Fight Aging!

Even in this age of single cell sequencing, a great deal of the categorization and counting of cells is still accomplished via assessment of cell surface proteins. The ability to cheaply create and manufacture novel antibodies that selectively bind to specific proteins naturally led to technologies such as flow cytometry that can separate and count cells that express a specific surface protein, or high versus low levels of that surface protein. The large number of proteins with names that start with "CD" for cluster of differentiation are so named because researchers have spent a lot of time looking for ways to distinguish different populations of immune cells with very different behaviors.

Recognizing specific surface markers is also an important foundation for the development of cell killing technologies and immunotherapies. Thus the cancer research field is very interested in categorizing cells by their markers. Similarly, now that the research community recognizes that senescent cells accumulate with age and are harmful, an important contribution to age-relaed loss of function and disease, there is interest in distinct markers of senescence. Firstly, senescent cells are not uniform, and it may be useful to distinguish their types. Secondly, cell killing technologies that are highly selective for senescent cells are very much a desirable goal. Thirdly, the well established approaches to assess the burden of senescence in tissues are likely suboptimal in a number of ways.

The exploration of markers of senescence is a work in progress, with ongoing debate over the merits of one approach over another, particularly when it comes to the immune system. To come full circle, cellular senescence in the immune system appears important to immune system aging - but so are a range of other issues. The immune system is very complex, and far from fully mapped. There is a great deal of room for improvement to the present state of knowledge, and today's open access paper is an example of this sort of ongoing work on the topic of immune cell senescence and how to best identify this state.

Re-evaluating CD57 as a marker of T cell senescence: implications for immune ageing and differentiation

Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features.

CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8+ and CD4+ T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers.

Our findings reinforce the association between CD57 expression, T cell differentiation, and cytomegalovirus seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for cytomegalovirus serostatus to avoid misleading conclusions, especially in oncology and ageing research.

Given the ability to accurately map the microbial species and relative population sizes of the gut microbiome via 16S rRNA sequencing, researchers are generating an enormous amount of data linking specific characteristics of the gut microbiome to specific medical conditions, including the changes that take place with age. Here, researchers use data from patients with fibrosis in the lungs to mount an argument for Bifidobacterium adolescentis to be a beneficial species, and then test this proposal in aged mice. Increasing the presence of Bifidobacterium adolescentis in the gut microbiome of mice proves capable of attenuating fibrosis in the lung, making it a potentially interesting intervention. At present many forms of lung fibrosis are hard to treat and largely irreversible.

The global burden of pulmonary fibrosis is increasing. Recent studies have shown that some pulmonary fibrotic lesions caused by COVID-19 infection may persist for a long time. Emerging evidence suggested a critical association between gut microbiota and pulmonary fibrosis. In this study, the clinical follow-up data from post-COVID-19 patients indicated that those with higher CT image scores were older, had a significantly lower Blautia and Bifidobacterium to Streptococcus ratio (B/S index).

We examined whether Bifidobacterium adolescentis could attenuate bleomycin-induced pulmonary fibrosis in mice, with particular attention in the aging mice. Aging mice exhibited more severe pulmonary fibrosis after bleomycin induction, while the intervention of B. adolescentis attenuated the degree of pulmonary fibrosis in aging mice to a state similar to that of young mice. B. adolescentis alleviated inflammatory responses by enhancing the gut barrier, and reduced fibrotic marker expression (TGF-β, IL-17, α-SMA, Collagen I, Collagen III) by modulating PPAR and Th17 signaling pathways. Furthermore, B. adolescentis stabilized gut microbiota and increased the abundance of Bifidobacterium, Turicibacter, and norank_f_Desulfovibrionaceae, thereby suppressed the prostaglandin E2 (PGE2) and affected collagen deposition.

In conclusion, B. adolescentis alleviates pulmonary fibrosis through the gut-lung axis by regulating PGE2/PPAR/Th17 signaling, providing a promising therapeutic approach for pulmonary fibrosis management.

Link: https://doi.org/10.1038/s41538-025-00613-6

Excess weight is a risk factor for Alzheimer's disease, but nowhere near as strongly as, say, for type 2 diabetes. It is likely not as straightforward a relationship in terms of the underlying biochemistry. Here, researchers note that obesity correlates with low levels of choline in blood samples, and low levels of choline in turn are established in animal studies to worsen age-related inflammation and progression of neurodegeneration. The researchers propose that low choline contributes to the metabolic consequences of obesity, but note that it is unclear as to whether obesity causes low choline. As is usually the case when looking at human data, correlations are easily established, but finding definitive evidence of causation is challenging.

Here, we demonstrate a relationship between early-life obesity, insulin resistance, circulating choline, and inflammation, emphasizing their potential as risk factors for disorders such as Alzheimer's disease (AD). Choline levels were lower in obese participants compared to those with a healthy body mass index (BMI). Importantly, several metabolic indicators were elevated in the obese group, and body composition markers (BMI and %Body Fat) and insulin sensitivity markers (insulin levels and HOMA-IR) were negatively correlated as well as associated with choline levels.

Obese participants also exhibited dysregulated inflammatory profiles; 11 cytokines were elevated. Additionally, levels of aldolase B and sorbitol dehydrogenase - liver enzymes involved in sugar metabolism - were higher in obese individuals and negatively correlated with choline levels, paralleling our previous findings in AD mice on a choline-deficient diet. Evidence of neuronal axonal damage was observed in obese participants; as plasma NfL was elevated and inversely correlated with choline levels, this relationship was validated in independent mild cognitive impairment (MCI) and AD cohorts.

Collectively, these findings support the idea that low circulating choline levels may contribute to the metabolic and inflammatory dysfunctions associated with obesity and may increase the risk of neurodegenerative diseases.

Link: https://doi.org/10.14336/AD.2025.1207

The glymphatic system parallels blood vessels where they enter the brain, providing a path for drainage of cerebrospinal fluid from the brain into the body. The other well described path is through channels in the cribriform plate bone. These drainage routes become dysfunctional with age, allowing metabolic waste to build up in the brain, and thus contributing to the dysfunctional environment that causes pathology and neurodegeneration.

An approach to measure drainage of cerebrospinal fluid through the glymphatic system via magnetic resonance imaging was developed relatively recently, known by the unwieldy name of diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). DTI-ALPs has been having its time in the sun over the past few years, with numerous research groups working to expand the body of data for this measurement in various patient populations. Today's open access paper is an example of this sort of work, focused on patients with cerebral small vessel disease.

Cerebral small vessel disease, also known as microangiopathy, emerges from a combination of endothelial dysfunction in microvessels, a loss of microvessel density that impairs blood flow, and other issues that affect the integrity and function of the smallest vessels that support brain tissue. It is worth considering that the aspects of aging that harm the vasculature likely also harm the near neighbor glymphatic system. That patients with cerebral small vessel disease also exhibit impaired glymphatic drainage of cerebrospinal fluid doesn't necessarily mean that one condition causes the other. They may both be emergent properties of the cell and tissue damage of aging, and likely each makes the other worse in a variety of different ways.

Glymphatic system impairment in cerebral small vessel disease: associations with perivascular space volume and cognition

Cerebral small vessel disease (CSVD) is a progressive cerebrovascular disease characterized by diverse clinical manifestations, especially neurocognitive dysfunction, a primary contributor to vascular cognitive impairment. The glymphatic system, a brain waste clearance system first described in 2012, facilitates the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). In this process, CSF enters the brain parenchyma via para-arterial perivascular spaces, passes through astrocytic aquaporin-4 (AQP4) water channels, and mixes with ISF before being cleared along perivenous routes, thereby promoting the removal of metabolic waste.

Recent evidence suggests that impaired glymphatic function may represent a final common pathway in the pathogenesis of dementia and has been increasingly implicated in the pathophysiology of CSVD. However, the relationship between glymphatic dysfunction and CSVD is likely bidirectional and multifactorial. On one hand, CSVD-related pathologies, such as endothelial dysfunction, blood-brain barrier disruption, and reduced arterial pulsatility, may impair glymphatic flow by compromising perivascular pumping mechanisms and fluid transport. On the other hand, impaired glymphatic clearance may exacerbate CSVD by allowing the accumulation of neurotoxic waste products, such as amyloid-β and tau proteins, and pro-inflammatory molecules within perivascular spaces, further damaging vascular integrity and promoting white matter injury.

We enrolled 120 CSVD patients [52 with no cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI)] and 40 healthy controls. Glymphatic function was assessed using the left ALPS index derived from diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Group comparisons in the ALPS index and perivascular space (PVS) volume fraction (VF), and correlations among glymphatic function, perivascular burden, and cognition were analyzed.

Compared to healthy controls, CSVD patients showed decreased ALPS index and increased PVS VF in basal ganglia, caudate, putamen, and hippocampus, with more pronounced alterations in the left hemisphere. The ALPS index was inversely correlated with PVS VF in the basal ganglia (r = -0.232), thalamus (r = -0.213), caudate (r = -0.221), and putamen (r = -0.210) in CSVD. Furthermore, a lower ALPS index was associated with poorer performance in global cognition (r = 0.312), executive function (r = 0.242), processing speed (r = 0.264), and visuospatial function (r = 0.272). Finally, the ALPS index partially mediated the association between putamen-PVS VF and global cognitive function, especially in the left hemisphere. Our findings demonstrate that impaired glymphatic function was associated with enlarged basal ganglia PVS, especially in the putamen, and worse cognitive performance, highlighting its potential role in disease progression and cognitive decline in CSVD.

Much of the benefit of stem cell therapies results from the signals released by those cells in the short time they survive in the body following transplantation. Much of that signaling is carried by extracellular vesicles, membrane-wrapped packages of molecules. Extracellular vesicle therapies can in principle become considerably less costly than stem cell therapies, because manufacture can be centralized, and because extracellular vesicles are much more readily stored and transported, but we are not there yet. Thus while extracellular vesicle therapy is certainly available to those with the time and patience to navigate the medical tourism space, or find suppliers and a cooperative physician inside the US, the schedule of 36 doses over 18 months used in this study is beyond the financial reach of most individuals at the present time. Still, it is quite interesting to see that the researchers demonstrated improvement in cognitive function in the aged monkeys assessed in the study.

Aging humans and non-human primates both exhibit a similar pattern of cognitive decline beginning in middle age that is characterized by progressive impairments in rule learning, executive function, and working and recognition memory-functions often associated with dysfunction of prefrontal and medial temporal lobe regions. The heterogeneity and inter-subject variability in aging and age-related cognitive impairments present challenges for developing effective therapeutics and can be attributed to differing degrees of cortical white matter (WM) damage and alterations to local and long-range prefrontal and temporal networks.

A promising therapeutic that has been shown to be efficacious in mitigating WM damage and improving cognitive function in rodent models is mesenchymal cell-derived extracellular vesicles (MSC-EVs). In the present study, late middle-aged rhesus monkeys were systemically administered monkey-derived MSC-EVs every 2 weeks for 18 months. We demonstrate that MSC-EV treatment improves spatial working memory and decreases the frequency of perseverative responses with largely no effects on recognition memory. These cognitive improvements were associated with increases in MRI diffusion measures of WM structural integrity over time as well as preservation of inter-network functional connectivity as measured by resting-state functional MRI.

These findings suggest that MSC-EV treatment can slow or reverse age-related cognitive decline while strengthening WM integrity and improving functional connectivity in late middle-aged rhesus monkeys.

Link: https://doi.org/10.1007/s11357-025-01992-0

Researchers here describe an indirect method of inducing greater resistance to damage and regeneration following a heart attack via modulation of macrophage behavior. Macrophages are innate immune cells resident in tissues that play an important role in regeneration and response to injury. The approach taken here is to grant macrophages better control over internally mislocalized DNA, escaped from either the nucleus or mitochondria into the cytosol. This provokes mechanisms intended to react to the presence of infectious pathogens, and is a cause of inflammatory signaling in aged and stressed cells. The better protected macrophages engage in a pattern of behavior that aids tissue regeneration and resilience following the injury of a heart attack.

Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA.

In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or Trex1 overexpression. Inhibition of Trex1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for Trex1, TY1 attenuated DNA damage in the post-MI heart.

The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism - pharmacological upregulation of Trex1 in macrophages - establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity.

Link: https://doi.org/10.1126/scitranslmed.adp1338

A number of distinct cellular processes are labeled as forms of autophagy. These are ways in which a cell identifies unwanted structures and molecules, conveys those unwanted structures and molecules to a lysosome, and there breaks down the unwanted structures and molecules into raw materials. Autophagy is necessary for cell function, and has attracted attention in the aging research space for a number of reasons. Firstly the efficiency of autophagy appears to decline with age, secondly a number of ways to alter metabolism to modestly slow aging, such as calorie restriction and mTOR inhibition, appear to primarily function via increased efficiency of autophagy, and thirdly a few strategies to directly and selectively improve the efficiency of autophagy, such as LAMP2A upregulation, have also been shown to slow aging.

Today the focus is on chaperone mediated autophagy, in which unwanted proteins bind to a chaperone protein such as HSC70 that in turn binds to features such as LAMP2A on the surface of a lysosome, allowing the unwanted protein to be engulfed and then broken down. A pair of recently published papers from a team that has been working on LAMP2A for twenty years or so caught my attention. The work implicates an age-related decline in the efficiency of chaperone mediated autophagy in the aging of muscle tissue. The researchers show that maintaining efficient chaperone mediated autophagy in later life, achieved via upregulation of LAMP2A in a genetically engineered mouse lineage, can slow the age-related loss of muscle mass and strength. This approach likely works via helping to maintain muscle stem cell function into later life.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise, and tissue repair, but declines in ageing and obesity.

Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration.

Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

As a brief introduction to the way in which the statistical tools used by policy makers exhibit important disconnections from reality, one can start with the quality-adjusted life year (QALY) and value of statistical life (VSL). Sadly we live in a world in which medicine is ever more centralized and regulated, with an ever greater fraction of decisions made by regulators based on statistics rather than by the individual patient based on their preferences. The paper here is an interesting glance at the relationship between the value of QALY and the VSL as used in practice, in this course of arguing that the value of QALY used in policy decisions should change with age (and other circumstances) because the VSL changes with age (and other circumstances).

In the healthcare sector, cost-benefit analysis (CBA) using measures such as the value of statistical life (VSL) and quality-adjusted life years (QALY) is commonly employed to guide policy interventions and the efficient allocation of healthcare resources. The VSL is calculated based on willingness to pay for mortality risk reduction and is widely used in CBA to evaluate the economic benefits of a policy. The QALY, which considers both quality of life (QoL) and life expectancy, equates one QALY to one year of life in perfect health (QoL = 1).

The VSL and QALY are considered to be closely related, and research on their relationship has been active in recent years. This measure allows for cross-sectional comparisons of different healthcare policies and is widely used in many countries as a standard metric for public health policies and resource allocation decisions. By employing QALY-based CBA, policymakers can quantitatively assess the effectiveness of healthcare interventions based on scientific evidence, thereby facilitating informed decision-making. For instance, the UK's National Institute for Health and Care Excellence (NICE) uses QALY to assess pharmaceutical and medical technologies, providing guidelines for the effective use of limited healthcare resources.

However, the QALY has several limitations. For example, it applies uniformly across different age groups, despite significant differences in health status and life expectancy between younger and older individuals. The current QALY-based CBA may not adequately account for age-specific differences, potentially leading to biased results. Additionally, QALY values are often derived based on practices from other countries without fully considering regional characteristics such as population, economic conditions, and age distribution.

This study aims to present a QALY metric that considers age-specific health status (QoL) and life expectancy by deriving QALY from VSL. We model the VSL-based QALY and demonstrate its effectiveness through a scenario and policy evaluation analysis. In this study, we focus our analysis on the monetary value of a QALY that arises solely from life extension without incorporating QoL improvements and present the results of VSL, QALY, and policy cost reduction, using socioeconomic data from Japan.

Link: https://doi.org/10.1038/s41598-025-29794-6

Stressing cancer cells to induce a senescent state is a secondary goal of cancer therapy, after inducing cell death, as senescence brings a halt to replication. Senescent cell burden is an important component of degenerative aging, and so clearance of the senescent cells created by treatment following the completion of cancer therapy should be beneficial to patients. There is a complex relationship between the presence of senescent cells and the ability of a cancer to grow, however. Senescent cells draw the attention of the immune system, but also secrete signals that can help to support the growth of cancerous cells. There is some debate over whether one should expect clearance of senescent cells during cancer treatment to help or hinder the goal of eliminating the cancer. Here, researchers provide animal model data to suggest that removing senescent cells hinders cancer growth to some degree.

Immunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. A senolytic dendritic cell (DC) immunotherapy ("SenoVax") was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16.

SenoVax induced prophylactic and therapeutic tumor regression in Lewis Lung Carcinoma (LLC) primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection.

When SenoVax was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax also demonstrated reduction of glioma, pancreatic cancer, and breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.

Link: https://doi.org/10.1186/s12967-025-07393-3

Cells become senescent constantly throughout life, in tissues throughout the body, for a variety of reasons. Some senescence is a response to damage or stress or inflammatory signaling, some cells become senescent to help coordinate regeneration following injury, but most senescence is the result of cells reaching the Hayflick limit on replication. A senescent cell ceases to replicate, becomes larger, primes itself for programmed cell death, and secretes a potent mix of pro-growth, pro-inflammatory signals that attract the attention of the immune system.

In youth, senescent cells are efficiently removed by the immune system. In later life, this process slows as damage and stress increases, leading to the accumulation of senescent cells over time. Senescent cell signaling sustained over the long term by this growing, lingering population becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging.

The research community is engaged in finding ways to selectively destroy senescent cells, reverse the normally irreversible senescent state, or shut down senescent cell signaling. A range of programs are scattered across the length of the slow and expensive path that leads towards clinical trials and eventual regulatory approval. At the same time, researchers continue to expand on the presently understanding of how exactly senescent cells cause harm to their host tissues. Today's open access paper is an example of this sort of work, focused on skin aging. As is usually the case in biology, nothing is direct and simple.

Endothelial senescence drives intrinsic skin aging via the neuroimmune CGRP-mast cell axis in mice

Endothelial cells (ECs), lining the inner surfaces of blood vessels, are particularly vulnerable to senescence, a state of irreversible cell cycle arrest triggered by telomere dysfunction, oxidative stress, and chronic inflammation. Senescent ECs secrete a senescence-associated secretory phenotype (SASP), a pro-inflammatory mix of cytokines, chemokines, and matrix-degrading enzymes that disrupt tissue homeostasis and propagate senescence. Although EC senescence has been implicated in age-related pathologies such as neurodegeneration, metabolic disorders, and pulmonary dysfunction, its contribution to skin aging remains poorly understood.

Skin aging is classified into two distinct types: extrinsic aging, driven primarily by environmental stressors such as ultraviolet (UV) radiation and pollution, and intrinsic (chronological) aging, mediated largely by genetic, metabolic, and vascular factors. While extrinsic aging manifests as epidermal hyperplasia, elastosis, and pigmentation, intrinsic aging is characterized by dermal thinning, collagen degradation, and impaired wound healing. Given the high vascular density within the dermis, microvascular dysfunction may contribute significantly to intrinsic skin aging by disrupting tissue homeostasis. However, the precise molecular mechanisms underlying the relationship between vascular dysfunction and intrinsic skin aging remain unknown.

Here we show that EC senescence contributes to intrinsic skin aging through immune dysregulation. Using an EC-specific senescent mouse model, we observe mast cell activation driven by the neuropeptide calcitonin gene-related peptide (CGRP), independent of traditional immunoglobulin E mediated pathways. Senescent ECs secreted pro-inflammatory SASP factors, activating dermal neurons to produce CGRP, leading to mast cell degranulation and subsequent skin aging phenotypes. Pharmacological stabilization of mast cells or inhibition of the EC-SASP-CGRP pathway significantly attenuate dermal thinning, collagen degradation, and delayed wound healing, which are hallmarks of intrinsic skin aging. These findings identify vascular senescence as an upstream regulator of skin aging through a neuroimmune mechanism and suggest potential therapeutic targets for age-related skin deterioration.

Vaccination for the herpes zoster virus that causes shingles is generally done after age 50. Evidence from widely used vaccines suggests that many forms of vaccination produce long-term trained immunity effects, which include increased resistance to unrelated pathogens, and a reduction in innate immune system inflammatory signaling in older individuals. Insofar as vaccination is connected with reduced incidence of an inflammatory disease, this may well be the important mechanism. Equally, in the case of Alzheimer's disease, some evidence suggests that persistent viral infection may be an important contributing factor in the onset and progression of this condition for other reasons. None of this is completely cut and dried - there are contradictory findings and clinical trial outcomes. But on balance, the evidence leans towards a protective effect of vaccination.

Clinical and subclinical reactivations of the neurotropic herpesvirus (the varicella zoster virus) that causes chickenpox and shingles may constitute a chronic immune stressor that drives inflammatory pathways in both the peripheral and central nervous system, interfering with neuroimmune homeostasis in older age. The varicella zoster virus has also recently been linked to amyloid deposition and aggregation of tau proteins, as well as cerebrovascular disease that resembles the patterns commonly seen in Alzheimer's disease. Reducing clinical and subclinical reactivations of the virus through herpes zoster (HZ) vaccination might thus have a beneficial impact on the development or progression of dementia, as well as neuroimmune health and cognitive reserve in older age more broadly.

Moreover, it is possible that HZ vaccination, and potentially vaccinations in older age more generally, act on the dementia disease process through a pathogen-independent immune mechanism. Such an effect might counteract immunosenescence and would add to the growing body of evidence suggesting that vaccines frequently have broader health benefits beyond their intended target.

Using natural experiments, we have previously reported that live-attenuated HZ vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.

Link: https://doi.org/10.1016/j.cell.2025.11.007

TDP-43 is one of the few proteins known to form persistent aggregates in the aging brain. When this aggregation becomes excessive it is a cause of neurodegenerative conditions, notably ALS and LATE, but it is worth remembering that every aged brain exhibits some degree of this problem. Here, researchers show that TDP-43 is involved in regulating a form of DNA repair, and depletion of the functional TDP-43 protein by aggregation leads to increased DNA damage and consequent dysfunction in cells.

TDP43 is an RNA-binding/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons.

Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include changes in MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability.

We furthermore find that aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and in post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Link: https://doi.org/10.1093/nar/gkaf920

Since around the time at which the goal of extending life through improvements in medical technology became a respectable goal, let us say somewhere a little after 2010, perhaps around the time that the first demonstration of clearing senescent cells in mice was conducted, the official message from the academic research community to the public and politicians has been that the goal of the field is to extend healthspan, but not lifespan. Extending the healthy period of life is great, but extending overall lifespan is shady and disavowed. Why did the prominent figures of aging research so enthusiastically embrace this public messaging?

Today's open access paper provides one view on that question, but I don't think that it touches closely enough on what seems the actual answer. It seems quite clear to those of us who lived through that period of time that this messaging was a way to distance the dominant factions in academia, who are ever sensitive to any threat that might impact their perceived status and thus ability to raise funds, from the growing voices of patient advocates and a minority faction of researchers who had started to achieve some success in talking up radical life extension and the medical control of aging, while funding research into technologies to repair cell and tissue damage thought to cause aging. The "healthspan but not lifespan" messaging was a rush to conservatism undertaken in fear of reduced funding from conservative institutions. This is, after all, what happened in the field of aging research following the anti-aging advocacy and birth of the supplement industry in the 1970s. The leaders of the field disavowed any attempt to intervene in aging. It was an exclusion of those not following the orthodoxy, and a rebranding and message intended to distinguish the orthodox form the newcomers, all conducted to protect existing status and sources of funding.

But make your own mind up! One could also argue, much as is done in the paper here, that it was a reaction to the data obtained from decades of efforts to treat age-related diseases. Since those efforts did not in fact target causes of aging, they produced very little gain in life span, but heroic efforts in development and clinical practice had managed to incrementally extend healthspan. It takes enormous effort to coax a failing machine into continued function if repair is off the table, but it can be achieved to some degree. Still, some researchers may have felt that this outcome represented the bounds of the possible, and thus the newcomers who aimed to extend life span by changing the strategy to medicine to one of repairing causative damage were mistaken.

Against "Extending Healthspan but Not Lifespan" as a Goal for Biogerontology

Extending human healthspan is of course highly desirable. However, within the biogerontology field one increasingly encounters this view that our goal should be to extend healthspan but not lifespan. This view has been stated explicitly, for example by Jay Olshansky, who argued that "life extension should no longer be the primary goal of medicine when applied to people older than 65 years of age. The principal outcome and most important metric of success should be the extension of healthspan." From some perspectives, this is a strange position to take. What is wrong with extending lifespan? We suggest that this anomaly has arisen from conflation of the goals of two distinct disciplines, namely geriatric medicine, that addresses the health needs of older adults, and biogerontology, the study of the biology of aging.

A challenge for geriatricians is that all of their patients will inevitably die from the condition that ails them, namely the process of senescence (aging). Faced with this, laudable and inspiring goals for geriatric medicine were set out in the early 1980s in a vision that accepts the harsh fact that, as in most animal species, there exists an upper ceiling for human longevity. Thanks to improvements in public health during the last century or so, an increasing proportion of the population are living longer lives, coming closer to the longevity ceiling. This is reflected in an increasing rectangularization of population survival curves. It was argued that the goal of late-life medicine should be to reduce the proportion of later life in poor health: "The rectangularization of the survival curve may be followed by rectangularization of the morbidity curve and by compression of morbidity."

By contrast, the vision of biogerontology is very different. Central to it is the possibility of decelerating or even reversing the aging process as a whole, or in its greater part. That this is feasible is suggested by the existence of numerous interventions that extend both healthspan and lifespan in animal models, particularly rodents. In terms of medical applications, the main, ultimate goal of biogerontologists is much the same as that of most of medical research: to alleviate illness, reduce disease burden, and save lives. Anti-aging treatments will always reduce disease, and may extend lifespan, but whether they increase healthspan and compress morbidity is to a large extent a matter of chance. For a biogerontologist to say that their goal is to increase healthspan but not lifespan is as strange as for a practitioner of any other medical specialism (say, oncology) to say it.

The arguments for healthspan rather than lifespan originated in the field of geriatrics, in which they are cogent, but were subsequently imported into biogerontology, where they are not. Possibly this partly reflects efforts by biogerontologists to align themselves with the agenda of the broader and better funded biomedical field, particularly as part of the geroscience agenda. In the end, medical interventions that save lives and postpone death may or may not cause an expansion of morbidity. Whether they do or not, such interventions are beneficial to the patient, and a good thing. The prospect of a doctor denying a patient a life-saving treatment on grounds that they will remain alive for an extended period in poor health is not part of any ethical reality. We advocate that biogerontologists frankly state their goals of understanding and intervening in aging, to make any gains possible in terms of improvements to late-life health and saving of lives (i.e. life extension).

In discussions of aging, references to klotho usually mean α-klotho, a transmembrane protein, and specifically the fragment of α-klotho that projects beyond the cell membrane and is shed to circulate in the body, also known as soluble α-klotho. Soluble α-klotho interacts with cell receptors to produce beneficial changes in cell function in a range of tissues. Klotho has long been of interest to researchers because increased expression of α-klotho slows aging, whereas reduced expression accelerates aging. Past research has focused on beneficial effects resulting from soluble α-klotho in the kidney and brain. Improved function in these organs might be enough to explain systemic benefits throughout the body, but as shown here soluble α-klotho likely has direct effects on cells in other tissues as well.

We investigate the effects of α-Klotho, an anti-aging hormone, on cell proliferation across three tissues with varying regenerative capacities in the context of aging. Using young and old wild-type mice, alongside old heterozygous Klotho-deficient mice, we administered soluble α-Klotho (sKL) daily for 10 weeks to elucidate the impact of α-Klotho deficiency and its supplementation. Our investigation spanned three organs: the small intestine, the kidney, and the heart.

We measured cell cycle markers (BrdU, Ki-67, and phospho-histone-3), Sirtuin-1, DNA-damage response pathways (gamma-H2Ax, ATM, CHK2), and the aging phenotypes. Supplementation of sKL significantly enhances proliferative markers and attenuates many aging changes. Mechanistic studies show that sKL acts through the Sirt1-CHK2 pathway to promote cell proliferation. In summary, Klotho deficiency exacerbated aging phenotypes, reduced regenerative capacity, and impaired cellular proliferation. Supplementation with sKL effectively counters these age-related declines across multiple tissues by enhancing cellular proliferation and attenuating aging phenotypes through the Sirt1-CHK2 signaling pathway.

Link: https://doi.org/10.1038/s41514-025-00286-1

Myelin is a protein that forms an insulating sheath around the axons that connect neurons, enabling the effective transmission of nerve impulses. It is essential for the normal function of the nervous system and brain, and thus demyelinating diseases such as multiple sclerosis that cause extensive loss of myelin are particularly debilitating. A lesser but still significant loss of myelin integrity occurs with aging, and thus forms of therapy that encourage myelin formation that are under development as potential treatments for multiple sclerosis may eventually find more widespread use in the aging population. Myelin is maintained by a population of specialized cells called oligodendrocytes, and all aspects of aging that degrade cell function in the brain and nervous system thus contribute to a progressive loss of myelin integrity. The example here for cardiovascular disease is likely connected to a number of mechanisms, from reduced blood flow to the brain to the inflammation and high burden of cell and tissue damage that contributes to both cardiovascular and nervous system degeneration.

A new study applied a novel multivariate approach to brain assessment using 12 separate metrics. The researchers compared test results and MRI scans of 43 patients with coronary artery disease (CAD) to those of 36 healthy individuals. All participants were over age 50. The multivariate approach of bundling individual white matter metrics into one overarching metric provides advantages over past studies. It allows the researchers to simplify complex aspects of brain health into a single metric that can be compared to the same metric in healthy controls.

The researchers found that individuals with CAD had widespread structural changes in their white matter compared to their healthy counterparts. The changes were particularly noticeable in the parts of the brain fed by the middle cerebral artery and anterior cerebral artery. Both regions are key for cognitive and motor functions.

The researchers found that the changes were mainly linked to reduced myelin content - the fatty coating that insulates nerve fibers and allows signals to travel quickly through the brain. Myelin loss can slow communication between brain cells and is often an early sign of cognitive aging. Interestingly, participants with higher measures of myelin integrity performed better on tests of processing speed, a key aspect of thinking and attention. However, no significant differences were observed between groups in overall cognitive scores, suggesting that brain changes may precede noticeable symptoms.

Link: https://www.concordia.ca/news/stories/2025/11/25/concordia-researchers-identify-key-marker-linking-coronary-artery-disease-to-cognitive-decline.html