Fight Aging! Newsletter, March 17th 2025
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
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- An In Vitro Example of Pharmacological Induction of Yamanaka Factor Expression
- Potential Roads for Upheaval Ahead in Medical Regulation in the US
- Detrimental Changes in the Gut Microbiome Correlate with Loss of Cognitive Function in Later Life
- Continued Progress Towards Understanding the Regulators of the Senescence-Associated Secretory Phenotype
- On Medical Community Resistance to Treating Aging in Order to Extend Healthy Life
- Translational Errors Increase with Age in Some Organs in Mice
- Insulin Resistance Accelerates Biological Aging as Measured by Aging Clocks
- Reviewing the Role of the Glymphatic System in Neurodegenerative Disease
- Applying the Organage Proteomic Clock to Old Blood Samples to Assess Predictive Ability
- Long Term Non-Steroidal Anti-Inflammatory Medication Use Correlates with a Lower Risk of Dementia
- Towards Therapies that Adjust Macrophage Behavior to Provoke Heart Regeneration
- Senescent Cells in the Aging of the Lens of the Eye
- Dysregulated Hypoxia-Inducible Factor Signaling in the Aging Lung
- Altered Macrophage Behavior Can Accelerate Wound Healing
- Retinal Thinning Correlates with Pace of Cognitive Decline
An In Vitro Example of Pharmacological Induction of Yamanaka Factor Expression
https://www.fightaging.org/archives/2025/03/an-in-vitro-example-of-pharmacological-induction-of-yamanaka-factor-expression/
Cellular reprogramming involves expressing the Yamanaka factors discovered twenty years ago. Given robust expression over days, a somatic cell dedifferentiates into an induced pluripotent stem cell, replicating what happens to germline cells in early embryonic development. But with just a little expression of the Yamanaka factors, partial reprogramming occurs: the cell retains its state but resets its epigenetic control of nuclear DNA structure and gene expression to be more youthful. This is a desirable goal for the medical community, and in recent years a very large amount of funding has poured into early stage development programs aimed at producing rejuvenation therapies based on partial reprogramming. It remains to be seen as to how well this will go.
A hoped-for ideal is body-wide reprogramming, to hit every cell in an aged body and brain to restore youthful function to the degree that this is possible given damage to nuclear DNA, signaling environment, extracellular matrix, and so forth. One of the more interesting lines of research to emerge from the cellular reprogramming field is the use of small molecules to induce the expression of Yamanaka factors. Gene therapies are always going to be more effective at producing the altered gene expression one wants, and are more easily tailored to produce specific outcomes inside a cell, but gene therapies have at present several large disadvantages, all of which revolve around the delivery systems necessary to carry nucleic acids into cells. There is no good way to deliver a gene therapy fairly uniformly to the whole body; even the best approaches largely end up in the liver and lungs when injected intravenously. The delivery systems have dose limiting toxicities that mean that the largest whole body dose one could deliver, so as not to overload the liver and lungs, do not deliver meaningful amounts of the payload to other organs.
Small molecules, on the other hand, largely have this desirable characteristic of body-wide delivery. So there is a growing literature of studies making use of the few small molecules known to induce expression of one or more of the Yamanaka factors. A few companies appear to be quietly conducting screening programs to find more such small molecules, but these are early days yet. Today's open access paper is illustrative of some of the work taking place to assess the capabilities of existing reprogramming small molecules; it is in vitro rather than in vivo, and focused on one specific capability of tissue that declines with age. Researchers would typically move on from here to animal studies or screening for further similar small molecules with better specificity or side-effect profiles.
Restoration of angiogenic capacity in senescent endothelial cells by a pharmacological reprogramming approach
Vascular function is highly impaired during aging, and vascular dysfunction is the underlying cause of cardiovascular diseases, the leading cause of death worldwide. Clinically these alterations are among others observable by an increased systolic blood pressure and increased size and stiffness of the large arteries. Recent studies indicate that these alterations mainly result from a dysfunctional endothelium developing with advancing age. The existence of senescent endothelial cells can draw a causal correlation between aging, endothelial dysfunction, and cardiovascular diseases. Senescent cells accumulate over the life span in the vasculature, in older healthy humans and in diseased tissue in the pathogenesis of heart failure or ischemic heart disease. Senescent cells negatively impact several downstream pathways such as inflammation, DNA damage, molecular regulators as well as cell cycle regulation. Together, these processes lead to an impaired function of the aged endothelium by mainly minimizing the angiogenic and regenerative potential.
This makes reversing and rejuvenating senescent endothelial cells a highly interesting target to improve vascular regeneration in old individuals. Currently, different approaches to counteract cellular senescence are under intensive investigation, such as the use of senolytics to induce cell death or the process of cellular reprogramming mainly relying on viral transduction. The concept of cellular reprogramming was originally used to illustrate the transformation of somatic cells into induced pluripotent stem cells using retroviral overexpression of OCT3/4, SOX2, KLF4, and c-MYC (OSMK). This reprogramming has exhibited therapeutic promise and has also indicated the potential to reverse aging-related traits, particularly evident in initial experiments conducted on senescent and centenarian cells. However, prolonged induction of OSKM using viral methods in living organisms has led to teratoma formation and changes in DNA methylation patterns. In the context of aging and cellular senescence, the term cellular reprogramming has been more commonly associated with the rejuvenation process of senescent cells rather than the generation of pluripotent stem cells.
Here, we aimed to develop a pharmacological strategy to improve senescent endothelial cell function, especially in the context of angiogenesis. Recently, a cocktail of small pharmacological compounds was presented, that contributed to liver regeneration and hepatic function in vivo by promoting cellular reprogramming. This cocktail is composed of three compounds, namely tranilast, valproic acid, and lithium carbonate. All three substances are not only described for their supporting regenerative effect but also for beneficial effects on aging. Indeed, here we are the first to demonstrate that the cocktail favors a reversion of the EC senescent phenotype in vitro. Importantly, all three substances are FDA-approved drugs already in use in clinical settings or at least clinical trials simplifying a potential transition from bench to bedside.
Potential Roads for Upheaval Ahead in Medical Regulation in the US
https://www.fightaging.org/archives/2025/03/potential-roads-for-upheaval-ahead-in-medical-regulation-in-the-us/
Insofar as I have an opinion on politics, I'm against it. Generally it runs in its own noisy part of the world, involves a lot of unnecessary angst and drama, and at the end of the day has little to no influence on my day to day life. It is best ignored. I'll talk about it a little today because it seems likely that some upheaval lies ahead for the regulation of medical development in the US, and by extension that portion of the rest of the world that has outsourced much of its medical regulation to the US. The Department of Government Efficiency and related factions have yet to turn their eyes in earnest to the FDA, but they seem likely to do so.
One old idea that appears ripe for revival is have the FDA cease to require proof of efficacy for new drugs, and only enforce proof of safety before permitting use in the market. By extension, this also implies preventing the FDA from attempts to sabotage the already permitted off-label use of existing approved therapies for new indications. The various payers in the system, everything from medical insurers to individuals, could then make their own decisions as to the proof and standards of efficacy they would like to see upheld before paying for a treatment. It would go back to being a market with a plurality of opinions on any given drug and use case in question, rather than having to accept the dictates of one set of bureaucrats, one size fits all.
One present manifestation of this ethos is the Right to Try law in Montana, which states that any drug that passes a phase 1 safety trial is open for use by any patient - though in practice obtaining that drug would be challenging for any novel therapeutic, requiring cooperation on the part of the developer that the leadership of that company might justifiably view as a risk to their ongoing relationship with the FDA. However, one could envisage a world in which this Right to Try approach effectively becomes federal law in the US, because that is a fairly simple change from the point of view of the executive branch: just alter the way the FDA behaves, and all clinical trial activity beyond phase 1 is optional. At that point, the incentives on developers change considerably, and the complexity thereafter is left to evolve in the market of consumers and payers.
It seems likely that the immediate response of the largest insurance companies and other payers would be along the lines of "great, but keep on running phase II and phase III clinical trials that demonstrate efficacy if you want us to pay for your medicines." I'd expect this to result in only short-term chaos for the network of investments, valuations, and stock prices that depend upon medicine being very expensive to bring to the clinic, and thus only short-term opposition from large investors, pharma entities, and other vested interests with political influence and lobbying capital to spend. After matters settle down to be more or less a continuation of the status quo, at least at first, greater freedom will emerge over time: payers will selectively defect from the consensus regarding standards for efficacy, where they feel it is justified, biotech and pharma companies will gain a much greater freedom to bring new medicine to the market earlier and at a lower cost than would otherwise be the case, and patients would gain the choice of earlier access. All of this is already happening via medical tourism for a small number of people and organizations; adding the option to do this in the US would greatly broaden access.
Another possible path forward is to make the US clinical trial ecosystem look a lot more like that in Australia. This would require more extensive changes to the regulatory system, which may or may not meet with opposition. In Australia there is no central government body akin to the FDA with the role of assessing and approving every phase 1 safety trial. Instead a competing market of specialized clinical sites and institutional review boards exists to assess and approve proposed new drugs and clinical trials, balancing their incentives to receive business versus their incentives to minimize harm to patients. Since something like 10% of all phase 1 trials worldwide are conducted in Australia, at something like half the cost and a fraction of the time required for approval in the US, it is a system that appears to work fairly well. Setting this up in the US would require dismantling regulations applying to institutional review boards and removing the FDA function of up-front vetting and approving of trials. As before, this change would likely produce short-term chaos and scrambling, but if the end goal remained to work towards the same present format of data and reporting that results from clinical trials, then the existing marketplace of contract research organizations (CROs) that run trials and package data would adapt, form standards, and those standards would likely look very much like the present status quo, at least at first. Moving forward, competition and freedom to choose would allow a greater plurality of options to emerge.
A harder and more disruptive change would be to alter the way in which the production of drugs is regulated in order to reduce the costs of compliance. Regulating manufacture under the banner of Good Manufacturing Practice (GMP) is sizable chunk of the work conducted by the FDA, and conforming to FDA requirements on manufacturing processes is certainly a very large slice of the cost and effort required to bring a drug to the clinic. The guidelines put out by the FDA are standard and vague. Every single class of drug has accumulated over years and decades a deep and very detailed culture and tradition of non-public material and experience among consultants and regulators to describe the precise details of an acceptable interpretation of those vague standards. This cannot be discovered without engaging with regulators and consultants at considerable expense. Further, the requirements for GMP manufacture of any given drug class tend to expand over time, as efforts to remove any novel assay or other addition that regulators and consultants have seen used widely will be opposed.
Trying to change GMP requirements runs into a range of problems: firstly, there will be a great deal of political opposition from those who hold the unreasonable fear that any change to GMP regulation will make drugs unsafe; secondly, there will be a great deal of political opposition from large organizations that use the high cost of compliance to reduce competition, the usual problem of regulatory capture; thirdly, the specific interpretations of compliance that have become so very costly have very little do with the published regulations, vary widely by drug type, are very complicated, are are near entirely documented privately, making them hard to target; fourthly, many smaller countries reference US GMP standards and rely upon them to inform their own medical regulation, essential outsourcing that function.
To return to Australia, for example, the consensus that has emerged among institutional review boards, clinical trial running CROs, and clinical sites, is that the drug used in a phase 1 clinical trial should be manufactured to GMP-like quality. What "GMP-like" means in practice is that the FDA has accepted the proposed technical/scientific details of the manufacturing process and quality control assays, the drug batch is manufactured using that process and those assays, but the manufacture is not conducted with the very expensive addition of the full audit trail, checking in triplicate, form-filling, checkboxes, and validation at every step that is required for a process to be GMP grade. In drug manufacture circles this is called an engineering batch, and in present practice is the last full scale non-GMP batch that successfully tests all of the manufacturing processes and passes all of the quality assurance tests. The engineering batch is usually used for toxicity studies in animals that are conducted as a part of submitting an IND proposal to the FDA - except that in Australia one can also use the engineering batch for a phase 1 safety trial in human volunteers.
If engineering batches are safe enough for humans in Australia, why not everywhere else? Why not have the minimum regulated safety requirement for medicines at any stage of approval or commercial use be that manufactured batches be made as if engineering batches? This would reduce manufacture cost by 50% for many drug classes. The batches would still have to pass quality testing that has been reviewed by regulators, institutional review boards, and others. The answer to the question "why not?" is probably that (a) this would be a hard change to make, politically, and (b) while it is easy to state the change in a single sentence, actually wrangling into shape the vague regulations and hidden details of the present state of the art regarding compliance would be challenging.
But it seems likely that we shall see how this all turns out!
Detrimental Changes in the Gut Microbiome Correlate with Loss of Cognitive Function in Later Life
https://www.fightaging.org/archives/2025/03/detrimental-changes-in-the-gut-microbiome-correlate-with-loss-of-cognitive-function-in-later-life/
The balance of microbial species making up the gut microbiome changes with age in ways that (a) promote chronic inflammation, such as via infiltration of microbes into tissue and production of harmful metabolites, and (b) reduce the supply of beneficial metabolites, such as butyrate. A growing body of work characterizes these changes and links them to specific age-related conditions. A number of studies have demonstrated that common neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, correlate with distinct dysfunctional changes in the aging gut microbiome.
Today's open access paper adds to this body of work, and in addition to assessing cognitive function and composition of the gut microbiome also incorporates a measure of brain biological age derived from imaging of brain tissue. All three of these measures tend to move with one another; those people with greater dysbiosis of the gut microbiome also have an older brain age and greater loss of cognitive function. One might hypothesize that either the changes in the gut microbiome are contributing to neurodegeneration, or that immune aging contributes to all of the above. Or both!
There is a bidirectional relationship between the state of the aging immune system and the state of the aging gut microbiome. On the one hand the immune system gardens the gut microbiome, removing problem microbes. As the immune system falters with age, it becomes less able to conduct this duty. On the other hand, changes in the composition of the gut microbiome can affect the immune system both directly, by provoking chronic inflammation, and indirectly, via metabolites and other signaling that affects the state of tissues and organs needed for immune function, such as bone marrow and the thymus.
Brain age mediates gut microbiome dysbiosis-related cognition in older adults
The human gut microbiome, a complex and dynamic ecosystem of microorganisms, plays a vital role in maintaining host health and influencing disease progression. Central to this understanding is the concept of the "gut-brain axis," a bidirectional communication network linking the enteric and central nervous systems (CNS) through neural, endocrine, immune, and humoral pathways. Through these mechanisms, the gut microbiome has been hypothesized to affect brain development, behavior, and cognitive function.
Emerging research suggests that gut microbiome dysbiosis - a state of microbial imbalance - is associated with accelerated gray matter aging. Dysbiosis has been linked to inflammation and increased intestinal permeability, leading to systemic and neural inflammation that can negatively impact cognitive function. Aging appears to exacerbate these changes, marked by decreased diversity in beneficial microbial species, such as anti-inflammatory Bifidobacterium, and increased prevalence of pro-inflammatory species like Enterococcus. These microbial shifts, coupled with reduced immunological function and heightened release of inflammatory products, may further accelerate brain aging, contribute to cognitive decline, and even promote amyloid and tau deposition associated with Alzheimer's disease.
We recruited 292 participants from South Korean memory clinics to undergo brain magnetic resonance imaging, clinical assessments, and collected stool samples. We employed a pretrained brain age model derived from imaging data - a measure associated with neurodegeneration. Using cluster analysis, we categorized individuals based on their microbiome profiles and examined the correlations with brain age, Mental State Examination (MMSE) scores, and the Clinical Dementia Rating Sum of Box (CDR-SB).
Two clusters were identified in the microbiota at the phylum level that showed significant differences on a few microbiotas phylum. Greater gut microbiome dysbiosis was associated with worse cognitive function including MMSE and CDR-SB; this effect was partially mediated by greater brain age even when accounting for chronological age, sex, and education. Our findings indicate that brain age mediates the link between gut microbiome dysbiosis and cognitive performance. These insights suggest potential interventions targeting the gut microbiome to alleviate age-related cognitive decline.
Continued Progress Towards Understanding the Regulators of the Senescence-Associated Secretory Phenotype
https://www.fightaging.org/archives/2025/03/continued-progress-towards-understanding-the-regulators-of-the-senescence-associated-secretory-phenotype/
Nearly 15 years have passed since the first compelling demonstration of rejuvenation produced by clearance of senescent cells in the tissues of aged mice. At that time the study of senescent cells was fairly slow and sedate, not a major area of research. How things change! At present a very energetic community of academic groups and biotech companies is mining the biochemistry of cellular senescence in search of better ways to selectively destroy these cells, ways to change their behavior to reduce their contribution to systemic inflammation and tissue dysfunction, and even ways to turn back the normally irreversible transition into the senescent state. There are incentives: any new discovery could be the starting point for development of a therapy that significantly slows or reverses aspects of aging.
The damage done by the growing burden of senescent cells found in aged tissues is thought to be near entirely caused by the senescence-associated secretory phenotype (SASP), the mix of pro-growth, pro-inflammatory signaling that is energetically produced by these cells. As the thinking goes, a way to eliminate the SASP could be as beneficial as clearing senescent cells from tissues. There are drawbacks to this approach, which is that the SASP is actually beneficial in the short term, helpful in wound healing and suppression of potentially cancerous cells. Periodic destruction of senescent cells would not interfere in their beneficial short-term behaviors, while chronic dosing to suppress the SASP would do so. Nonetheless, as today's open access paper illustrates, there is a growing interest in finding ways to reduce or even eliminate SASP signaling.
ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation
The senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. Acetate-dependent acetyl-CoA synthetase 2 (ACSS2) produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear.
Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces deoxyribonucleotide triphosphate (dNTP) pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP.
Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.
On Medical Community Resistance to Treating Aging in Order to Extend Healthy Life
https://www.fightaging.org/archives/2025/03/on-medical-community-resistance-to-treating-aging-in-order-to-extend-healthy-life/
People taken en masse are reflexively conservative, grumbling and resistant to all change, whether or not that change is evidently, clearly positive. So if one takes a tour of what the medical community has to say about the prospects of extending healthy life spans via the development of new forms of therapy that target mechanisms of aging, one will find at least as much grumbling and resistance as optimism. It seems self-evident that more healthy life is a good thing. But it is change, and people don't like change.
A clever editorial is presently doing the rounds, pointing out the parallels between the present development of treatments for aging with the early development of anesthesia for surgical patients across the span of the 1800s. That was a development process that we might today, in hindsight, characterize as much delayed past the point of the initial discovery of the first practical approach to anesthesia. Exactly how much of that delay can be attributed to grumbling and resistance on the part of the medical community is up for debate, but the authors of the editorial have uncovered some choice quotes from influential figures of the time.
Turning Fate into Choice: Patient Self-Determination and Life Extension
The foundations of modern medicine rest upon two revolutionary changes in medical practice. The first is the development of effective treatments that have transformed previously fatal diseases into manageable or curable conditions. A child who developed diabetes in 1900 would have died within months, while today, insulin therapy can provide them with a normal lifespan. The second was a fundamental shift in the doctor-patient relationship, replacing physician paternalism with patient self-determination. Whereas physicians once withheld diagnoses and made unilateral decisions, clinical practice now centers on informed consent and shared decision-making.
This progress in expanding patient choice was neither smooth nor inevitable. Consider anaesthesia, the astonishingly slow development of which reveals how physician attitudes can constrain patient autonomy. After the discovery of nitrous oxide's anaesthetic properties in 1799, patients should have been quickly granted the option of avoiding gratuitous surgical and obstetrical pain. Instead, the potential applications were neglected for 50 years, with one prominent surgeon dismissing it entirely when stating that "The abolishment of pain in surgery is a chimera. It is absurd to go on seeking it." When surgical anaesthesia was finally demonstrated successfully in 1846, one might have expected rapid adoption to promptly provide patients the choice of pain-free surgery. Instead, resistance persisted, with some surgeons in 1847 still insisting that "Pain in surgical operations is in a majority of cases even desirable, and its prevention or annihilation is for the most part hazardous to the patient." While skepticism of new treatment safety is understandable - and indeed, anaesthesia-related complications still occur today - it seems clear that 19th century patients would have welcomed the choice of pain-free surgery, had they been granted the opportunity.
Despite medicine's progress since the 1800s, we believe that the aforementioned neglect and paternalism are repeating themselves again today in attitudes towards aging and death. Take the 2022 Report of the Lancet Commission on the Value of Death, which declared that "it is healthy to die" and "without death every birth would be a tragedy" - statements that echo 19th century claims about the necessity of pain in surgery. This philosophical stance is arguably also manifest institutionally: the U.S. Food and Drug Administration does not even classify aging as a disease process, while the National Institutes of Health dedicates less than 1% of its budget to basic research into ageing and senescence. While we welcome the increasing emphasis on patient choice in end-of-life care, these attitudes reveal a troubling disregard for the wish of many dying patients, no matter their age, to live longer if only they were able. Indeed, one survey found that 70% of terminally ill individuals, including those in their eighties, maintained a strong will-to-live even when death was imminent. Just as patients facing amputation in 1825 would likely have jumped at the chance for pain-free surgery, surely many patients today would choose to extend their lives if offered ways to do so while maintaining their quality of life.
Translational Errors Increase with Age in Some Organs in Mice
https://www.fightaging.org/archives/2025/03/translational-errors-increase-with-age-in-some-organs-in-mice/
Researchers here produce a mouse model incorporating a DNA sequence that produces a luminescent protein only in the case of a readthrough error, where the translation machinery ignores a stop codon in the DNA sequence. This is a way to gauge the degree to which readthrough errors increase with age, producing aberrant RNA molecules and consequent dysfunction. A range of evidence supports an age-related increase in translation errors in the production of RNA from DNA, though as is always the case in these matters understanding how much of degenerative aging results from this sort of dysfunction in gene expression is a challenge. One would have to fix just this one problem without affecting other mechanisms, a difficult prospect.
The accuracy of protein synthesis and its relation to ageing has been of long-standing interest. To study whether spontaneous changes in the rate of ribosomal error occur as a function of age, we first determined that stop-codon readthrough is a more sensitive read-out of mistranslation due to codon-anticodon mispairing than missense amino acid incorporation. Subsequently, we developed knock-in mice for in-vivo detection of stop-codon readthrough using a gain-of-function Kat2-TGA-Fluc readthrough reporter which combines fluorescent and sensitive bioluminescent imaging techniques.
We followed expression of reporter proteins in-vivo over time, and assessed Kat2 and Fluc expression in tissue extracts and by whole organ ex-vivo imaging. Collectively, our results provide evidence for an organ-dependent, age-related increase in translational error: stop-codon readthrough increases with age in muscle (+ 75%) and brain (+ 50%), but not in liver. Together with recent data demonstrating premature ageing in mice with an error-prone ram mutation, our findings highlight age-related decline of translation fidelity as a possible contributor to ageing.
Insulin Resistance Accelerates Biological Aging as Measured by Aging Clocks
https://www.fightaging.org/archives/2025/03/insulin-resistance-accelerates-biological-aging-as-measured-by-aging-clocks/
A diabetic metabolism is widely considered to accelerate aging, on the basis of very good evidence, and to the point at which researchers have often used diabetic mice as a faster, cheaper stand-in for aged mice in their studies. Reasonably, one should expect any decent measure of biological age to report accelerated biological aging in diabetic animals or people. Indeed, that is what is shown here for two of the commonly used aging clocks developed in recent years. This is one of the many yardsticks that an aging clock should be able to meet in order to give confidence that it reflects biological age sufficiently well to be broadly useful.
Insulin resistance (IR) has been reported to be associated with aging; however, few studies have investigated the relationship between IR and biological age. The Triglyceride-glucose (TyG) index is a recognized marker of IR. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES), including 12,074 adults (aged 20 and older) from the 2001-2010 and 2015-2018 cycles. Comprehensive TyG and biological age data were extracted for analysis.
We included 12,074 participants with a mean age of 46.91 years; of these, 50.25% were female and 49.75% were male. Each 1-unit increase in the TyG index was associated with a 1.64-year rise in Klemera-Doubal method (KDM) biological age and a 117% higher risk of accelerated aging. Similarly, each 1-unit increase in the TyG index corresponded to a 0.40-year increase in phenotypic age, resulting in a 15% higher risk of accelerated aging. The analysis also revealed nonlinear positive relationships between the TyG index and biological aging, particularly for KDM biological age and phenotypic age, with a turning point at 8.66. Across all subgroups, the TyG index consistently showed a positive correlation with biological aging, even in the presence of significant interactions.
Reviewing the Role of the Glymphatic System in Neurodegenerative Disease
https://www.fightaging.org/archives/2025/03/reviewing-the-role-of-the-glymphatic-system-in-neurodegenerative-disease/
The glymphatic system of the brain is a recently discovered pathway allowing cerebrospinal fluid to drain from the brain into the body, carrying metabolic waste with it. Another path through pores in the cribriform plate behind the nose also appears important. Both of these drainage pathways decline in efficacy with age. It is thought that this loss of function allows various forms of metabolic waste, such as the protein aggregates characteristic of neurodegenerative conditions, to accumulate in the brain. This provokes cells into dysfunction and inflammatory behavior.
The glymphatic system theory introduces a new perspective on fluid flow and homeostasis in the brain. Here, cerebrospinal fluid and interstitial fluid (CSF-ISF) moves from the perivascular spaces (PVS) of arteries to those of veins for drainage. Aquaporin-4 (AQP4) plays a crucial role in driving fluid within the PVS. The impairment of AQP4 is closely linked to the dysfunction of the glymphatic system. The function of the glymphatic system is less active during waking but enhanced during sleep.
The efficiency of the glymphatic system decreases with aging. Damage to the glymphatic system will give rise to the development and progression of many brain diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and vascular dementia (VaD). Here, we reviewed previous research associated with the glymphatic system, including its concepts, principles, and influencing factors. We hypothesize that AQP4 could be a target for the prevention and treatment of certain brain diseases through the regulation on the glymphatic system.
Applying the Organage Proteomic Clock to Old Blood Samples to Assess Predictive Ability
https://www.fightaging.org/archives/2025/03/applying-the-organage-proteomic-clock-to-old-blood-samples-to-assess-predictive-ability/
Repositories of well-characterized 20+ year old stored blood samples that can be accessed for analysis are few and far between. Here, researchers make use of one such resource to characterize a proteomic aging clock for its ability to predict future health outcomes. This clock, organage, assesses a biological age for different organs based on levels of circulating proteins specifically produced by each organ. As one might expect, people who later developed an age-related dysfunction of an organ and consequent disease tended towards a higher biological age for that organ in the 1990s, as measured by organage.
In this observational cohort study, to assess the biological age of an individual's organs relative to those of same-aged peers, ie, organ age gaps, we collected plasma samples from 6235 middle-aged (age 45-69 years) participants of the Whitehall II prospective cohort study in London, UK, in 1997-99. Age gaps of nine organs were determined from plasma proteins. Following this assessment, we tracked participants for 20 years through linkage to national health records. Study outcomes were 45 individual age-related diseases and multimorbidity.
Over 123,712 person-years of observation (mean follow-up 19.8 years), after excluding baseline disease cases and adjusting for age, sex, ethnicity, and age gaps in organs other than the one under investigation, individuals with large organ age gaps showed an increased risk of 30 diseases. Six diseases were exclusively associated with accelerated ageing of their respective organ: liver failure (hazard ratio [HR] per standard deviation increment in the organ age gap 2.13), dilated cardiomyopathy (HR 1.65), chronic heart failure (HR 1.52), lung cancer (HR 1.29), agranulocytosis (HR 1.27), and lymphatic node metastasis (HR 1.23). 24 diseases were associated with more than one organ age gap or with organ age gaps not directly related to the disease location. Larger age gaps were also associated with elevated HRs of developing two or more diseases affecting different organs within the same individual (ie, multiorgan multimorbidity): 2.03 for the arterial age gap, 1.78 for the kidney age gap, 1.52 for the heart age gap, 1.52 for the brain age gap, 1.43 for the pancreas age gap, 1.37 for the lung age gap, 1.36 for the immune system age gap, and 1.30 for the liver age gap.
Long Term Non-Steroidal Anti-Inflammatory Medication Use Correlates with a Lower Risk of Dementia
https://www.fightaging.org/archives/2025/03/long-term-non-steroidal-anti-inflammatory-medication-use-correlates-with-a-lower-risk-of-dementia/
Neurodegenerative conditions are characterized by chronic inflammation. Does reducing that inflammation help? As researchers here note, studies attempting to find correlations between dementia risk and use of common anti-inflammatory medications have produced conflicting results. This study looks at the duration of use of anti-inflammatory medications and total dose over time, and finds that only consistent long term use is associated with a modestly reduced risk of dementia.
Non-steroidal anti-inflammatory (NSAID) medication could reduce dementia risk due to anti-inflammatory and possibly amyloid-lowering properties. However, the results of observational studies and short-term randomized-controlled trials have been inconsistent, and duration and dose-response relationships are still unclear. We included 11,745 dementia-free participants from the prospective population-based Rotterdam Study (59.5% female, mean age 66.2 years). NSAID use from 1991 was derived from pharmacy dispensing records, from which we determined cumulative duration and dose. We defined four mutually exclusive categories of cumulative use: non-use, short-term use (less then 1 month), intermediate-term use (between 1 and 24 months), and long-term use (longer than 24 months).
During an average follow-up period of 14.5 years, a total of 9,520 (81.1%) participants had used NSAIDs at any given time, and 2,091 participants developed dementia. Use of NSAIDs was associated with lower dementia risk for long-term users (hazard ratio, HR: 0.88), and a small increased risk with short-term use (HR 1.04) or intermediate-term use (HR: 1.04). The cumulative dose of NSAIDs was not associated with decreased dementia risk. Associations were somewhat stronger for long-term use of NSAIDs without known effects on amyloid-β than for amyloid-lowering NSAIDs (HR 0.79 versus 0.89).
Long-term NSAID use, but not cumulative dose, was associated with decreased dementia risk. This suggests that prolonged rather than intensive exposure to anti-inflammatory medication may hold potential for dementia prevention.
Towards Therapies that Adjust Macrophage Behavior to Provoke Heart Regeneration
https://www.fightaging.org/archives/2025/03/towards-therapies-that-adjust-macrophage-behavior-to-provoke-heart-regeneration/
Regeneration from injury might be thought of as an intricate and scheduled set of interactions between immune cells, various types of somatic cell present in the injured tissue, and the stem cells that support the tissue. On the immune cell side of the house, a great deal of research is focused on the innate immune cells known as macrophages. Altering macrophage behavior to, for example, encourage greater somatic cell replication in poorly regenerative tissues such as the heart, seems a promising approach to regenerative medicine. This is a still an ongoing area of development in its relatively early stages, however. The primary challenge is that macrophage behavior, such as the reactions of macrophage cells to the environment, is complex and incompletely understood at the detail level. Thus attempts to produce favorable changes in macrophage activities based on what is presently known have so far resulted in mixed or unreliable outcomes in animal models.
In the mammalian heart, cardiomyocytes undergo a transient window of proliferation that leads to regenerative impairment, limiting cardiomyocyte proliferation and myocardial repair capacity. Cardiac developmental patterns exacerbate the progression of heart disease characterized by myocardial cell loss, ultimately leading to cardiac dysfunction and heart failure. Myocardial infarction causes the death of partial cardiomyocytes, which triggers an immune response to remove debris and restore tissue integrity. Interestingly, when transient myocardial injury triggers irreversible loss of cardiomyocytes, the subsequent macrophages responsible for proliferation and regeneration have a unique immune phenotype that promotes the formation of pre-existing new cardiomyocytes.
During mammalian regeneration, mononuclear-derived macrophages and self-renewing resident cardiac macrophages provide multiple cytokines and molecular signals that create a regenerative environment and cellular plasticity capacity in postnatal cardiomyocytes, a pivotal strategy for achieving myocardial repair. Consistent with other human tissues, cardiac macrophages originating from the embryonic endothelium produce a hierarchy of contributions to monocyte recruitment and fate specification. In this review, we discuss the novel functions of macrophages in triggering cardiac regeneration and repair after myocardial infarction and provide recent advances and prospective insights into the phenotypic transformation and heterogeneous features involving cardiac macrophages. In conclusion, macrophages contribute critically to regeneration, repair, and remodeling, and are challenging targets for cardiovascular therapeutic interventions.
Senescent Cells in the Aging of the Lens of the Eye
https://www.fightaging.org/archives/2025/03/senescent-cells-in-the-aging-of-the-lens-of-the-eye/
Age-related cataract formation in the lens of the eye causes blindness. This growing opacity of the lens appears to be driven in large part by a growing burden of cellular senescence in lens cells. Could senolytic therapies to clear senescent cells reduce the need for surgery and the development of cell therapies and tissue engineered replacement lenses? This seems plausible, but cataract are a long way removed from the top of the priority list of conditions that might be beneficially affected by senolytic treatments. It is unclear as to whether any group is working towards clinical trials of senolytics in patients at risk of cataract formation.
Cellular senescence plays a dual role in health and disease, acting as both a guardian against uncontrolled proliferation and a driver of age-related pathologies, including cataract formation. The intricate interplay between oxidative stress, mitochondrial dysfunction, and chronic inflammation underscores the complexity of senescence in lens epithelial cells (LECs), essential for maintaining lens transparency and particularly vulnerable to oxidative stress-induced senescence.
The progressive senescence of LECs represents a critical factor in age-related cataractogenesis. Advances in senotherapeutics may offer promising strategies to mitigate LEC senescence, either by eliminating senescent cells through senolytics or modulating the harmful effects of the senescence-associated secretory phenotype (SASP) with senomorphics. Natural compounds like fisetin, luteolin, and metformin, along with innovative therapies such as FOXO4-DRI and gene editing, highlight the growing potential for targeted interventions to delay cataract progression.
Future research on cellular senescence in cataract formation holds significant potential to uncover novel therapeutic strategies aimed at delaying or preventing lens opacity. A deeper understanding of the molecular drivers of LEC senescence, particularly the role of oxidative stress, mitochondrial dysfunction, and protein aggregation, will be essential for developing targeted interventions. Investigating the interplay between SASP factors and changes in the lens microenvironment could provide insights into how chronic inflammation accelerates cataract progression. Senescence research could pave the way for innovative treatments that preserve lens transparency and prevent age-related cataracts.
Dysregulated Hypoxia-Inducible Factor Signaling in the Aging Lung
https://www.fightaging.org/archives/2025/03/dysregulated-hypoxia-inducible-factor-signaling-in-the-aging-lung/
This review paper looks at what is known of hypoxia-inducible factor (HIF) signaling in the aging of lung tissue, with a particular focus on the burden of cellular senescence as a measure of age-related dysfunction. In the view of these researchers, chronic expression of HIF with age promotes cellular senescence. Why HIF expression becomes dysregulated with age is one of many questions that are hard to answer; it takes a great deal of effort to trace the chain of cause and consequence that leads to any given alteration in gene expression, and in near all cases the long and winding connection to some fundamental causative mechanism of aging has not been definitively established.
Hypoxia-inducible factor (HIF) is a key transcriptional mediator of cellular responses to low oxygen, which regulates lung physiology and pathogenesis. It is a central regulator of hypoxic adaptation in lung tissues and plays a dual role in maintaining homeostasis and driving pathological processes. At low levels, hypoxia induced activation of HIF is hormetic, triggering adaptive cellular responses that enhance stress resistance and longevity. However, excessive or prolonged HIF activation skews this adaptive response, fostering fibrosis, inflammation, and disease progression.
During normal aging, HIF maintains oxygen homeostasis, regulates mitochondrial activity, and supports adaptive stress responses in lung tissues. With advancing age, HIF signaling efficiency declines, leading to reduced stress tolerance and impaired repair mechanisms in lung cells. Chronic HIF dysregulation in aging lungs has been linked to increased oxidative stress, senescence induction, and pro-inflammatory signalling. In the lungs, HIF is also essential for oxygen homeostasis and adaptation to hypoxic environments. Beyond its role in oxygen sensing, HIF modulates cellular metabolism, inflammation, and senescence pathways, directly influencing lung aging.
Recent studies indicate that HIF and cellular senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression.
Altered Macrophage Behavior Can Accelerate Wound Healing
https://www.fightaging.org/archives/2025/03/altered-macrophage-behavior-can-accelerate-wound-healing/
Macrophages of the innate immune system exhibit a range of different states known as polarizations. M1 macrophages are inflammatory and focused on attacking pathogens and errant cells. M2 macrophages are anti-inflammatory and focused on tissue maintenance, playing an important role in regeneration from injury. Not a vital role, strictly speaking, as wounds still heal in the absence of macrophages, but the presence of macrophages in the M2 polarization accelerates the process. As researchers demonstrate here, ways to guide macrophages into the desired pro-regenerative M2 state can further speed wound healing.
Macrophages play a key role in wound healing. Dysfunction of their transition from the M0 unpolarized state to the M2 polarization leads to disorders of the wound immune microenvironment and chronic inflammation, which affects wound healing. Regulating the polarization of M0 macrophages to M2 macrophages is an effective strategy for treating wound healing. Mesenchymal stem cells (MSCs) deliver endogenous regulatory factors via paracrine extracellular vesicles, which may play a key role in wound healing, and previous studies have shown that apoptotic bodies (ABs) are closely associated with inflammation regression and macrophage polarization. However, the specific regulatory mechanisms involved in ABs remain unknown.
In the present study, we designed an MSC-AB (MSC-derived AB)-loaded polycaprolactone (PCL) scaffold, evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro, and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing. Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs, and drives M0 macrophages to program M2 macrophages to regulate inflammation and angiogenesis, thereby synergistically promoting wound healing. This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immune responses.
Retinal Thinning Correlates with Pace of Cognitive Decline
https://www.fightaging.org/archives/2025/03/retinal-thinning-correlates-with-pace-of-cognitive-decline/
The central nervous system is inconveniently situated for those who wish to examine it in detail in living people, but one tiny portion is at least readily available for visual inspection - the retina at the back of the eye. To the degree that the retina is subject to the same mechanisms of aging as the brain, one might expect to be able to use retinal imagery as a measure of brain aging. A number of studies have done just that, and a number of different aging clocks have been derived from standard forms of retinal imagery. Here, researchers look at just one aspect of retinal structure as a measure of age-related degeneration, the thickness of its different layers.
The retina, an extension of the central nervous system, reflects neurodegenerative changes. Optical coherence tomography (OCT) is a non-invasive tool for assessing retinal health and has shown promise in predicting cognitive decline. However, prior studies produced mixed results. This study investigated a large cohort (n = 490) of Asian individuals attending memory clinics. Participants underwent comprehensive neuropsychological testing annually for five years. Retinal thickness was measured by OCT at baseline. We assessed the association between baseline retinal thickness and subsequent cognitive decline.
Participants with a significantly thinner macular ganglion cell-inner plexiform layer (GCIPL) at baseline (≤ 79 μm) had a 38% greater risk of cognitive decline compared to those who did not (≥ 88 μm). In a multivariable model accounting for age, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes and smoking, thinner GCIPL was associated with an increased risk of cognitive decline (hazard ratio = 1.14). Retinal nerve fiber layer (RNFL) thickness was not associated with cognitive decline.