Fight Aging!

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

PD-L1 and PD-L2 are components of immune checkpoints, widely expressed in tissues throughout the body. They act by binding to the PD-1 receptor on immune cells to suppress immune activation, and are part of the panoply of biochemical interactions that provide self-tolerance to prevent the immune system from inappropriately attacking healthy cells. Autoimmunity is a breakdown of these mechanisms. Cancerous cells abuse the strategies by which normal somatic cells are shielded from immune cell attention, and thus most research into immune checkpoints has taken place in the cancer research community. Inhibition of checkpoint interactions to unleash the immune system now forms the foundation for a number of cancer therapies, albeit that most work has focused on PD-1 and PD-L1 rather than on PD-L2.

In today's open access paper, researchers show that PD-L2 is generated by senescent cells in aged tissues, allowing these cells to shield themselves from the immune system. In youth senescent cells are generated constantly, in response to stress, damage, or cells reaching the Hayflick limit on replication. Senescent cells secrete inflammatory signals that attract the immune system, and are promptly destroyed after serving this purpose. Senescence helps reduce cancer risk, and is involved in the coordination of wound healing. Clearance of senescent cells becomes inefficient with age, however, and a growing population of lingering senescent cells contributes to chronic inflammation. It seems that PD-L2 contributes to this growing burden of senescent cells in later life.

PD-L2 inhibition seems a plausible basis for senolytic therapies that allow the immune system to destroy senescent cells. It seems likely that many of the same caveats apply here as for the use of checkpoint inhibitors in cancer therapy. Broad checkpoint inhibition can cause meaningful damage to normal tissues, as immune checkpoints do serve a useful, necessary purpose in the regulation of immune activity. Checkpoint inhibition is one of the many classes of therapy that can become a great deal safer, more effective, and more useful when narrowly targeted to specific cells. There are now ways to do this for senescent cells, such as PROTACs that only activate inside senescent cells, so it will be interesting to see what emerges from this line of research.

Blocking a Protein May Reduce Buildup of Harmful Aging Cells

A team has identified a protein that may hide aging cells from the body's immune system, allowing them to build up and contribute to age-related health problems. The findings suggest that the protein, called PD-L2, could serve as a target for treatments designed to remove harmful aging cells or as a blood marker that helps researchers track them. These harmful aging cells, called senescent cells, become damaged and stop dividing but do not die. The cells remain in tissues and release substances that promote inflammation and interfere with the function of nearby cells. Their buildup has been linked to age-related health problems.

Investigators found that in laboratory mice, removing or blocking PD-L2 reduced the number of aging cells and levels of the inflammatory substances they produce. The mice were better able to process sugar and could grip objects with greater strength. Investigators also found that human aging cells produced more PD-L2 than younger cells, and levels of the protein increased in some human tissues with age. "If we can find a way to block this protein, we may be able to help the immune system get rid of these cells and potentially improve health problems linked with aging."

Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.

Damage to nuclear DNA occurs constantly, and near all of it is immediately repaired. A tiny fraction lingers, however, and over time a burden of mutational damage builds up in tissues throughout the body. It is an open question as to how large a component of degenerative aging is a direct result of this damage, under normal circumstances. High rates of mutation in individuals with disabled DNA repair mechanisms shorten life span and accelerate the onset of age-related conditions, sometimes dramatically, but that doesn't necessarily mean the DNA damage is important in aging at levels exhibited in normal individuals. The best approach to firm data is to find a way to suppress or repair mutations without affecting other mechanisms, but the life-extending interventions that are known to slow the accumulation of DNA damage also have many other beneficial effects on metabolism. As reported here, for example, calorie restriction slows the pace at which the burden of DNA damage grows over time. Calorie restriction also improves cell function and health in numerous other ways, however, producing sweeping changes in the operation of cells and systems throughout the body that are unrelated to DNA damage.

Past studies in animals have shown that a large reduction in the number of calories they consume, called caloric restriction, extends their lifespans and slows aspects of aging. But whether caloric restriction also slows the rate at which mutations occur with age had not been investigated across the genome, the complete set of genetic material present in every cell. A new study has shown that caloric restriction reduced the level of mutations across several tissues in mice that were fed 30 percent fewer calories than they would have ingested if allowed to eat freely.

The study analyzed the effect of caloric restriction on different types of genetic changes. They found that to varying degrees across tissues, it dialed down the level of substitution mutations, in which one DNA letter is swapped for another, and insertion and deletion mutations, in which one or more DNA letters are added to or missing from the genome. The study results also showed that the impact of caloric restriction varies across tissues and cell types, as well as across the genome. For example, liver cells showed a greater reduction in mutation burdens with caloric restriction than kidney or brain cells.

Surprisingly, in liver and kidney cells, the reduction in the number of mutations from caloric restriction was greatest in the least-active regions of the genome, which contain either no genes or genes not being used by a given cell. One possible explanation is that if caloric restriction reduces DNA damage across the genome, active regions of the genome would not benefit as much because those regions already repair DNA damage frequently.

Link: https://nyulangone.org/news/feeding-mice-fewer-calories-reduces-dna-mutations

Sports medicine is somewhat focused on specific functional aspects of health, and so it was probably inevitable that factions in that community found the measures of life span and even health span to be lacking. Here, for example, a researcher proposes movement span as a useful concept, the period of life in which one is capable of navigating the world easily - the inverse of physical frailty, more or less. Interestingly, life span and health span in nematode worm studies of aging and longevity are already in practice forms of movement span, as manual or automated measures of worm movement is how researchers assess that the worms remain healthy and alive.

How we conceptualize aging shapes how we measure it, how we respond to it, and ultimately how we experience it. For much of the past century, longevity served as the dominant metric of successful aging. As population health science matured, researchers and clinicians began emphasizing not merely how long people live but also how well they live, giving rise to the concept of health span, which redirected attention from mortality to morbidity. Yet even health span fails to capture something more immediate and experientially salient: the degree to which an individual can move through the world with ease, confidence, and adaptive capacity.

This opinion proposes movement span as a third, conceptually distinct dimension of aging, addressing the trajectory of functional movement capacity over the life course. Movement span is not reducible to either life span or health span, though it is deeply related to both. Its decline may precede the onset of diagnosable chronic disease or may be driven instead by patterns of reduced demand on the sensorimotor system. Understanding movement span has significant implications for how clinicians assess patients, how public health frameworks are constructed, and how individuals respond to their own aging.

Link: https://doi.org/10.1016/j.jshs.2026.101150

A great deal of advocacy for the development of therapies to slow and reverse aging has moved on from a focus on reducing suffering. That the majority of the arguments now focus on economic productivity and reduced entitlement costs reflects a broad and possibly quite correct cynicism about what motivates the politicians, wealthy political influencers, and bureaucrats who collectively control the largest flows of funding and support in our societies. Private funding for research and development focused on longevity remains very motivated by the potential reduced suffering, and indeed the potential to reduce one's own personal suffering in the years ahead. However, the longevity industry of the recent past, and for the near future, exists in a state of tension as it attempts to make the transition from a privately supported new venture to an established field supported by the full panoply of state controlled medical systems - to be as openly and comprehensively backed by governments as cancer research and development.

Most advocates these days appear to believe that the way to make this happen is to exploit the high level of anxiety in the ruling classes of much of the world that centers around the demographic transition to ever increasing numbers of older people, and the costs of old age. The governments of the world have largely chosen to exert a great deal of control over the development and provision of medicine, to the point of it becoming an expense for them, a burden much akin to the mess that was made of pension entitlements, the creation of large enough promises of future expenditure to financially ruin the systems created to manage them. Treatments for aging are a deus ex machina that will save the system, or that is the hope being pushed into government circles by advocates attempting to achieve greater support for the development of longevity therapeutics. The realpolitik always seems somewhat shabby in full daylight when it departs utterly from the considerations of what aging does to an individual, physically and mentally. The true reason to build therapies to treat aging is because this offers the strong possibility of a very sizable reduction in human suffering and death, not because it can prop up dysfunction systems of governance.

The longevity dividend: Why governments and markets must catch up

'How much' often matters less than 'how fast'. Financial systems might comfortably accommodate a decade increase in life expectancy if it emerges gradually over half a century, but could they accommodate the same increase within 5 years? Economies are built to absorb gradual change and are much less comfortable with discontinuities. Human longevity may be approaching that kind of discontinuity. The latest scientific advances point to the emergence of what we have termed 'system-level' therapeutics capable of bringing about rapid, non-linear changes in both healthspan and lifespan trajectories, challenging the incremental paradigms that underpin current economic and demographic forecasting models. If they do, governments, healthcare systems, insurers and pension funds will have to respond to a break with history, not a continuation of it.

Public debate often treats longevity as a cost curve. That is only half the ledger. In an era of demographic ageing and stagnant economic growth forecasts, one overlooked truth is emerging: longevity science may be the most powerful economic productivity lever of all time. Governments spend billions annually on education, digital transformation and industrial innovation - all in the name of boosting national productivity. Yet few acknowledge that the single largest drag on workforce participation is declining health in midlife and beyond due to ageing. In the United States, the direct costs of chronic health conditions total around $1.1 trillion - equivalent to 5.8% of US gross domestic product (GDP). When indirect costs of lost economic productivity are included, the total costs of chronic diseases in the United States increase to $3.7 trillion - in other words, they equate to almost 20% of the US GDP.

The economic argument for longevity research is clear: targeting the root causes of ageing is not just a healthcare imperative, it is set to become a non-negotiable economic strategy. Governments should treat it as such, allocating funding accordingly and incentivising translational research, clinical trials, and public-private partnerships in this field. In the 20th century, public investment in antibiotics and vaccines changed the world. In the 21st century, ageing biology has the potential to do the same.

Sarcopenia is the name given to severe age-related loss of muscle mass and strength. This loss occurs steadily throughout later life. The present state of research into this condition is representative of aging more generally, in that while a range of quite different mechanisms all have strong supporting evidence for a meaningful contribution to sarcopenia, their relative importance to one another is unclear, how they connect to one another at the detail level is unclear, which are largely causes and which are largely consequences of one another, and their relationship to the known underlying forms of cell and tissue damage that drive aging is unclear. See the evidence for loss of muscle stem cell function to be the primary cause of sarcopenia, and surrounding discussions on that topic, for example. Here, researchers point instead to disruption of lactate metabolism in both liver and muscle tissue as the primary cause of sarcopenia; the involvement of the liver a reminder that no one tissue stands alone in the matter of aging. All organs communicate with one another and are interdependent in many different ways.

Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle.

Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1α improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1α in the liver as a pharmacological target for sarcopenia.

Link: https://doi.org/10.1126/sciadv.aeb4011

Normal cell metabolism, particularly the activities of mitochondria, generates oxidizing molecules that react with proteins to disrupt their function. This damage occurs constantly, and is repaired constantly. Cells remove damaged proteins, undo oxidative changes, and make use of antioxidant enzymes such as SOD1 to prevent damage from occurring in the first place. With age, oxidation increases and becomes an important component of cell dysfunction. Here, researchers note that SOD1 itself can become oxidized and harmful, and discuss the importance of antioxidants disabled by oxidization in the growth of age-related oxidative stress in cells. The specific focus is on skin aging, but the points have relevance to all tissues.

As the body's primary barrier against environmental insults, the skin is continually exposed to oxidative stress, which may contribute to progressive proteotoxic stress. Excess reactive oxygen species (ROS) can overwhelm cellular protein-quality-control systems, promoting the accumulation of damaged and misfolded proteins, proteome instability, and eventual protein homeostasis (proteostasis) collapse. Superoxide dismutase 1 (SOD1), a Cu/Zn-dependent cytosolic antioxidant enzyme and key component of cellular defense against superoxide radicals, is itself vulnerable to oxidative modification. ROS-mediated post-translational oxidation of SOD1 may promote its misfolding and the formation of toxic protein species, potentially establishing a self-amplifying cycle of superoxide accumulation, further protein damage, and impaired cellular homeostasis.

In cutaneous cell types, including dermal fibroblasts and epidermal cells, these processes may be especially relevant to age-associated declines in proteostatic capacity and skin aging. This review distinguishes established skin-specific evidence from hypotheses extrapolated from other systems and synthesizes current evidence on the interplay among ROS-induced protein damage, proteostasis failure, SOD1 dysfunction, and cutaneous aging. We highlight the bidirectional relationship between proteostasis collapse and mitochondrial dysfunction, which may establish a self-reinforcing cycle of oxidative stress, cellular senescence, and chronic low-grade inflammation. These interconnected processes may converge to promote extracellular-matrix remodeling and tissue dysfunction, contributing to wrinkles, reduced elasticity, and impaired barrier function.

Link: https://doi.org/10.1016/j.arr.2026.103351