Fight Aging!

Clearly change must occur constantly in the adult brain. However we suppose information to be encoded in physical structures of the brain, the information content of a brain evidently changes over time, as illustrated by the processes of memory and learning, and thus the structure of the brain must also change. Nonetheless, if one backtracks to the early 1990s, the consensus at the time was that new neurons were not created in the adult brain. Any change in the brain's information content was thought to be a matter of rearranging axonal connections between neurons or to involve alterations in other, smaller-scale structures such as dendritic spines. Then it was persuasively demonstrated that the creation of new neurons does in fact occur in adult mice.

In the grand scheme of progress in the life sciences, that something occurred thirty years ago makes it a relatively recent realization. Follow up and debate are still very much in progress. Over the past decade, a debate in the scientific literature occurred over whether the limited human data in fact supported the existence of adult neurogenesis in our own species. Matters appear to have settled to a consensus that human adult neurogenesis does occur. Nonetheless, it remains the case that most of the data for adult neurogenesis is (a) obtained from studies in mice, and (b) focused on the hippocampus, an important region for the function of memory.

Today's open access paper is a brief and readable review on the question of aging and neurogenesis in the hippocampus. Neurogenesis is interesting in this context because, as shown in mice, it declines with age. This is thought to contribute to loss of memory function, and there is a sizable contingent of researchers engaged in trying to boost neurogenesis as a possible basis for future therapies. As this review makes clear, however, after nearly thirty years of work on this topic there are still looming gaps in knowledge everywhere you look.

Extent and activity of adult hippocampal neurogenesis

There is strong evidence for human hippocampal neurogenesis occurring well into adulthood, albeit at a steadily decreasing rate, but we lack a cohesive scientific discourse surrounding its physiological role, particularly the relationship between neurogenic extent and activity. Research emphasis is generally on the former, relying on the assumption that the number of newborn neurons sufficiently explains any functional implications. This approach ignores the reality that individual neurons vary drastically in activity, even in otherwise identical cell populations. This review focuses on the relationship between the extent of neurogenesis and activity of the newborn neurons themselves, with a particular emphasis on how we might use this information to inform future studies.

Adult hippocampal neurogenesis is the process by which new neurons are generated in the dentate gyrus of the hippocampus in the adult brain. The generation of new neurons is a hierarchical, activity-dependent process that starts with radial glia-like precursors that quickly transition to progenitors before eventual differentiation into neuroblasts. This immature neuronal population matures and migrates a short distance from the subgranular zone of the dentate gyrus to the granular layer, where it integrates into pre-existing circuits.

Newly generated neurons progress through dynamic stages important for their normal functioning, finally resulting in behavioral modulation with their integration into hippocampal circuitry. This complex process is regulated by various factors that can increase or decrease neurogenesis, leading to alterations in both the number and function of newly generated neurons. For example, aging is a major physiological factor that contributes to the decline of adult hippocampal neurogenesis by pushing the neural stem cell pool into a quiescent stage and reducing the ability of neural stem cells to proliferate.

Even if the neural stem cells produce new neurons, aging impairs the survival and integration of these newborn neurons into existing circuits. Indeed, aging disrupts the dentate gyrus microenvironment by reducing synaptic density and compromising vascularization, ultimately creating a less supportive niche for neurogenesis. The dentate gyrus plays a critical role in pattern separation and episodic memory, and age-related reductions in hippocampal neurogenesis have been directly linked to cognitive decline; studies show that diminished neurogenesis contributes to impairments in spatial learning, memory precision, and cognitive flexibility, all hallmark features of age-related cognitive decline.

In nematode worms, SKN-1 is a known longevity-related gene, and researchers here explore its role in the lysosomal enlargement that occurs with aging. Lysosomes are necessary for the cellular maintenance processes of autophagy to function. Lysosomes carry out the last step in the recycling of damaged and excess proteins machinery and structures in the cell, which is to break down those materials into components that can be reused. It has been observed that lysosomes become larger in cells in aged tissues, but this is apparently a compensatory behavior rather than a form of dysfunction. It is an attempt to maintain lysosomal function and thus the health of the cell in the face of the damage of aging.

Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes.

Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.

Link: https://doi.org/10.1371/journal.pbio.3003540

Researchers here build an aging clock based on the expression levels of three microRNAs as a proof of principle that microRNA clocks are viable. This should not be a surprise; if the past twenty years of work on aging clocks have taught us anything, it is that any sufficiently complex body of data that changes with age can be used as the basis for a clock. Clocks are now relatively easily produced. The much harder challenge is to take any given clock and amass sufficient human data to (a) demonstrate that it is usefully measuring biological age or something closely related to biological age, and (b) understand its quirks and limitations to the point at which one can trust the use of that clock in the assessment of potential rejuvenation therapies, in order to guide and accelerate progress in the field.

The extension of human longevity has intensified the search for biomarkers that capture not only chronological age but also biological aging and functional healthspan. Among molecular candidates, microRNAs (miRNAs) have emerged as promising regulators and indicators of aging-related processes. In this pilot study, we explored whether selected circulating miRNAs could serve as potential biomarkers of biological age and lifestyle-associated aging dynamics.

Based on current literature, we focused on three miRNAs - miR-24, miR-21, and miR-155 - previously linked to inflammation, senescence, and metabolic regulation. Capillary blood samples from a heterogeneous adult cohort were analyzed using quantitative PCR. Values were integrated into a composite "miRNA-3Age" model through multivariate regression analysis to estimate biological age. Associations between lifestyle variables (diet, exercise, stress, and smoking) and miRNA-based biological age were examined.

The miRNA-3Age model predicted biological age with moderate correlation to chronological age and revealed variability consistent with individual health profiles. Participants with favorable lifestyle factors (e.g., frequent consumption of fish, whole grains, and green tea; regular exercise) tended to exhibit lower miRNA-3Age estimates, whereas stress and smoking were associated with higher predicted biological age. The miRNA-3Age model provides a preliminary step toward a scalable, lifestyle-sensitive aging metric that warrants validation in diverse populations.

Link: https://doi.org/10.3389/fnut.2025.1659730

Reprogramming involves exposing cells to expression of one or more of the Yamanaka factors, c-Myc, Oct4, Sox2, and KLF4. This slowly alters cell state in a small fraction of exposed somatic cells, and these cells transform to become induced pluripotent stem cells, essentially the same as embryonic stem cells. This recapitulates some of the processes involved in embryogenesis. More rapidly and reliably than this change of state, a cell exposed to Yamanaka factor expression also exhibits rejuvenation of nuclear DNA structure and patterns of gene expression, leading to a restoration of youthful function. This cannot fix everything in an aged cell, such as mutational DNA damage, but it has a sizable enough effect on cells, and in mice, that partial reprogramming as a basis for rejuvenation therapies has become a popular area of development.

Can reprogramming of cell state be efficiently separated from reprogramming of nuclear structure? If we want reliable rejuvenation therapies, it seems likely that progress must be made on this front. Researchers are investigating the regulation of reprogramming downstream of the Yamanaka factors, but this is a painfully slow process. Still, every incremental advance in tracing the interactions of proteins might be the one that disentangles rejuvenation from state change, unleashing a much more efficient approach than offered by the present options capable of triggering reprogramming.

Most of the longevity industry now consists of reprogramming initiatives if measuring by investment size. Related to that, we might argue that most of the work carried out on reprogramming as a basis for rejuvenation therapies is in fact conducted outside academia at this point. In the long run this work will become just as visible as academic efforts, but for now it is dark matter. Thus to find ongoing indications of progress on picking apart the systems of regulation that produce rejuvenation in response to Yamanaka factor expression, one must keep up with the publication of academic papers - such as today's example.

Conserved Master Regulators Orchestrate Cellular Reprogramming-Induced Rejuvenation

Partial somatic cell reprogramming has been proposed as a rejuvenation strategy, yet the regulatory architecture orchestrating age reversal remains unclear. What molecular systems allow partial relaxation of identity to restore youthful regulatory function while avoiding dedifferentiation? Previous work has identified chromatin regulators as central to this process. DNA methyltransferases Tet1 and Tet2 may be required for reprogramming-induced rejuvenation, and reprogramming-induced rejuvenated cells exhibit restored nucleosome regularity and recalibrated histone modification balance. However, identifying genes that change during rejuvenation does not reveal which factors actively drive the process versus those that respond as downstream consequences. Distinguishing upstream regulators from effector genes requires network-level analysis that can infer causal regulatory relationships.

Here, we performed gene regulatory network reconstruction across several independent systems to identify master regulators that coordinate reprogramming-induced rejuvenation (RIR). In mouse mesenchymal stem cells, mouse adipocytes, and human fibroblasts undergoing partial reprogramming, we identified genes showing opposite expression dynamics during aging and reprogramming. This approach revealed regulators governing rejuvenation rather than developmental programs. Despite divergent overall network architectures, nine transcription factors converged as master regulators across all three systems, including Ezh2, Parp1, and Brca1. These regulators undergo coordinated reorganization during reprogramming, characterized by broader target engagement and enhanced regulatory coherence.

We further demonstrated that direct perturbation of Ezh2 bidirectionally modulates transcriptomic age. Notably, overexpression of a catalytically inactive Ezh2 mutant achieved rejuvenation, suggesting mechanisms distinct from canonical H3K27me3-mediated regulation are involved in RIR. Our findings reveal that cellular rejuvenation is orchestrated by conserved master regulators whose network coordination can be targeted independently of the reprogramming process.

Senescent cells grow in number with age, lingering to cause harm via inflammatory secretions. This is a problem in every tissue. Here researchers focus on the endothelial lining of blood vessels, and demonstrate that a strategy to reduce the pace at which endothelial cells enter a senescent state can slow the development of vascular stiffness and atherosclerosis in a mouse model of these cardiovascular issues. There are many different ways in which one might go about making cells more resistant to stress-induced senescence, and here the approach is to improve cell defenses against oxidative molecules.

Terazosin (TZ), a well-known antagonist of the α1-adrenergic receptor (α1-AR), has demonstrated protective effects on vascular endothelial cells (ECs) and reduced vascular stiffness in clinical studies. Endothelial dysfunction and oxidative stress are central drivers of cardiometabolic diseases such as diabetes, where sustained reactive oxygen species burden accelerates EC senescence and barrier failure. These findings suggest its potential role in combating vascular aging and atherosclerosis; however, the underlying mechanisms remain partially understood.

In this study, we investigated whether TZ can prevent atherosclerosis in ApoE-/- mice fed a high-cholesterol diet and aimed to elucidate the mechanisms involved. Our results showed that TZ significantly reduced plaque size, EC senescence, vascular permeability, and reactive oxygen species (ROS) levels, effectively inhibiting atherosclerosis independently of α1-AR signaling.

In cultured primary human umbilical vein ECs (HUVECs), TZ inhibited EC senescence via the Pgk1/Hsp90 pathway. It enhanced the interaction between Hsp90 and the antioxidant enzyme peroxiredoxin 1 (Prdx1), leading to lower reactive oxygen species levels - a key driver of cellular senescence. These findings were confirmed in atherosclerotic ApoE-/- mice.

Furthermore, senescent ECs exhibited increased levels of vascular endothelial growth factor A (VEGFA) and decreased levels of angiostatin, contributing to higher vascular permeability and exacerbating atherosclerosis. TZ effectively reversed these changes.

Overall, our study demonstrates that TZ primarily alleviates EC senescence and atherosclerosis through the Pgk1/Hsp90/Prdx1 pathway, highlighting Pgk1 activation as a strategy that may also mitigate endothelial dysfunction and oxidative stress in broader cardiometabolic contexts (e.g., diabetes), suggesting that TZ is a promising senomorphic agent for treating vascular aging and that Pgk1-targeted interventions could have implications beyond atherosclerosis.

Link: https://doi.org/10.1186/s12933-025-02976-2

The aging of the extracellular matrix is not as well studied as is the case for cell biochemistry. There are likely many important changes that take place in the extracellular matrix over a lifetime that meaningfully affect cell function in aged tissues, but have yet to be discovered and understood. One example is outlined here, a matrix protein that declines with age but seems necessary to maintain the normal function of muscle stem cells. Declining muscle stem cell function is one of the important contributions to the characteristic loss of muscle mass and strength that occurs with age.

Skeletal muscle regeneration occurs through the finely timed activation of resident muscle stem cells (MuSC). Following injury, MuSC exit quiescence, undergo myogenic commitment, and regenerate the muscle. This process is coordinated by tissue microenvironment cues, however the underlying mechanisms regulating MuSC function are still poorly understood.

Here, we demonstrate that the extracellular matrix protein Tenascin-C (TnC) promotes MuSC self-renewal and function. Mice lacking TnC exhibit reduced number of MuSC, and defects in MuSC self-renewal, myogenic commitment, and repair. We show that fibro-adipogenic progenitors are the primary cellular source of TnC during regeneration, and that MuSC respond through the surface receptor Annexin A2. We further demonstrate that TnC declines during aging, leading to impaired MuSC function. Aged MuSC exposed to soluble TnC show a rescued ability to both migrate and self-renew in vitro.

Overall, our results highlight the pivotal role of TnC during muscle repair in healthy and aging muscle.

Link: https://doi.org/10.1038/s42003-025-09189-z

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