levels on three longevity outcomes: the parental lifespan, the top 1% and 10% extreme longevity, utilizing Mendelian randomization and multi-traits colocalization, combining the latest genetics data of gene expression (eQTLGen and GTEx) and proteomics (4746 proteins from five studies). We then evaluated associations of these potential genetic targets with mortality risk and life expectancy in the UK Biobank cohort. We performed in vitro cellular senescence experiments to confirm their effects.

Fourteen plasma proteins and nine transcripts in whole blood had independent causal effects on longevity, where a cascading effect of both the tissue-specific transcripts and plasma proteins of LPA, PDAP1, DNAJA4, and TMEM106B showed negative effects on longevity. PDAP1, also known as platelet-derived growth factor subunit A-associated protein 1, is a multi-tissue-expressed protein in the pathway that suppresses T-cell function. It has become a potential target for c-myc and contributes to carcinogenesis. Mediation analysis suggested that PDAP1 decreased longevity via decreased SHBG, increased waist circumference, blood pressure, smoking, and alcohol consumption in addition to cancer.

Studies also suggested that lower SHBG levels may increase testosterone levels, leading to cardiovascular risk factors. The harmful effects of altered diseases or traits were also consistent with the epigenetic acceleration of aging caused by PDAP1. These results were consistent with our findings from the UK Biobank, where the plasma level of PDAP1 was significantly associated with all-cause mortality and life expectancy. In addition, the in vitro experiments indicated targeting PDAP1 offers a dual advantage by potentially promoting senescence in cancerous cells to inhibit growth, while delaying senescence in healthy cells to enhance tissue regeneration and extend cellular lifespan.

Reactive astrocytes in brain tissue are those that have become inflammatory in response to the local environment. With aging this becomes a prevalent phenomenon, driven by forms of molecular damage characteristic of aging, which range from greater inflammatory signaling from other cells, including senescent cells, to the build up of metabolic waste in the brain as drainage of cerebrospinal fluid falters. Widespread astrocyte reactivity is maladaptive, and contributes to the onset and progression of neurodegenerative conditions. The research community tends not to focus on how to prevent reactivity, such as by repairing the damage of aging, but rather on the worse course of trying to force reactive astrocytes into better behavior, one aspect at a time. The research here is one example of this strategy in practice. Even if successful, the reactive astrocytes remain present, causing other problems in other ways.

Astrocytes, once thought to only support neurons, are now known to actively influence brain function. In Alzheimer's disease, astrocytes become reactive, meaning they change their behavior in response to the presence of amyloid-beta (Aβ) plaques, a hallmark of the disease. While astrocytes attempt to clear these plaques, this process triggers a harmful chain reaction. First, they uptake them via autophagy and degrade them by the urea cycle, as discovered in previous research. However, this breakdown results in the overproduction of GABA, which dampens brain activity and leads to memory impairment. Additionally, this pathway generates hydrogen peroxide (H2O2), a toxic byproduct that causes further neuronal death and neurodegeneration.

Researchers set out to uncover which enzymes were responsible for excessive GABA production, hoping to find a way to selectively block its harmful effects without interfering with other brain functions. Using molecular analysis, microscopic imaging, and electrophysiology, the researchers identified SIRT2 and ALDH1A1 as critical enzymes involved in GABA overproduction in Alzheimer's-affected astrocytes. SIRT2 protein was found to be increased in the astrocytes of the commonly used AD mouse model as well as in post-mortem human AD patient brains.

"When we inhibited the astrocytic expression of SIRT2 in AD mice, we observed partial recovery of memory and reduced GABA production. While we expected reduced GABA release, we found that only short-term working memory of the mice was recovered, and spatial memory was not. This was exciting but also left us with more questions. We found that inhibition of SIRT2 continued H2O2 production, indicating that neuronal degeneration might continue even though GABA production is reduced."

Link: https://ibs.re.kr/cop/bbs/BBSMSTR_000000000738/selectBoardArticle.do?nttId=25775

As researchers here note, age-related diseases of the retina are age-related because underlying mechanisms of damage and dysfunction place stress on cells, changing their function and even killing them. Measuring changes in gene expression that take place in stressed cells is one way to look at these unfortunate effects, though it gives little insight into the fine details of why cell behavior changes. The various forms of damage and dysfunction that cause aging are fairly well catalogued, but it is presently unknown as to how they interact with one another in detail, and which of them is the most important in any given context. The easiest way to find out at present is to build a therapy that can address a form of damage, and test it in animal models.

Aging of the retinal pigment epithelium (RPE) leads to a gradual decline in RPE homeostasis over time, significantly impacting retinal health. During the physiological aging process, retinal tissues undergo functional decline and degeneration with the RPE serving as the primary site of damage in many age-related retinal diseases. While aging itself may not invariably lead to the onset of conditions such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR), age-related changes can predispose the eye to these diseases

Understanding the mechanisms underlying RPE aging is crucial for elucidating the background in which many age-related retinal pathologies develop. In this study, we compared the transcriptomes of young and aged mouse RPE and observed a marked upregulation of immunogenic, proinflammatory, and oxidative stress genes in aging RPE. Additionally, aging RPE exhibited dysregulation of pathways associated with visual perception and extracellular matrix production.

Link: https://doi.org/10.18632/aging.206219

About a decade ago, researchers developed a way to use magnetic resonance imaging (MRI) to measure the passage of fluid through channels leading from the brain into the body. One can use MRI to assess the diffusion of water molecules in many small volumes of scanned tissue. If there is a flow, then it appears as though the "diffusion" is biased in a specific direction. There is one small section of the glymphatic system that drains cerebrospinal fluid from the brain in which the vessels run in parallel, and this allows researchers to measure the flow of cerebrospinal fluid from the brain.

This ability to measure glymphatic fluid flow is important because the drainage of cerebrospinal fluid from the brain into the body carries away metabolic waste with it. This process of drainage occurs through a few different important channels, but the flow rate declines with age in all of them. Researchers hypothesize, and with a growing body of experimental and epidemiological data to support these hypotheses, that impaired drainage allows a buildup of waste in the brain that contributes to inflammation and neurodegeneration. You might recall a recent study linking reduced glymphatic flow with progression of Alzheimer's disease. In today's open access paper, researchers perform much the same study for the earlier progression of mild cognitive impairment leading into the initial onset of Alzheimer's disease. Again, an impaired drainage of cerebrospinal fluid correlates with worse loss of cognitive function and progression towards disease.

One can be done about this? Well, there are some promising initial signs. Loss of glymphatic flow may be largely a problem of dysfunctional lymphatic vessels, unable to contract efficiently enough to sustain a pulsatile flow of fluid. Classes of drug that affect the smooth muscle that surrounds these vessels were recently shown restore the ability of aged glymphatic vessels to drive fluid flow. Further, since a great deal of work has gone into ways to manipulate blood vessel behavior, and blood and lymphatic vessels share many similarities, there may be more existing options beyond this that will also work to restore cerebrospinal fluid drainage.

Poor glymphatic function is associated with mild cognitive impairment and its progression to Alzheimer's disease: A DTI-ALPS study

The glymphatic and meningeal lymphatic systems are crucial for clearing metabolic waste from cerebrospinal fluid (CSF) in the brain, and their dysfunction, particularly regarding the accumulation of amyloid-β and extracellular tau, may contribute to Alzheimer's disease (AD). Recently, researchers developed a method to measure diffusivity along the perivascular space (ALPS) based on diffusion tensor images, which allows for noninvasive and efficient assessment of glymphatic function. This approach quantifies the diffusion of water within the perivascular space along deep medullary veins and has been correlated with glymphatic clearance by dynamic contrast-enhanced imaging. Recent studies have shown that the ALPS index is associated with cognitive decline, AD, and multiple neurological disorders, and might serve as a biomarker for neurodegenerative diseases. However, no studies have been conducted on the association of ALPS index with mild cognitive impairment (MCI) and its progression to AD.

This study included 519 adults including 253 cognitively normal (CN) and 266 MCI participants from Alzheimer's Disease Neuroimaging Initiative. Glymphatic function (assessed by along the perivascular space [ALPS] index) was measured by diffusion tensor image at baseline. During follow-up (median 3.6 years), 30 (11.86%) participants developed MCI in the CN cohort and 73 (27.4%) participants progressed to AD in the MCI cohort. The hazard ratios of the higher ALPS index, indicating greater glymphatic flow, was 0.605 for MCI and 0.501 for AD. In addition, participants with high ALPS index had 3.837 and 3.466 years prolonged onset of MCI and AD, separately.

In conclusion, high ALPS index decreases MCI risk and delays MCI progression to AD by approximately 3.5 years. Amyloid-β in choroid plexus, tau in cortex, and executive function may partially mediate the MCI-AD progression in relation to ALPS index.

Aged tissues are characterized by increased levels of oxidative stress, meaning the generation and presence of more oxidizing molecules than cells can comfortably handle. A major source of oxidizing molecules is the activity of mitochondria, and an increase in this production of oxidizing molecules is one of the reasons why mitochondrial dysfunction is important in aging. Oxidative reactions damage molecular machinery in the cell, impairing function. Lipid molecules are particularly vulnerable to oxidation that produces damaging consequences. To cope with this, cells can either more aggressively repair that damage or more aggressively produce antioxidants, but there are limits to the degree to which these approaches can compensate.

Lipid peroxidation involves a series of chemical reactions in which lipid molecules, particularly polyunsaturated fatty acids (PUFAs), are oxidatively attacked by free radicals or non-radical species in the cell membrane or intracellular structures. This process generates lipid radicals and peroxides, which damage the cell membrane structure and function, triggering a chain reaction that further impairs cellular function and induces apoptosis.

Cells have endogenous defense mechanisms to counteract this oxidative damage. The main defense mechanisms include antioxidant enzyme systems (such as superoxide dismutase, catalase, and glutathione peroxidase) and non-enzymatic antioxidants (such as glutathione, vitamin E, and vitamin C). These mechanisms protect cells from oxidative damage by scavenging reactive oxygen species (ROS) and neutralizing lipid peroxidation products. However, under aging or chronic disease conditions, these endogenous defense mechanisms may be impaired, leading to elevated lipid peroxidation levels and exacerbating cellular damage, potentially contributing to diseases such as muscle atrophy.

In sarcopenia, lipid peroxidation may impact muscle health through several pathways. Firstly, lipid peroxidation products directly damage muscle cell membranes, leading to apoptosis and muscle loss. Secondly, lipid peroxidation products can induce inflammation and oxidative stress, further exacerbating muscle damage. Additionally, lipid peroxidation influences sarcopenia through various mechanisms, including metabolic disorders, ferroptosis, mitochondrial dysfunction, autophagy and apoptosis, extracellular matrix remodeling, cell signaling pathways, as well as lifestyle and nutritional factors. This review summarizes the current research on lipid peroxidation and sarcopenia, including the molecular mechanisms by which lipid peroxidation influences muscle atrophy, protective mechanisms that reduce lipid peroxidation in slowing sarcopenia progression, and lipid peroxidation-based therapeutic strategies for sarcopenia.

Link: https://doi.org/10.3389/fmed.2025.1525205

Researchers here find that one of the protein components of nuclear pore structures has an independent function in regulating the response to nutrient sensing. As is now well known, low nutrient availability resulting from reduced calorie intake triggers a range of adaptive responses that collectively act to slow the progression of aging. Evidence suggests that increased autophagy is the most vital of these mechanisms, but it is far from the only mechanism involved. Thus interventions such as mTOR inhibitors that increase autophagy are beneficial, but not as beneficial as calorie restriction.

The nuclear pore complex (NPC) is a massive protein complex that is best known for its role in gating communication between the cell cytosol and nucleus. The NPC consists of about 30 different proteins, known as nucleoporins, as a heteromultimeric assembly of more than 1000 protein subunits that mediate nuclear pore permeability, active transport, and on-site transcription.

In this study, we demonstrate that the NPC subunit NPP-16/NUP50 bridges energy sensing and metabolic adaptation independently of its canonical role in nuclear permeability and transport. In response to energetic and nutrient stress, NPP-16/NUP50 is post-translationally activated by AMPK, and subsequently promotes the transcription of lipid catabolic genes. Overexpression of NPP-16/NUP50 is sufficient to induce lipid catabolism in both nematodes and mammalian cells. NPP-16/NUP50 overexpression robustly extends the lifespan in C. elegans by enhancing the transcriptional activity of the metabolic transcriptional regulators NHR-49/HNF4 and HLH-30/TFEB, driving lipid catabolism.

Unlike scaffold nucleoporins, altered levels or activity of NPP-16/NUP50 do not affect nuclear transport and permeability; instead, increased NPP-16/NUP50 levels are necessary and sufficient to promote metabolic adaptation and longevity via interaction of its intrinsically disordered region (IDR) with the promoters of lipid catabolic genes. Our findings identify a heretofore unappreciated, conserved role of a specific nucleoporin in energy sensing and deployment of metabolic stress defenses against aging and further uncover a noncanonical role for nucleoporin IDRs in direct transcriptional regulation.

Link: https://doi.org/10.1101/2025.02.17.638704

To what degree is the burden of senescent cells in the tissues of old or obese people dynamic, capable of being reduced by circumstances? Cells become senescent constantly throughout life, and are then cleared by the immune system or destroy themselves via programmed cell death mechanisms. That clearance falters with advancing age, however. We might also think that the pace at which cells become senescent is likely higher in tissues stressed by the molecular damage of aging or by the aberrant metabolism of obesity, but there is less direct evidence for this to be the case than there is for impaired immune clearance of senescent cells. It is certainly the case that obese individuals have a higher burden of senescent cells than their similarly aged peers, and this makes it worth paying some attention to what is learned of the way in which this burden changes in response to lifestyle.

Can one produce much the same effects of a senolytic therapy to clear senescent cells, but slowly over time via exercise? It seems to the case that either slowing the creation of senescent cells or incrementally improving clearance via the immune system can reduce the number of senescent cells in tissue over time. A study of senescent cells in skin treated with a topical mTOR inhibitor, which does not kill senescent cells, but does slow their creation, shows that even in older people the immune system is still destroying senescent cells. Given enough time of a lower pace of creation the immune system can catch up to reduce the burden of senescent cells to a lower level. Whether exercise is acting through a slowed pace of creation of senescent cells or an improvement to immune function is an interesting question - there are good arguments in either case.

That said, the size of the effect of exercise on the burden of cellular senescence leaves something to be desired; today's open access paper shows that exercise clearly isn't as good as a senolytic drug after only four weeks of physical training. The aforementioned topical mTOR inhibition study ran for half a year, so it is always possible that better effects would be be seen after a much longer period of training. Nonetheless, there really isn't that much data on how the burden of cellular senescence can be shifted by lifestyle choice alone. Given the amazing results in reversal of age-related conditions produced by senolytic therapies in mice, and the inability to achieve the same outcome by exercising mice, it does seem unlikely that six months of becoming more fit could achieve the same results as a robust senolytic treatment, however.

Physical training reduces cell senescence and associated insulin resistance in skeletal muscle

Cell senescence (CS) is a conserved aging mechanism characterized by the irreversible arrest of the cell cycle along with alterations in cell function and the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). This process contributes to chronic inflammation, tissue dysfunction and a reduced capacity for cell regeneration. As individuals age, senescent cells accumulate in various tissues, including skeletal muscle (SkM), impairing muscle function and leading to sarcopenia, the age-related loss of muscle mass and strength. Impairment of SkM function can lead to significant metabolic disturbances. Since SkM is a primary site for glucose uptake, dysfunction in this tissue results in reduced insulin responsiveness, contributing to metabolic disorders such as type 2 diabetes (T2D). This highlights the importance of maintaining muscle health to prevent adverse metabolic outcomes.

Obesity is a well-established risk factor for numerous chronic diseases which can accelerate the onset of aging in several metabolic tissues, including SkM, by promoting CS. Indeed, obesity triggers local tissue inflammation, oxidative stress and metabolic abnormalities, which are key drivers of CS also in SkM. Chronic low-grade inflammation originating from the adipose tissue in obesity, as well as insulin resistance and altered muscle metabolism, are factors that can contribute to the acceleration of muscle aging and dysfunction.

CS can impact multiple cell types within SkM, including muscle stem cells (satellite cells), fibrogenic/adipogenic progenitors and resident immune cells, each of which plays a crucial role in muscle regeneration and maintenance. Satellite cells, which are normally quiescent, become activated in response to muscle injury or stress leading to proliferation and differentiation into new muscle fibers, thereby playing a critical role in skeletal muscle generation and repair. Thus, senescence in satellite cells can have profound consequences on SkM health, leading to diminished muscle maintenance, impaired regeneration, reduced responsiveness to exercise, and increased metabolic dysfunction.

Regular physical exercise is a highly effective strategy for preserving SkM function and metabolic health, while also reducing several chronic diseases associated with age. Exercise interventions have also been shown to reduce circulating biomarkers of CS in man and the burden of senescent cells linked to aging and age-related conditions in colon mucosa. However, very little is known about the impact of exercise on CS in SkM itself. Understanding if exercise may influence senescence markers in SkM is crucial, as it could provide insights into mechanisms that promote healthy aging of SkM and improve metabolic health.

In this study, we investigated the effects of physical exercise on CS markers in human SkM by analyzing muscle biopsies from people with normal body weight and with obesity, before and after regular exercise. Notably, physical intervention led to significant improvements in metabolic parameters, a reduction in CS markers and activation of satellite cell responses. Moreover, in vitro experiments demonstrated that senescence negatively impacts satellite cells by reducing key regulatory genes and impairing insulin signaling. Together these findings underscore the critical role of CS in regulating insulin sensitivity and highlight the potential of physical exercise as a therapeutic strategy to mitigate these effects in human.