Fight Aging!

It is well understood in the aging research community that the lack of a useful, consensus measure of biological age or pace of biological aging is a considerable hindrance to progress. If researchers could quickly measure the pace of aging or the state of aging in a robust way, then discovery and optimization of interventions would proceed a great deal more rapidly. At present, too many suboptimal lines of research are maintained despite the likely lack of effectiveness at the end of the day, and the discovery of new approaches to slow aging and extend life is a slow and expensive process; even in mice, life span studies take years to run.

There are a great many age-related changes in health, biochemistry, and physical function that can be measured, and many of those have their advocates. The "just measure grip strength and get on with it already" faction is a sizable one. Various aging clocks produce decent correlations with age-related mortality and morbidity. And so forth. But the challenge with all of the existing options is that we have no idea as whether then can be trusted to accurately reflect the effects of any new class of intervention. Maybe they will overstate the outcome. Maybe they will understate it. The only way to find out is to calibrate assays against interventions in long-running and expensive studies. And so development remains stuck in the slow lane.

In today's open access paper, researchers propose one possible way forward to an incrementally better situation. The idea is to look through the existing high quality studies of slowed aging in mice conducted by the Interventions Testing Program, and find common biochemical and metabolic measures that appear in mice exhibiting slowed aging. This seems relevant to the classes of therapy that slow aging by provoking cellular stress responses, repair and maintenance and defense activities that improve cell function: calorie restriction, calorie restriction mimetics, and the like. It seems tough to argue that metrics uncovered via these studies could then be applied to completely different approaches to therapy that do not touch on these shared stress response systems, such as senolytics or stem cell therapies, however.

Aging rate indicators and the search for anti-aging drugs

Evidence that drugs, diets, and single-gene mutations can slow aging and extend the healthy lifespan of mammals has begun to convert biogerontology from an observational science into one based on interventions that could provide people with additional years of healthy, productive life. However, the research and development of anti-aging drugs is hampered by the lack of instantaneous and continuous measures of the rate of aging itself. This article presents recent work on anti-aging drugs that are effective in mice, provides evidence for candidate "aging rate indicators" (ARIs), and outlines a roadmap for translating these into clinical research to slow aging in humans.

Thus far, 14 agents or combinations have significantly increased the lifespan of mice in studies conducted under the Interventions Testing Program (ITP) of the National Institute on Aging, often when initiated in late adulthood. Recent evidence suggests that many, perhaps all, interventions that slow aging in mice induce common, shared changes in physiological status and molecular pathways. We have proposed 12 such mechanisms as candidate ARIs, i.e., measurable outcomes that reflect a slow-aging state and that could discriminate between normal mice (and perhaps humans) and those exposed to effective anti-aging interventions - thereby accelerating research.

Research priorities now include testing the robustness of these ARIs, extending them to include plasma constituents, elucidating the mechanisms through which diverse interventions alter them, uncovering the links between the ARIs and late-life diseases, and extending research to dogs, non-human primates, and humans. The growing recognition of the legitimacy and promise of evidence-based interventions resulting from aging biology should elevate this field to a level of urgency and respect comparable to that of current research on individual age-related conditions.

Researchers have started on the long process of transferring promising genes from long-lived species into short-lived species, one by one, with each such transfer as a test of how important that specific difference is to the progression of aging and species longevity. Differences in the presence of hyaluronan in the extracellular matrix are thought to improve the health and resilience of long-lived naked-mole rats, and so researchers generated a mouse lineage that manufactures naked mole rat hyaluronan. The result is improved healthspan, and so now researchers are beginning to assess this novel lineage of mice more deeply. Here, for example, researchers show that this alteration to hyaluronan doesn't have any effect on age-related hearing loss.

Approximately one in three adults aged 65-74 years reports hearing difficulty, including age-related hearing loss (AHL, presbycusis). The C57BL/6 mouse is widely used in preclinical AHL research because it develops AHL relatively early. Calorie restriction (CR) attenuates AHL and improves healthspan and longevity in this strain. A recently developed transgenic C57BL/6 mouse expressing naked mole-rat hyaluronan synthase 2 (nmrHas2), which produces very high molecular mass hyaluronan (vHMM-HA), also exhibits improved healthspan, reduced inflammaging, and increased longevity. Therefore, we evaluated nmrHas2 mice for evidence of alleviated AHL.

The goal of this experiment was to determine whether ubiquitous expression of the nmrHas2 transgene, including within the cochleae, attenuated AHL. Our results indicate that a genetic intervention that had previously been shown to improve healthspan, reduce inflammaging, and increase longevity in C57BL/6 mice did not attenuate AHL, i.e., these outcomes were decoupled in nmrHas2 mice, which contrasts with outcomes following CR. This points to differences in the mechanisms of action of these two interventions, at least within the cochleae.

Link: https://doi.org/10.3389/fragi.2026.1936677

Many approaches to modestly slow aging in short-lived species involve a mild mitochondrial dysfunction that that somewhat increases the level of reactive oxygen species generated in the course of producing adenosine triphosphate (ATP) to power the cell. Reactive oxygen species react with and damage molecular machinery throughout the cell, damage that needs to be repaired. The cell reacts with an increase in repair and maintenance activities that address oxidative damage and other forms of damage, producing a net benefit to function. Here, researchers investigate one portion of how this response is regulated, looking at the metabolism of nematode worms.

The reactive oxygen species superoxide is generated by mitochondria during the process of producing energy. While superoxide can cause oxidative damage to the cell, we and others have shown that a mild increase in mitochondrial superoxide extends longevity in multiple model organisms. To elucidate the molecular mechanisms involved, we identified transcriptional changes in mitochondrial superoxide dismutase deletion mutants (sod-2 worms) using RNA sequencing. sod-2 mutants exhibit a number of changes in nuclear gene expression resulting from elevated mitochondrial superoxide suggesting that mitochondria-to-nucleus signaling is contributing to their longevity.

Gene ontology enrichment analysis demonstrated that genes involved in innate immunity and cuticle formation are significantly upregulated in sod-2 worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of selected kinases to sod-2 longevity. From this screen, we found 25 kinases which are required for the long lifespan of sod-2 mutants including mak-2, which has a role in a kinase signaling pathway involved in axon regeneration. Disruption of mak-2 specifically reduces sod-2 lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act with mak-2 in established signaling pathways, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required for sod-2 longevity but not wild-type lifespan.

Combined these results suggest a novel role for kinases with established roles in axon regeneration in promoting longevity through a mitochondria-to-nucleus signaling pathway.

Link: https://doi.org/10.1016/j.redox.2026.104385

The cGAS protein is a sensor for mislocalized DNA in the cell cytoplasm, and responds by triggering STING, a regulator of the inflammatory response to damage and dysfunction. The cGAS-STING interaction produces some fraction of the maladaptive chronic inflammation characteristic of aging, as, among other reasons, mitochondrial dysfunction tends to spill mitochondrial DNA fragments into the cell cytoplasm. Nothing in the cell has only one purpose, however, and cGAS is also involved in the regulation of the DNA damage response in the cell nucleus. It is known to inhibit homologous recombination of double strand breaks, for example.

An examination of cGAS in different species suggests that different variants can aid or hinder late life health via their actions in either the DNA repair context or the chronic inflammation context. Introducing naked mole rat cGAS into mice improves DNA repair and reduces the impact of aging, and a rare lineage of humans exhibits a variant form of cGAS that reduces cGAS-STING activation, and thus late life inflammation.

cGAS does serve a useful purpose, despite producing a maladaptive contribution to degenerative aging. This is demonstrated in today's open access paper, in which disabling cGAS entirely in killifish does not extend life. Benefits are provided by removing its maladaptive activity, and harms are caused by removing its helpful activity. This is characteristic of interventions in the regulation of inflammation: chronic inflammation is harmful, but the normal short term inflammatory response serves a necessary purpose in tissue maintenance, and both run through the same regulatory pathways, making it challenging to intervene in a selective way.

Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span

A major source of inflammaging stems from chronic activation of the nucleic acid-sensing innate immune pathway cGAS/STING. Cytosolic DNA fragments arising from DNA damage, mitochondrial dysfunction, or infection bind cGAS to stimulate production of 2'3'-cGAMP (cGAMP). Subsequently, cGAMP activates STING, triggering the type I interferon response and inflammatory cytokine production. While this pathway is important for host defense, its chronic stimulation promotes age-related pathology. The cGAS-STING pathway also plays a central role in cellular senescence. Cytosolic DNA in these cells is detected by cGAS, triggering the senescence-associated secretory phenotype (SASP), whose persistence fosters chronic inflammation. Hence, limiting cGAS/STING pathway activity may improve late-life health.

Despite its importance in age-related disease, the effect of cGAS/STING on lifespan itself remains unknown. Here, we elucidated the role of cGAS in the short-lived African turquoise killifish Nothobranchius furzeri, a vertebrate model of aging. In this work, we used CRISPR-engineering to knock out killifish cGAS to examine its impact on senescence and aging. We hypothesized that cGAS loss would improve health and extend life. Although cGAS deficiency reduced senescence markers, attenuated age-related transcriptional changes, and maintained higher proliferative capacity with age, lifespan was unchanged, indicating that cGAS is not limiting for organismal longevity.

Researchers here take a very broad tour of the established literature on the comparative biology of aging in long lived species of all sorts, picking from those that can live more than 250 years, whether plant or animal, and comparing reported differences in biochemistry both between species and between individuals of the same species. It seems just as interesting to ask which mechanisms are important in individual variation in pace of aging in a long-lived species as to ask why the species is long-lived in the first place. The usual challenges exist, in that one can identify differences in biochemistry that seem reasonably likely to contribute to differences in longevity, but establishing the relative importance of each contribution is near impossible without some form of intervention that sabotages or enhances one mechanism in isolation of all of the others.

Certain molecular processes shape the lifespan of each species and each individual. Deciphering these processes, which underlie the diversity in lifespan across and within species can help us better understand how they evolved and why. Such knowledge may inform the design of effective strategies towards increasing human and other species' healthspan and lifespan. Here, we consider 101 species that live past 250 years, including the longest-living beings on Earth. Among these species, 90 are plants and only 11 are animals. Some barely reach an age of 250 years, while others live for up to 80,000 years. Few, such as the freshwater planarian and the Turritopsis dohrnii jellyfish, are considered potentially immortal. None of these species are mammals; indeed, no known mammal lives for over 250 years.

We surveyed the genetic, transcriptional, proteomic, metabolomic, regeneration-, stress-, and cancer-related components of intraspecific and interspecific lifespan variation, across these species. We examined whether the mechanisms regulating intraspecific lifespan variation across these species are the same or different from mechanisms regulating interspecific lifespan variation. We identified several similarities: both types of variation include mechanisms related to DNA maintenance, stemness, and stress management. Such mechanisms are also typical of early developmental stages and germ cells. Nonetheless, caution should be exercised when attempting to draw robust conclusions based on available data, given the lack of in-depth molecular studies on the healthspan and lifespan across thousands of individuals and species, the methodological variation across published studies, and our partial understanding of the interplay between physiology and the environment across species.

Link: https://doi.org/10.18632/aging.206419

Rationing of sugar in the United Kingdom in the years immediately following the Second World War forms a natural experiment in the long term effects of changes in human nutrition that can be explored in great detail given the establishment of the UK Biobank. Researchers here show that lower sugar intake in early life correlates with improved later life health, reduced biological age measures, and reduced mortality. A number of other natural experiments around the time of the Second World War have been used to explore the effects of calorie restriction in early life, but this particular episode of rationing is a way to separate lower sugar intake from overall calorie restriction; it is interesting to see positive results.

Excessive intake of free or added sugars is strongly linked to childhood dental caries and is also associated with higher risks of incident obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), obesity-related cancers, and dementia in adulthood. Britain's post-World War II sugar rationing provides a unique natural experiment. Unlike famine, rationing constrained access to added sugars without broad caloric deprivation, offering a rare opportunity to isolate the long-term impact of early-life sugar reduction to determine the impact on a variety of ageing-related outcomes.

Exposure to sugar rationing during the first 1,000 days of life is associated with a 9% lower incidence of hallmark-related disease, with a hazard ratio of 0.91, and a 19% lower risk of all-cause mortality. Mediation analysis indicates that the survival association is statistically mediated, by approximately 60%, through differences in incident hallmark-related disease. Rationed individuals show 1.0-1.2-year younger biological ages across multiple clocks and lower organ ages, particularly in the lung, heart, and liver. Proteomic profiling identifies 47 altered proteins, with enrichment of adenosine monophosphate-activated protein kinase (AMPK) and longevity pathways and suppression of mechanistic target of rapamycin (mTOR) signaling.

Link: https://doi.org/10.1038/s41467-026-76257-1

A range of gene therapies are presently available in the medical tourism community of clinics outside the US and Europe, largely originating with a small number of companies such as BioViva Sciences and Triple Helix Science. These gene therapies tend to involve intramuscular (targeting muscle) or intranasal (targeting the brain) delivery of a modern adeno-associated virus (AAV) vector, such as AAV8 or AAV9. While AAV therapies have exhibited a concerning risk of life-threatening immune response when injected systemically at high doses, lower doses used in conjunction with local delivery appear to be relatively safe. The genes delivered by these gene therapies include follistatin for muscle growth, VEGF for vascular growth, and some well-known genes hoped to improve the state of the aging body and brain such as telomerase, SIRT1, and so forth. One can argue that perhaps the largest body of direct and practical experience in the implementation of gene therapies is now this community, outside the regulated medical community, and publishing relatively little of the data on what works that they have accumulated.

So it is interesting to see the Triple Helix folk here reporting on their experience in the use of grip strength as a biomarker of aging to assess the results of gene therapies intended to improve function. One of the largest challenges in the matter of measuring aging is the uncertainty over whether any given biomarker that appears to work well in normal aging will then continue to work well when a patient receives some form of regenerative or anti-aging therapy. The best way to stress test a biomarker is to gather data on how it actually performs given a range of different types of regenerative or anti-aging therapy. Until recent years, the range of available interventions known to reliably affect aging has been quite narrow, essentially diet and exercise and first generation stem cell therapies, with newcomers like senolytics and mTOR inhibitors starting be used widely enough for data to emerge. Now, AAV gene therapies can provide a dozen or more very different effects to assess.

Grip strength as a systems biomarker of aging: neuromuscular junction constraints and biomarker decoupling in gene therapy

Grip strength occupies a privileged position among biomarkers of biological aging. Meta-analyses encompassing hundreds of thousands of participants consistently demonstrate that grip strength predicts all-cause mortality with effect sizes comparable to established risk factors such as systolic blood pressure. This predictive relationship persists across age groups, ethnicities, and disease states, extending beyond mortality to encompass cognitive decline, disability onset, hospitalization risk and quality of life measures. Yet the mechanistic basis for this remarkable predictive breadth remains incompletely understood. The dominant interpretation treats grip strength as a convenient proxy for overall muscle mass or general frailty. We argue this view is incomplete and increasingly problematic. When grip strength remains predictive after statistical adjustment for lean mass - while lean mass alone loses significance - something beyond simple muscularity must be at work.

This interpretive challenge becomes urgent as longevity medicine enters a new era. Longevity gene therapies are being explored in early translational and compassionate-use settings and include follistatin for muscle enhancement, klotho for multi-system protection, FOXO3 for stress resistance, hTERT for telomere extension, SIRT1 for metabolic regulation, PGC-1α for mitochondrial biogenesis, VEGF for vascular function, and FGF21 for metabolic health. These therapies represent a fundamental shift from observational aging assessment to interventional aging modification.

The central question this article addresses is: How should clinicians interpret grip strength changes in patients receiving longevity gene therapies? We propose that grip strength predicts mortality because it integrates information from multiple aging systems. We highlight the neuromuscular junction (NMJ) as a particularly critical and often-overlooked rate-limiting factor, noting that age-related strength loss (∼2.5-4% annually) outpaces mass loss (∼0.6-1% annually) by two-to fivefold - a disparity attributable in large part to NMJ deterioration. Critically, we argue that follistatin's anabolic efficacy is contingent on intact NMJ integrity, with denervated muscle fibers exhibiting a blunted net anabolic response despite elevated follistatin expression - creating a therapeutic paradox wherein mass gains can occur without proportional functional improvement. We provide a conceptual analysis of how each therapy may influence grip strength, predict decoupling risk based on the breadth of systems affected, outline plausible timing windows for intervention, and propose a heuristic framework for clinical interpretation.

Senescent cells accumulate with age, likely largely because the aging of the immune system slows down the clearance of senescent cells, but the relative importance of different contributions to the growing burden of senescence in aging tissues is an area of ongoing discussion. Senescent cells secrete inflammatory signals that are disruptive to tissue structure and function when sustained over the long term. Separately, cells throughout the body accumulate mutations over the course of aging. Much of this has little to no effect, occurring in cells with few replications remaining, or in genes not used by the cell. However, a growing burden of mutation in stem cell populations spreads slowly into the tissues they support via the daughter somatic cells generated to replace those cells lost to the Hayflick limit; this somatic mosaicism is thought to produce a meaningful disruption of function, as well as set the stage for rare cancer-inducing mutations to prosper. All distinct causes of aging are thought to interact with one another, to make one another worse, which is one of the reasons why degenerative aging is not a linear process, but cellular senescence and somatic mutation are somewhat challenging to reason about in this respect. Nonetheless, researchers here make the attempt.

Cellular senescence is widely recognized as a driver of age-related phenotypes, intrinsically linked to other aging hallmarks such as telomere dysfunction, chronic inflammation, and stem cell exhaustion. Differently, the potential interplay of somatic mutations (as distinct from the broader concept of genome instability) with the other hallmarks of aging is still unprobed, and the contribution of an altered DNA sequence to aging needs deeper understanding. More broadly, our discussion of cellular senescence and somatic mutations illustrates the wider challenge of biogerontology in distinguishing driver from passenger mechanisms of aging.

Cellular senescence and mutation accumulation are distinct events, and it is presently unclear how these pathways relate to each other. Notably, among the limited evidence connecting the two paradigms, an important discovery is that they can functionally converge when mutations cause oncogene activation and consequent cellular senescence. In addition, although senescent cells are mitotically arrested and thus immune to replication errors, they may still accumulate mutations due to increased production of genotoxic reactive oxygen species and the reactivation of retrotransposons, which can cause insertional mutagenesis. The observation that senescent cells repress several DNA repair genes and have decreased repair efficiency upon irradiation, combined with their resistance to apoptosis, provide the bases for mutation accumulation in these cells.

Defining the interplay between cellular senescence and mutations remains a significant challenge, with a limited number of dedicated studies in the literature, because both processes derive from DNA damage and are difficult to disentangle. Such analyses are further complicated by the low abundance of senescent cells in aged tissues and by the impossibility of expanding these arrested cells. Therefore, elucidating this relationship represents a largely unexplored area of research in the field, one that will refine our understanding of the aging network.

Link: https://doi.org/10.18632/aging.206414

Researchers here suggest yet another possible use for retinal imaging, in this case an assessment of the burden imposed on the central nervous system by atrial fibrillation in its early stages. The retina is a window into the health of the central nervous system; many of the pathologies of the aging brain also take place in the retina. Retinal imaging is a relatively low cost procedure, and machine learning techniques make it feasible to reliably categorize features in the retina that change with aging and disease.

Atrial fibrillation, one of the most common heart conditions causing an irregular heart rhythm, affects millions of people worldwide and significantly increases the risk of stroke and heart failure. Detecting it early, before symptoms arise, remains a major clinical challenge. In this study, we explored whether the retina could offer clues about a person's cardiac health. Because the retina shares structural and vascular similarities with the brain and heart, changes visible on routine eye scans may reflect broader changes occurring elsewhere in the body.

Using eye imaging data from over 90,000 individuals across two large independent datasets, we found that people with atrial fibrillation show measurable thinning of specific inner retinal layers, the ganglion cell and inner plexiform layer, and the inner nuclear layer, compared to those without atrial fibrillation. Crucially, individuals with a thinner retina at baseline were significantly more likely to develop atrial fibrillation in the future, even before any cardiac diagnosis had been made, underlining the difficulty of establishing the diagnosis. These findings suggest that standard, non-invasive retinal scans which are widely used both in eye clinics and community settings, could potentially help identify individuals at elevated cardiac risk, potentially enabling earlier intervention and improved outcomes.

Link: https://doi.org/10.1371/journal.pdig.0001661

Like many age-related conditions, atherosclerosis is accelerated by the chronic inflammation of aging. An atherosclerotic plaque is an inflammatory environment, in which macrophage cells are overwhelmed by excess cholesterol and toxic derivatives of cholesterol. Macrophages attempt to remove cholesterol from the plaque, returning it to the bloodstream attached to HDL particles, and otherwise repair the damage. Inflammatory signaling both attracts macrophages to the plaque and hinders macrophage repair efforts, overall making it more likely that the macrophages will die and add their mass to the growing plaque. Further, it distorts the behavior of cells close to the plaque, which can also act to accelerate plaque growth, such as via the transformation of smooth muscle cells into more macrophages.

Thus there are good reasons to try anti-inflammatory strategies in the context of atherosclerosis, and a range of studies exist in which varieties of anti-inflammatory therapy were assessed for their ability to affect atherosclerotic plaque. In general, results were little more effective than drugs that statins that lower cholesterol bound to LDL particles in the bloodstream, which is to say that treatments only modestly slow plaque growth and modestly reduce the risk of a plaque rupture leading to heart attack or stroke. This is interesting, and perhaps suggests that researchers have not yet found the right inflammatory signals or regulatory mechanisms to target. The research community remains interested in further exploration of novel anti-inflammatory strategies, in search of better outcomes.

Targeting Inflammation in Atherosclerosis: Mechanistic Rationale, Clinical Trials, and Regulatory Considerations

Atherosclerosis remains the leading cause of global mortality, most commonly manifesting as ischemic heart disease, stroke, and peripheral arterial disease. Although age-adjusted cardiovascular mortality has declined in many developed nations, the global burden of atherosclerotic disease continues to rise due to population aging and growth. This narrative review examines the evolving understanding of atherosclerosis, which has shifted from a predominantly lipid-centric model to a chronic inflammatory disease.

Atherosclerosis is initiated by the retention and modification of apolipoprotein B-containing lipoproteins within the arterial wall and propagated by innate and adaptive immune responses. Central to this process is activation of the NLRP3 inflammasome and downstream IL-1β-IL-6 signaling and pyroptotic cell death, which amplify vascular inflammation and promote plaque progression and instability. Clinical evidence demonstrates that targeting inflammation, independent of lipid lowering, reduces cardiovascular events, as exemplified by agents such as canakinumab and colchicine. Consequently, the therapeutic landscape is rapidly evolving, with ongoing efforts to refine cytokine-targeted approaches (e.g., IL-6 inhibition), develop selective NLRP3 inhibitors, and advance innovative modalities including cell-based interventions. These strategies aim to provide more durable, precise, and potentially disease-modifying or even curative approaches. However, challenges related to safety, the high cost of biologic agents, and optimal patient selection have limited widespread implementation.

A major barrier remains the lack of sensitive and specific biomarkers to identify patients with active vascular inflammation, complicating trial design and therapeutic targeting. In addition to circulating markers such as high-sensitivity C-reactive protein (hsCRP) and IL-6, emerging insights highlight the liver as a central hub linking inflammation and thrombosis through complement and coagulation pathways, offering potential avenues for developing novel biomarkers. Despite promising advances, clinical translation faces persistent challenges, including increased infection risk, inadequate biomarkers for patient selection, cost constraints, and regulatory and payer requirements for hard clinical endpoints.

Every tissue in the body exchanges signals with every other tissue. Every tissue is dependent on specialized functions that are conducted elsewhere in the body. Thus in the matter of neurodegenerative disease, it is possible to focus too much on the brain, where the damage is taking place. Other organs and biological systems in the body do make a contribution to the onset and progression of neurodegenerative conditions. The brain requires a functioning circulatory system, a kidney to clear out metabolic waste, a lymphatic system to drain cerebrospinal fluid, and so forth. The functions of the brain are disrupted by chronic inflammatory signaling originating in other parts of the body, or by unwanted metabolites originating in the gut microbiota. The list continues; it is a long one. Thinking about neurodegeneration in this way naturally leads one to a view of medicine that looks very much like that of the longevity industry, as illustrated here.

Alzheimer's disease is a progressive neurodegenerative condition characterised by amyloid-β and phospho-tau pathology, causing synaptic and neuronal loss that leads to decline in memory, cognition, and ability to perform daily tasks. The exact causal mechanisms of neurodegenerative conditions such as Alzheimer's disease remain unclear, and the pathophysiological changes in the brain and body during the prodromal stage are not well understood. Significant changes in the physiopathology of body systems occur before and after the onset of these conditions. Several studies suggest that Alzheimer's disease progression involves complex, multi-scale interactions across genetic, metabolic, proteomic, and physiological domains. However, current approaches are limited in their ability to capture and interpret the complex interactions and interconnections among these dynamics.

This systemic framing is supported by recent large-scale plasma proteomic studies of dementia cohorts, which identify circulating protein signatures associated with neurodegeneration and shared across distinct neurodegenerative conditions. Such peripheral signatures are difficult to reconcile with a brain-focused model alone, but follow naturally if the underlying pathology reflects a common breakdown in cellular clearance and energy regulation, expressed throughout the body. The fact that these signatures are detectable in blood is significant in itself. It places markers of the proposed systemic dysfunction within reach of routine, longitudinal measurement. This opens the possibility of tracking cellular dysregulation across the lifespan and identifying the critical time points, or windows of opportunity, at which interventions are more likely to alter the disease trajectory.

The case for a systemic view of neurodegenerative conditions such as Alzheimer's disease is reinforced by recent therapeutic trials. Anti-amyloid monoclonal antibodies achieve substantial amyloid clearance; however, they yield only modest slowing of clinical decline. If amyloid were the principal driver of disease, effective clearance would be expected to produce a correspondingly significant clinical benefit. This gap between biological target engagement and clinical outcome, together with the limited effect on long-term disease trajectory, instead suggests that amyloid is one component of a broader, multifactorial process, and that effective disease modification may require strategies that address underlying systemic dysfunction rather than targeting a single downstream target.

Link: https://doi.org/10.1038/s43856-026-01831-z

Researchers here process data from a longitudinal study of several thousand people to show that better cardiovascular heath in the early 40s correlates with better outcomes in later old age. There are many reasons to put in the effort to maintain a better state of physical fitness, and that it meaningfully slows the pace of degenerative aging is one of them. In some metrics, such as odds of surviving until age 90, the spread of outcomes between least fit and most fit is sizable - a 6-fold increase in survival. It is food for thought for an age of sedentary comfort.

We examined how low cardiovascular risk in early midlife is associated with frailty, quality of life, happiness, and well-being in old age. At mean age of 42 years, five low-risk factors (non-smoking, BMI < 25 kg/m2, systolic blood pressure < 140 mmHg, total cholesterol < 6.0 mmol/L, one-hour post-load glucose < 9.0 mmol/L) were measured among 2,690 healthy men. Phenotypic frailty, health-related quality of life (HRQoL, RAND-36), psychological wellbeing, and feeling of happiness (a Cantril ladder-type 10 cm visual analogue scale) were assessed in 2007 at a mean age of 79 years. Mortality was retrieved from national registers through 31 January 2025 (2,524 men died).

At baseline, 59 men had zero, 422 one, 855 two, 832 three, 417 four and 105 five low-risk factors. The proportion reaching 90 years increased accordingly: 6.8%, 14.2%, 18.3%, 26.7%, 36.6%, and 41.9%. At mean age of 79 years (n = 907, response rate 63% and similar in baseline groups), compared to those with no low-risk factors in midlife, men with five factors had less frailty (2.2% vs. 24.5%), reported greater happiness (8.0 vs. 7.5), higher psychological wellbeing (55.1% vs. 39.0%), and better HRQoL in several domains. Thus low cardiovascular risk in early midlife was associated with greater longevity, less frailty, better quality of life, and higher levels of happiness and well-being in old age.

Link: https://doi.org/10.1093/eurjpc/zwag429

The major neurodegenerative conditions are characterized by pathology deriving from a small number of misfolded or otherwise altered proteins. Amyloid-β misfolding and aggregation is thought to be the initiating event in Alzheimer's disease, which leads to the spread of altered forms of tau protein that cause the real damage. α-synuclein, once misfolded, spreads from cell to cell through the nervous system like a prion, encouraging other molecules of α-synuclein to also misfold in the same way. Once in the brain, α-syncuclein pathology gives rise to Parkinson's disease. In recent years, researchers have connected the spread of misfolded TDP-43 in the brain to a number of conditions such as frontotemporal dementia. All of these pathologies exist in aged brains to some degree, overlapping and driving dysfunction, and eventually that dysfunction will rise to the level of a named neurodegenerative condition, absent some other form of mortality cutting that process short.

As the past few decades of efforts to develop anti-amyloid therapies for Alzheimer's disease had demonstrated, the biochemistry of protein aggregates and their pathology is enormously complex and remains incompletely understood, even for amyloid-β, even after years of enormous funding for research and development. Amyloid-β clearance took decades to achieve, but does not produce the sizable benefits hoped for in patients, and the reasons why this is the case are yet to be established. It seems likely that the road ahead will be similarly challenging for the development of ways to target other common protein aggregates in the brain. With that in mind, today's open access paper is a tour of the state of development of therapies targeting tau protein aggregation in the aging brain; very different from past anti-amyloid therapy development at the detail level, but quite similar in many ways at the high level.

Therapeutic Targeting of Tauopathies: From Druggable Biology to Precision Intervention

Tauopathies comprise a group of neurodegenerative disorders caused by abnormal tau pathology, including Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), etc. Despite the wide spectrum of tau-related diseases, therapeutic strategies directly targeting pathological tau remain relatively underdeveloped, and no broadly effective clinical treatment has yet to be established.

Most current tau-directed therapeutic approaches have been designed around the tau pathological cascade. Microtubule-associated protein tau (MAPT) mutations and other disease-associated processes can promote abnormal post-translational modifications (PTMs) of tau, with hyperphosphorylation being the most characteristic. Aberrantly modified tau loses microtubule-binding and stabilizing functions, aggregates into neurofibrillary tangles (NFTs), and ultimately contributes to neuronal dysfunction and degeneration. Based on the pathological mechanism, existing therapeutic strategies can be broadly classified into three categories: (1) reducing overall tau levels at both the RNA and protein levels, (2) regulating tau modifications, and (3) interfering with tau aggregation.

However, these approaches have not achieved satisfactory clinical outcomes, probably due to the complexity of tau pathology. Pathological tau can also spread between neurons, thereby facilitating the propagation of neurodegeneration. In addition, tau interacts with other pathogenic proteins, such as amyloid-β (Aβ) and α-synuclein (α-syn), creating mutually reinforcing pathological cycles that accelerate disease progression. Furthermore, tau exhibits remarkable isoform diversity, beyond abnormalities in protein structure and total amount, an imbalance in tau isoform ratios can itself drive disease development.

In this review, we summarize recent advances focusing on these challenges. Emerging therapeutic strategies are not only targeting more precise molecular sites, but are also placing greater emphasis on co-pathogenic proteins and the broader pathological processes involved in tauopathies. Moreover, by deepening our understanding of tau pathological mechanisms, we propose several potential therapeutic targets that may offer new directions for future drug development and therapeutic strategies for tau-related diseases.

The research community is in the early stages of development of therapies for age-related neurodegeneration based on reprogramming the supporting glial cells of the brain to provoke transformation into neurons. A supply of new neurons can restore lost function, integrating into existing neural circuits. As noted here, however, much of this research and development has been conducted in young mice. In old mice, a combination of chronic inflammation and changes in glial cells acts to reduce the efficiency of reprogramming. Attempts to build therapies based on generating new neurons from glial cells will have to address these issues.

Reprogramming resident glia into neurons holds great therapeutic promise for neurodegenerative diseases across the central nervous system, yet these strategies have been developed largely in young animals. Because aging is the primary risk factor for neurodegeneration, whether glia-to-neuron reprogramming remains effective in aged tissue is a critical unanswered question. Here, using the retina as an accessible part of the central nervous system, we show that aging is a major barrier to glia-to-neuron reprogramming in vivo.

Across three transcription factor-based strategies, aged Müller glia exhibit consistently reduced neurogenesis. Single-cell transcriptomics reveal that aged glia fail to activate progenitor programs and instead adopt reactive and inflammatory states. Concurrently, the aged retina mounts an exacerbated neuroimmune response to injury. Immunomodulation with dexamethasone partially restores neurogenesis. Thus, aging imposes both glial-intrinsic and microenvironmental barriers to neuronal regeneration that can be partially overcome by immunomodulation.

Link: https://doi.org/10.1073/pnas.2612369123

Atherosclerosis, the growth of fatty plaques in blood vessel walls, is the largest cause of human mortality. Unstable plaques rupture to block blood vessels to cause a heart attack or stroke, while the narrowing of arteries by plaque contributes to heart failure, dementia, and other conditions. A plaque is in essence a growing macrophage graveyard. Macrophage cells of the innate immune system constantly arrive from the bloodstream, drawn to the plaque, and attempt to repair it. The macrophages are instead overwhelmed by the toxic plaque environment, become inflammatory to call in more macrophages, and die to add their mass to the plaque. The largest plaques also distort the biochemistry of the smooth muscle surrounding blood vessels, and smooth muscle cells transform into macrophages to further accelerate the process of plaque growth - almost a cancer-like mechanism of growth.

Atherosclerosis, the fundamental pathological basis of most cardiovascular diseases which remain the leading cause of global mortality, is driven by both lipid accumulation and dynamic cellular reprogramming within the vessel wall. Central to this process is the remarkable phenotypic plasticity of vascular smooth muscle cells (VSMCs). Far from being terminally differentiated, VSMCs undergo profound transitions from a contractile state to diverse states, including synthetic, macrophage-like, foam cell-like, and fibroblast-like states, which critically influence plaque formation, stability, and rupture.

This review synthesizes the multilayered molecular mechanisms governing VSMC plasticity, encompassing transcriptional networks, epigenetic reprogramming, and microenvironmental cues. Moreover, this review highlights recent breakthroughs enabled by single-cell omics and lineage tracing, that have revealed unprecedented heterogeneity and clonal expansion of VSMCs within atherosclerotic lesions. Furthermore, we explore the translational potential of targeting VSMC plasticity, and discuss emerging strategies, including phenotype-specific modulation, immunotherapy, nanomedicine, and senotherapeutics.

Finally, we outline future directions focused on dynamic regulatory networks, spatial pathophysiology, and the integration of aging biology to advance precision medicine in atherosclerosis. In summary, VSMC phenotypic plasticity is a core mechanism underlying the initiation and progression of atherosclerosis. Precise modulation of this process holds promise for overcoming current therapeutic limitations and driving a paradigm shift toward mechanism-guided personalized therapy for cardiovascular diseases.

Link: https://doi.org/10.31083/RCM50363