Fight Aging!

Astrocytes make up a sizable fraction of the supporting cells of the brain, and undertake a wide range of tasks in order to maintain function. They supply metabolites needed for neural function, maintain other aspects of brain chemistry, provide structural support, and are a component of the blood-brain barrier, among many other activities. It has been noted that astrocytes tend towards greater inflammatory behavior in the aged brain, and like all cell populations a greater number of astrocytes become senescent in later life. Behaviors change in many other ways in response to the aged environment, some adaptive and some maladaptive. It remains an interesting open question as to what degree aging can be treated by simply forcing cells to behave as though they were young; answers should hopefully emerge from continued work on partial epigenetic reprogramming of living tissue, the imposition of a youthful epigenetic pattern of gene expression on aged cells.

In today's open access paper, researchers discuss two less drastic approaches to favorably changing the behavior of astrocytes in the aging brain. In one case, a small molecule is used to induce a lesser degree of inflammatory overactivation in astrocytes, leading to improved function in brain tissue in an animal study. In the other case, a gene therapy is used to enable astrocytes to manufacture more of a secreted extracellular matrix protein that is important to the creation and function of synaptic connections between neurons; levels of this protein decline with age and in neurodegenerative conditions. Again, this intervention improves function in aged brain tissue, as assessed in an animal study.

Astrocytes in Brain Aging and Neurodegeneration: Cellular Mechanisms and Interventional Strategies

We discuss how astrocyte aging contributes to cognitive decline and highlight emerging evidence on how targeting astrocytes, both genetically and pharmacologically, may rescue cognitive decline associated with aging and neurodegenerative diseases. Astrocytes produce several molecules that control synapse formation and function, which are decreased in the aging brain and in Alzheimer's disease models. In this context, recent studies indicate that astrocytes undergo significant molecular and functional remodeling during aging. Notably, astrocyte senescence has been associated with loss of lamin-B1, nuclear alterations, impaired synaptogenic and neuritogenic capacity, altered glutamate metabolism, and mitochondrial dysfunction, all of which may contribute to reduced neuronal support and circuit integrity. In parallel, recent advances have shown that astrocyte responses during aging also include diverse reactive states that vary according to brain region, microenvironment, and disease stage. Importantly, senescence-associated and reactive features are not mutually exclusive and may coexist or interact, further contributing to synaptic dysfunction and increased vulnerability to neurodegeneration.

Recent studies have emphasized the value of astrocyte phenotype and function-oriented strategies, such as restoring astrocytic metabolic and mitochondrial competence, regulating chronic inflammation, and re-establishing proper astrocyte-synapse interactions, rather than broadly suppressing astrocyte activation/reactivity. In parallel, advances in cell-type-targeted delivery and pharmacological modulation have strengthened the translational potential of astrocyte-centered interventions. In this context, we recently demonstrated that by modulating astrocyte phenotypes, either pharmacologically or through gene therapy, we can reverse cognitive decline associated with aging and in a preclinical model of Alzheimer's disease (AD).

Histone deacetylases (HDAC) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. HDAC inhibitors (iHDAC) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. To address the role of iHADC in AD, we have used the beta-amyloid (Aβ) oligomers (AβOs) toxicity model. AβOs are soluble oligomers of the amyloid-peptide that accumulate in AD brains and are considered an important toxin that lead to synaptic loss in AD. We previously found that AβOs target murine and human astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro. Recently, we have shown that the iHDAC LASSBio-1911 mitigates the effects of AβOs on synapse loss and cognitive decline in mice. This was mainly due to its ability to modulate the astrocyte phenotype.

Astrocytes from distinct brain regions contribute to synapse formation through the secretion of various synaptogenic molecules. Among these, the extracellular matrix protein, Hevin, secreted by astrocytes, has emerged as a key player. Hevin promotes the formation of excitatory synapses by bridging pre- and postsynaptic proteins. Recent evaluation of data set from AD animal models and patients demonstrated that Hevin is downregulated in both animals and patients' brain samples. We employed adenovirus-mediated overexpression of Hevin in hippocampal astrocytes of aged and APP/PS1 transgenic mice. The use of a GFAP (glial fibrillary acidic protein) gene promoter ensured astrocyte-specific expression of the transgene. Behavioral analyses revealed that Hevin overexpression not only ameliorated cognitive, synaptic, and behavioral deficits in APP/PS1 mice, but also improved performance in aged wild-type animals.

Teeth do age, becoming more brittle and prone to fracture as the cell populations of the dental pulp become less capable of conducting the necessary maintenance processes. This has only relatively recently become a topic of interest in the dental community, and so relatively little is understood in detail of the mechanisms of tooth aging. Researchers here identify loss of NFATC1 in dental pulp cells as a driver of age-related dysfunction in the maintenance of tooth structural properties, and show that this mechanism is in large part a downstream consequence of the presence of senescent cells in that tissue. Clearance of senescent cells via senolytic therapies reduces the impact of aging on teeth.

Although tooth aging is causally linked to age-associated dental degeneration and regenerative disability, its pathogenesis remains largely unelucidated, despite extensive documentation of its phenotypic alterations. Over time, alongside senescence of the mineralized parenchyma, dental pulp undergoes irreversible changes impairing its renewal capacity. This leads to brittle teeth prone to fracture and susceptible to damage as pulpal degeneration progresses and dentinogenesis fails. These age-related issues remain unresolved due to the unknown drivers. Recognition of this problem in dentistry is relatively recent, dating back only two decades.

There is now growing consensus on the importance of developing methods to counteract tooth aging, particularly pulp aging, as a crucial strategy for tooth conservation. Combining in vivo genetic tools with tissue clearing, advanced 3D imaging, and serial histological and molecular analyses, we identified and validated loss of NFATC1 activity in dental pulp mesenchymal stromal cells (MSCs) as a driver of tooth aging. Induced loss of NFATC1 activity accelerated aging, causing premature tooth aging in young adult mice. Mechanistically, we confirmed it as the cause of age-associated pulpal degeneration and regenerative disability.

Crucially, we demonstrated that senolytics therapeutically ameliorate pulpal degeneration and restore regenerative capacity to preserve vital teeth by eliminating senescent dental pulp MSCs. Similar to reports showing that senescent skeletal stem cells create an inflammatory, degenerative environment impairing skeletal repair in aged bone, our findings demonstrate that driver-induced dental pulp MSC senescence underlies poor regenerative activity in aging teeth.

Link: https://doi.org/10.1016/j.stemcr.2026.102925

Researchers here note a mechanism that encourages the innate immune cells known as microglia to better clear amyloid-β in the aging brain. The protein PM20D1 acts in the formation of N-acylamides, and generation of the product N-oleoyl-leucine encourages microglia to more efficiently remove amyloid-β aggregates. In animal models of Alzheimer's disease based on an excessive creation of amyloid-β aggregates this improves matters. As is usually the case, it remains to be seen as to whether this will help in the human condition; so far, clearance of amyloid-β via immunotherapies has not performed well, suggesting that it doesn't play as significant a role in the condition as hoped.

There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD.

OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.

Link: https://doi.org/10.1038/s41419-026-08791-1

The Apolipoprotein E (APOE) gene exhibits a small number of common sequence variants across the human population, of which the desirable APOE2 variant is associated with modestly greater longevity, and the undesirable APOE4 variant is associated with a sizable increase in the risk of Alzheimer's disease. APOE is one of only a few genes to exhibit a reliable correlation with human life expectancy that replicates in epidemiological data from multiple study populations. APOE is involved in the transport of lipids, particularly cholesterol, as a component part of different forms of transport particle that carry these molecules around the body, such as low density lipoprotein (LDL) particles. In this context it is important to note that the lipid manufacture and transport systems of the brain are somewhat distinct from those of the body, and APOE is involved separately on both sides of the blood-brain barrier.

Investigations into how exactly APOE variants affect Alzheimer's disease risk and progression have focused on lipid metabolism. It seems likely that APOE may have roles inside the cell as well as outside the cell, as few proteins have only a single function. Those roles are not well understood, however. A body of evidence links APOE to inflammatory behavior in immune cells, such as microglia in the brain, but it is not settled as to how exactly this emerges from or interacts with its role in lipid metabolism, or whether it is entirely distinct. To further complicate matters, today's open access paper provides cell culture data to show that APOE2 appears to reduce DNA damage and cellular senescence in neurons. The authors do not offer any mechanistic interpretation of this data, it is an observation only. It is definitely unclear as to how this outcome emerges given what is known of APOE.

Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons

APOE is a plasma glycoprotein critical for lipid transport and metabolism. In the central nervous system (CNS), it serves as the principal cholesterol carrier between astrocytes and neurons, supporting energy supply, synaptic remodeling, and neuronal repair. While astrocytes are the main producers of APOE in the CNS, neurons also express APOE under conditions of stress and aging. Given this background, we sought to evaluate the contribution of the APOE genotype to neuronal aging and vulnerability. Using bulk and single-cell RNA-sequencing (RNA-seq) of induced pluripotent stem cell derived GABAergic neurons, we identified genotype-dependent differences in gene expression and DNA damage pathways. Notably, APOE2 GABAergic neurons showed upregulated DNA repair signaling, and APOE4 neurons exhibited increased synaptic gene expression, DNA damage, and altered cell motility. In a separate model of Ngn2-induced glutamatergic neurons, APOE2 neurons resisted genotoxic stress and were less prone to acquiring a senescent-like phenotype than isogenic APOE3 and APOE4 neurons.

Consistent with these transcriptional and functional differences, APOE2 neurons displayed smaller nucleoli and preserved nuclear lamina integrity - features linked to longevity and genomic stability - while APOE4 neurons showed enlarged nucleoli and increased senescence-associated markers. Importantly, these anti-aging molecular features were recapitulated in the hippocampus of aged APOE2 knock-in mice, supporting the in vivo relevance of our findings. Together, these results suggest that APOE genotype shapes neuronal aging through differential regulation of DNA damage responses and nuclear homeostasis.

Aging and neurodegenerative diseases are marked by genomic instability in neurons, including dysregulation of repetitive elements expression and activity. In senescent human mesenchymal progenitor cells, the accumulation of APOE drives increased expression of repetitive elements. Additionally, ribosomal RNA production increases with age, leading to enhanced ribosome biogenesis, increased protein translation, and intracellular energy depletion. In our study, analysis of repetitive elements in GABAergic neurons revealed increased ribosomal RNA expression in APOE4 genotype under non-stress conditions, suggesting that APOE alleles differentially influence nucleolar activity.

Collectively, our findings support a model in which the APOE genotype influences neuronal aging trajectories through regulation of genomic stability.

A sizable proportion of past gains in human life expectancy arose from public health strategies to better control the burden of infectious disease. Exposure to pathogens doesn't just increase the risk of an earlier death due to fatal infection, but also places a burden of damage on the survivors that increases late life mortality. Researchers here discuss what the future of public health strategies might look like in the context of the present great shift from medicine that does not even consider the causes of aging to a medical community that will increasingly proficiently and deliberately target the causes of aging to slow and reverse age-related degeneration.

Over the past century, the most transformative gains in human health and longevity did not arise from high-technology medicine, but from the systematic application of public health. Clean water, sanitation, vaccination, safer housing, improved nutrition, poverty reduction, occupational safety, and access to education reshaped population health by preventing disease before it emerged. Yet the success of this model has brought us to a fundamentally different challenge. As populations age, the dominant burden of disease is no longer defined by malnutrition, accidents and acute infections, but by chronic conditions, multimorbidity, and progressive loss of function.

The foundational public health interventions that drove 20th-century progress remain essential, but they are no longer sufficient to address the systemic exposures that shape aging trajectories in the 21st century. Health is now influenced by a complex interplay of factors that operate continuously across the life course and directly interact with biological aging processes. In this context, the traditional distinction between prevention and treatment becomes increasingly inadequate. Modern health risks accumulate gradually and manifest across multiple systems, often long before clinical disease is diagnosed. Addressing them therefore requires a more integrated framework that recognizes health as a dynamic trajectory shaped by lifelong exposures, biological responses, and progressive functional decline across the life course.

Such a framework cannot rely exclusively on either conventional public health measures or disease-centered clinical medicine. Instead, healthy longevity will likely depend on the coordinated integration of multiple intervention layers operating at different stages of the disease trajectory. Public health strategies reduce baseline exposure and population vulnerability, clinical medicine manages established pathology, and emerging longevity-directed interventions may help delay or modify the biological processes that connect cumulative damage to disease manifestation and functional decline. Rather than representing separate or competing domains, these approaches should be viewed as complementary components of a unified strategy to improve population health across aging societies.

Link: https://doi.org/10.18632/aging.206381

Machine learning techniques can be used to generate aging clocks from any sufficiently complex set of biological data obtained from individuals of varying chronological ages. The research community is generating new clocks at a fair pace, most of which are doomed to vanish into obscurity, while trying to better understand best use cases and limitations of the small number of very well-studied clocks. As researchers here point out, when omics data is used as the foundation for a clock, it is typically only one type of omics data, most commonly epigenomic data. It is suggested that new clocks should be developed that employ multiple omics sources, not just one. While I'm sympathetic to this view, it seems to me that the priority remains to make better use of the well-studied clocks that exist. It remains the case that no-one has solved the issues that prevent the use of clocks as a low-cost, fast way to assess the effectiveness of novel approaches to rejuvenation.

Biological clocks can be broadly categorized by the outcome used to train them. Early clocks, including Horvath's clock and Hannum's clock, were trained to predict chronological age from DNA methylation (DNAm) patterns and demonstrated the ability to track biological aging across tissues and identify accelerated aging in conditions. Other clocks have since been developed, providing enhanced predictive accuracy for age-associated diseases, life expectancy, and personal aging patterns. However, clocks trained on chronological age have generally shown limited ability to predict age-related disease incidence or mortality in the general population. To address this limitation, a newer generation of clocks has been trained directly on hard outcomes such as all-cause mortality and disease incidence, DNAm-based approaches, metabolomics, and routine clinical biomarkers, consistently demonstrating superior performance in predicting health trajectories.

Organ-specific aging clocks differ conceptually from traditional biomarker-based approaches. While individual biomarkers reflect isolated molecular changes associated with aging, organ clocks integrate coordinated molecular patterns within a specific tissue to estimate its biological age relative to chronological age. This distinction is critical as organs do not age uniformly and may exhibit asynchronous aging trajectories that are not captured by systemic or single-biomarker models. By quantifying tissue-level functional decline rather than individual molecular alterations, organ clocks provide a framework for linking molecular aging to organ-specific disease risk and clinical outcomes.

However, single-omic approaches provide partial insights due to the multidimensional nature of biological aging which encompasses genetic, epigenetic, transcriptional, proteomic, and metabolic dimensions that interact across tissues and change dynamically over time. Therefore, multi-omics approaches have gained attention as integrative methods that capture interactions to provide a more holistic assessment of biological aging. Despite these advances, only a few studies have integrated multi-omics clocks. Even in the case of multi-omics, technical variability across different omics platforms and limited availability of longitudinal datasets limit the ability to track changes in biological aging. This review aims to evaluate current biological clock approaches, explore strategies for multi-omics integration, and suggest a respective framework.

Link: https://doi.org/10.1111/acel.70518

The aging of the adaptive immune system, made up of B cells and T cells, is a complex process. Broadly, the pace at which new adaptive immune cells are created declines to a tiny fraction of youthful levels in most people by age 50, and this lack of replacements allows the adaptive immune system to become ever more populated by exhausted, senescent, and malfunctioning cells. This decline in the supply of new adaptive immune cells is in part a problem of hematopoietic cells in the bone marrow, responsible for creating B cells and thymocytes that migrate to the thymus to mature into T cells. The decline is also in part a problem of the thymus, which atrophies with age, and of the lymphoid organs such as lymph nodes where B cells mature, which suffer their own age-related declines in structure and function.

Beyond the problems that arise from impaired replenishment of the adaptive immune system populations, it is also the case that immune cells, like all other cells, exist in the aged tissue environment, and will react in some combination of adaptive and maladaptive ways to the presence of damage, altered signaling, increased inflammation, and so forth. Today's open access paper presents data on what looks to be a consequence of this second class of issues, an altered secretion of signals by a subpopulation of T cells throughout the aged body that contributes to loss of cognitive function via disruption of normal operations in the hippocampus.

Relatedly, researchers are concerned about the infiltration of adaptive immune cells into the brain with advancing age. The brain is immunologically distinct from the body; it has its own classes of immune cell, and the blood-brain barrier prevents the passage of immune cells between body and brain. There are a few limited routes by which adaptive immune cells such as T cells find their way into the brain in very small numbers, but their presence in larger numbers is thought to be problematic. This occurs as the blood-brain barrier becomes dysfunctional and leaky with age, for example. Thus today's paper exists in the context in which researchers tend to think of T cells as harmful to the brain via infiltration into the central nervous system in later life, but in fact the problem exists even without that infiltration. The signals are the issue, and they readily pass into the brain once generated by immune cells outside the brain.

Aged circulating CD8+ T cells and their secreted factors drive cognitive decline

Transcriptional analyses of young and aged peripheral immune cells highlight changes in CD8+ T cells as a prominent hallmark of immune aging, with the emergence of an age-associated population characterized by expression of the serine protease granzyme K (GZMK). In the brain, infiltrating CD8+ T cells in aged mice decrease adult neurogenesis in the subventricular zone of the lateral ventricles, promote axon degeneration in the optic nerve, and induce neuroinflammation in the white matter. By contrast, only modest CD8+ T cell infiltration is reported in the aged hippocampus in the absence of neurodegenerative disease pathology in mouse models, while analysis of postmortem human hippocampi finds no age-related changes in infiltration.

Notwithstanding, despite the vast majority of CD8+ T cells residing in the periphery, the role of aged non-infiltrating circulating CD8+ T cells or their secreted factors in hippocampal-dependent cognitive decline is yet to be fully defined. We therefore sought to investigate the effect of peripheral aged CD8+ T cells on the hippocampus and ascertain the rejuvenating potential of selectively targeting this immune cell population in circulation at old age.

Using heterochronic parabiosis, we demonstrated that aged circulating CD8+ T cells were refractory to a young systemic environment, maintaining properties intrinsic to their cellular age. Systemic exposure of young mice to aged circulating CD8+ T cells elicited hippocampal aging transcriptional signatures and cognitive decline, which were attenuated by blocking T cell activation. We further showed that targeting aged circulating CD8+ T cells restored synaptic-related hippocampal signatures and ameliorated age-related cognitive impairments. Mechanistically, we demonstrated that GZMK, secreted by age-associated CD8+ T cells, impaired cognitive function, and inhibition of systemic GZMK in aged mice restored cognition. These findings identify activated aged circulating CD8+ T cells and their secreted factors as drivers of hippocampal-dependent cognitive decline in aging.

Increasing attention in the research community is being given to age-related dysfunction of microglia in the brain as a contribution to loss of cognitive function and onset and progression of neurodegenerative conditions. Microglia are innate immune cells analogous to macrophages elsewhere in the body, responsible not just for defense against pathogens, but also maintenance of neural tissue and supporting the function of neural networks. With age a growing population of microglia become senescent or otherwise inflammatory and disruptive to normal function of brain tissue. Given that established methods exist to either selectively destroy senescent microglia or completely clear the microglial population to allow it to reconsitute itself over a period of weeks, it seems that there should be more in the way of efforts to bring these approaches to the clinic than are actually taking place.

Microglial senescence has emerged as a potentially important aging-related mechanism in Alzheimer's disease (AD), shaped in part by epigenetic reprogramming and closely coupled to immunometabolic dysfunction. While microglia initially mount adaptive responses to amyloid-beta (Aβ), tau, and tissue stress, persistent exposure to chronic neurodegenerative cues may drive subsets of microglia toward senescence-like states characterized by altered chromatin regulation, transcriptional remodeling, stable cell-cycle arrest, and a sustained senescence-associated secretory phenotype (SASP). These changes are accompanied by impaired phagocytosis, lysosomal and autophagic dysfunction, mitochondrial stress, and disrupted lipid handling, collectively weakening homeostatic surveillance and promoting a neurotoxic microenvironment. In turn, senescence-associated microglial dysfunction may contribute to amyloid and tau pathology, synaptic injury, neurovascular unit impairment, and chronic neuroinflammation across the AD continuum.

In this review, we synthesize current evidence on the phenotypic and molecular features of senescent microglia, with particular emphasis on epigenetic and transcriptional reprogramming as an organizing framework linking aging, immune dysregulation, and metabolic vulnerability. We further discuss how senescent microglia relate to other disease-associated microglial states, and we highlight unresolved questions regarding causality, biomarker specificity, and the distinction between chronic activation and true senescence in human AD. Finally, we evaluate emerging therapeutic approaches - including senolytic strategies, microglial depletion-repopulation paradigms, and metabolic or epigenetic interventions - and discuss their opportunities, limitations, and translational challenges.

Link: https://doi.org/10.1016/j.exger.2026.113177

Past studies have indicated that the recommended 150 minutes per week of moderate to vigorous physical activity is lower than the optimal level. Here find another such study, in this case recommending something more like 600 minutes per week. Humans evolved in an environment of considerably more physical activity than is undertaken by people in wealthier regions of the world. This is an age of comfort and machineries of transportation, and the consequence difference in rates of age-related cardiovascular disease between relatively wealthy populations versus hunter-gatherers is sizable.

Moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF) are established, independent predictors of cardiovascular health. Current guidelines universally recommend ≥150 min/week of MVPA, yet whether this generic threshold confers equivalent cardiovascular protection across different fitness levels remains unclear.

In a large accelerometer-based cohort with estimated CRF, meeting the current 150 min/week guideline was associated with a consistent but modest reduction in composite cardiovascular disease risk of approximately 8%-9% across low-fitness to high-fitness stratifications. Achieving substantial cardiovascular protection (of more than a 30% risk reduction) required MVPA volumes 3-4 times higher than current minimum recommendations (~560-610 min/week), with low-fitness individuals needing slightly more MVPA than high-fitness peers to attain comparable relative benefits.

Thus current MVPA guidelines provide a universal but modest safety margin, whereas optimal cardiovascular protection may require substantially higher activity volumes.

Link: https://doi.org/10.1136/bjsports-2025-111351

Atherosclerosis is the development of fatty plaques that narrow blood vessels and eventually rupture to cause a stroke or heart attack, the most common cause of human mortality. Atherosclerotic plaque is a consequence of a runaway process of failure in the behavior of cells responsible for clearing excess cholesterol from blood vessel walls. Cholesterol is needed by every cell in the body, but largely only manufactured in the liver. A complex system of transport particles moves cholesterol to and from the liver via the bloodstream. Macrophages in the blood vessel walls clean up excess cholesterol and move it back into the bloodstream, but as aging progresses these macrophages become ever more vulnerable to being overwhelmed by localized cholesterol excess. Eventually, a plaque forms as an area of inflammation and toxic cholesterol and cholesterol derivatives, drawing in macrophages to be killed, adding their mass to the plaque.

As you may know, I founded Repair Biotechnologies with Bill Cherman back in 2018. The company has since been developing a means to regress atherosclerotic plaque. The biggest challenge for present cardiovascular medicine is that the primary strategy of lowering circulating LDL cholesterol via lifestyle, statins, PCSK9 inhibition, and other more recently developed methods only slows plaque growth and very slowly over years somewhat stabilizes the most unstable plaques. It does not produce sizable or reliable regression of plaque, and this is why atherosclerosis remains the single largest cause of human mortality: 27% of all deaths are via heart attack and stroke, and other varieties of cardiovascular disease caused by obstructive plaque may contribute meaningfully to the demise of another 10-15% of our species. Here I'll point out a recent interview and update on our progress and explanation of our lead drug and how it works.

Developing a Drug To Reverse Heart Disease

So let's get straight into the lead candidate. REP-0003, can you give us the quick, layman's version on how that works?

Firstly, it's actually REP-0004 now that is the lead candidate. We updated the sequence, but these two drugs are both very similar. They are lipid nanoparticles that encapsulate messenger RNA (mRNA) and then deliver it directly to the liver and nowhere else in the body. It goes to the liver via the normal mechanisms of lipid nanoparticle delivery. The particles are sized to pass through the blood vessel walls for glands like the liver, and the liver is the usual destination for things that are injected intravenously anyway.

Secondly, there's a ligand on the surface that only interacts with receptors present on hepatocytes in the liver, so that then delivers the mRNA into the cells through the receptor-mediated endocytosis; the mRNA escapes the endosome into the cell, where it is processed into a fusion protein. That fusion protein is just a selection of human proteins that are not normally expressed together in any cell. When acting together they very selectively break down only excess intracellular free cholesterol. By free cholesterol, I mean unmodified cholesterol.

This produces a variety of benefits to your liver, because excess free cholesterol serves no useful purpose and is toxic if you have too much of it inside a cell. Normally, a cell will attempt to take that free cholesterol and keep just a little bit of it, and the rest of it gets esterified into lipid droplets or put into the cell membrane or handed off in some way. But, if you get fat or you get old, in both cases, this process stops working as well, and you have too much free cholesterol inside your cells. I should emphasize this really isn't just a problem of obesity. You can have thin people with excessive intracellular free cholesterol in their liver and elsewhere in their bodies.

Now, when you reduce free cholesterol in the liver, the organ kicks it back into working properly. It also makes the liver feel like it's in a cholesterol deficit, even if it isn't. So, it will try to pull as much cholesterol back from the rest of the body as it can. Various mechanisms of homeostasis will dial up reverse cholesterol transport, and drag back free cholesterol from the rest of the body to the liver, where it then gets intercepted by our fusion protein and broken down. This feedback loop operates for the few days that the protein is present in the body as a result of an mRNA therapy, and the outcome is a draining of excess free cholesterol everywhere, not just the liver. That reduces inflammation. It improves tissue function throughout the body, outside the brain at least, as the brain has its own fairly distinct cholesterol metabolism.

The two outcomes of greatest interest at the moment are, firstly, a dramatic regression of atherosclerotic plaque very rapidly, and secondly, a reversal of liver disease, such as metabolic dysfunction-associated steatohepatitis. You also get a reduction in fibrosis. It happens very rapidly and dramatically, and that is how the drug works.

How receptive has the FDA been to this approach?

They like it. The FDA looked at our materials for the pre-IND and said, "Yes, we agree. Go do this." No, they didn't note any meaningful objections, just the usual small feedback. They granted us an orphan drug designation for treatment of the accelerated atherosclerosis that characterizes the rare disease of homozygous familial hypercholesterolemia, and they don't hand that out like candy. The FDA has to really be interested in what you're doing for that to happen. We were granted orphan drug designation mid last year, and right now we're applying to the Rare Disease Evidence Principles (RDEP) program, which is a new next-level addition to the orphan drug designation. This was announced late last year, and right now nobody really knows, including the FDA, how this program will work out in detail. In principle, it should speed the path to approval for these rare disease therapies where it's somewhat more difficult to organize trials than for a more common condition. The FDA is going to rely more on preclinical evidence and post-approval assessment of the drug than on trials. We'll see how it develops.

This interview was conducted a few months ago at this point, and Repair Biotechnologies has since been granted eligibility for the Rare Disease Evidence Principles program.

It remains an open question as to whether anything discovered about the roots of individual variation in life expectancy within a species will give rise to usefully effective interventions to treat aging. Some researchers hold up the passage of late life aging in centenarians as a goal to aim for - but centenarians, while having evaded death for longer than most, are nonetheless greatly impacted by degenerative aging and exhibit significant dysfunction and mortality rates. We must aim higher, to create therapies that produce results that do not happen naturally in old people, such as comprehensive clearance of senescent cells in aged tissues, replacement of damaged mitochondria with functional mitochondria, and so forth. Actual repair of dysfunction, not just slowing it down a little.

Ageing is an inevitable, yet highly heterogeneous process shaped by genetic, epigenetic, and environmental influences. While most individuals experience progressive functional decline, a minority exhibits accelerated degeneration due to rare pathogenic mutations, whereas others achieve exceptional healthy longevity. This continuum - from progeroid syndromes to centenarians - provides a unique framework to examine how deleterious and protective genetic variants differentially modulate conserved biological pathways. Genetic models of accelerated ageing reveal mechanisms driving premature functional deterioration, whereas studies of exceptionally long-lived individuals highlight variants associated with resilience, stress adaptation, and preserved homeostasis. Together, these extremes define a genetic dichotomy that informs, but does not deterministically predict, ageing trajectories.

This review critically highlights current evidence on genetic factors and molecular mechanisms that regulate human ageing across this spectrum. Beyond established hallmarks such as cellular senescence and chronic inflammation, we discuss emerging pathways implicated in successful ageing, including hypoxic adaptation, transcriptional and chromatin regulation, autophagy, and metabolic reprogramming. We further evaluate epigenetic clocks as quantitative tools for assessing biological ageing, emphasising their strengths, limitations, and context dependence. Throughout, we distinguish between genetic associations, mechanistic findings, and preclinical evidence, explicitly addressing gaps, biases, and translational uncertainty.

Link: https://doi.org/10.1016/j.arr.2026.103176

Epidemiological evidence is strong for particulate air pollution to contribute to dementia risk. The primary underlying mechanism is thought to be increased systemic chronic inflammation via the interaction of pollutants with lung and airway tissue. Dementia is an age-related condition, however, and thus regardless of efforts to reduce air pollution, the incidence of dementia is increasing as the population undergoes demographic aging, where the proportion of old people grows over time. Demographic aging changes nothing of the moral and ethical arguments centered around prevention of suffering and death for developing means to effectively treat aging as a medical condition, but it does make the economic motivation more pressing. Suffering age-related disease and loss of function is expensive, both in terms of direct costs and opportunity costs. Sadly, the powers that be seem much more motivated by economic concerns rather than by ethical and moral concerns.

Air pollution was recently recognised as one of the 12 major modifiable risk factors for dementia. Although China's clean air policies have substantially reduced fine particulate matter (PM2.5) concentrations since 2013, the implications for dementia-associated mortality remain unclear in the context of an ageing population. In this health impact assessment study, we integrated exposure data, population data, exposure-response association data, and mortality information from multiple sources, to estimate PM2.5-attributable dementia deaths in China from 2000 to 2024.

From 2000 to 2013, PM2·5-attributable dementia deaths increased from 55,668 to 106,571. From 2013 to 2024, despite substantial declines in population-weighted PM2.5 concentration, PM2.5-attributable dementia deaths dramatically increased from 106,571 to 171,420, with population ageing as the dominant driver of increasing dementia deaths, contributing approximately 67,000 PM2.5-attributable dementia deaths, with reductions in PM2.5 exposure avoiding approximately 11,000 deaths during this period.

Link: https://doi.org/10.1016/j.lanhl.2026.100841

One of the defining features of the field of aging research is the lack of consensus at the detail level regarding what exactly aging is, why it happens, how it happens, how best to measure it, and how best to treat aging as a medical condition. Thus a fair amount of the scientific debate in the field is either implicitly or explicitly arguing over the definition of the field in some way, not just reporting data or proposing programs. The past three decades have been characterized by the development of overarching taxonomies of the manifestations and mechanisms of aging that attempt to provide answers to pressing questions for scientists such as "what should we study in order to improve our understanding of aging" and "how should we proceed towards the development of therapies for aging".

Initially the Strategies for Engineered Negligible Senescence (SENS) emerged from scientific outsiders as both a proposed description of root causes of aging and a call to action to do something about these causes from a humanitarian perspective. Later, the Hallmarks of Aging and Pillars of Aging emerged from scientific insiders, descriptions of manifestations of aging with no attached ethical imperative, the Hallmarks in particular coming to dominate discussions of the taxonomy of mechanisms of aging. The Hallmarks, for better or worse, are now treated much like a checklist for planning out future research aimed at understanding or treating aging. How these shifts within a field occur, how a field of scientific endeavor describes itself, is of course a well studied topic in and of itself. Thus one can find commentary such as today's open access paper on the transformation of the aging research field in recent decades.

The Hallmarks of Aging: Paradigms and Scientific Progress

Aging matters. Many lives are at stake. In this work, we have examined in detail what is probably the most influential conceptual framework in contemporary geroscience, analyzing the Hallmarks through philosophical tools that had also already been partially invoked in the literature of the field itself.

In Kuhnian terms, the dominant model in contemporary geroscience understands aging as the accumulation of molecular and cellular damage, and the Hallmarks represent its most characteristic exemplar: the canonical structure through which normal science operates, defining what counts as valid evidence, what types of intervention are considered pertinent, and what problems are considered solvable. From a Lakatosian perspective, this same process can be interpreted as the consolidation of a theoretical core based on the same ontology, surrounded by a protective belt of alternative models and classifications - such as the Strategies for Negligible Senescence, SENS - in the debate, and which allow the empirical horizon to be expanded without questioning their fundamental assumptions.

From Laudan's approach, this process can be understood as a reorganization of the problem-space of the field, where the consolidation of the framework has not eliminated the open empirical or conceptual problems, but has restructured them within a more coherent methodological environment. From Kitcher's view, its success can be explained in more contextual than purely theoretical terms, as a result of its organizational capacity and its diffusion as a common reference. Finally, following Galison's ideas, the Hallmarks can be understood as a pragmatic device that harmonizes methods, data, and scientific communities, functioning as a stabilized trading zone in which collaboration can continue even in the absence of full theoretical convergence.

This reading also connects with a concern that is increasingly visible in the recent debate: the problem of consensus in the biology of aging. Faced with the persistence of disagreements on fundamental questions, our analysis suggests that the role of the Hallmarks in this context may have been greater than has usually been recognized. Rather than resolving the disagreement, they have contributed to structuring the field by allowing its practical coordination despite the absence of theoretical consensus, and we believe we have offered sufficient reasons to justify this interpretation. This structuring function becomes especially clear when one considers the recent catalogue of 100 open questions in research in the field. What is significant is not only the magnitude of the issues identified, but the fact that many of them are formulated within the conceptual space that the Hallmarks have helped to stabilize. Returning to Laudan, this can be interpreted as evidence of how a framework contributes to defining which problems are considered scientifically relevant.

The expression of genes from nuclear DNA is determined by the structure of nuclear DNA, meaning which regions are spooled and inaccessible versus which regions are unspooled and accessible to transcription machinery. This is visible as the structure of chromatin in the cell nucleus, where chromatin is the name given to the complex structures formed by nuclear DNA and its supporting molecules such as histones. Epigenetic mechanisms control DNA structure by adding and removing decorations to DNA and histones, and this control changes with age in ways that are ultimately detrimental. A range of potential approaches to treatments for aging revolve around the question of whether there are safe enough, effective enough ways to change this epigenetic landscape to make the structure of DNA more youthful in nature, and thus gene expression and cell behavior also more youthful in nature. The most well developed example is partial reprogramming, but it is not the only one.

Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline, and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Our multi-omics approach, combining ATAC-seq, methylome, and RNA-seq shows that aging leads to increased chromatin accessibility in the male murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways.

Remarkably, SIRT6 overexpression reverses these changes in chromatin structure, reducing inflammation and enhancing metabolic function. Notably, ETS family members and liver-enriched transcription factors are enriched in regions with increased and reduced accessibility during aging, respectively. ChIP-seq shows that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging, and that SIRT6 can reverse this effect. Furthermore, AAV-mediated SIRT6 overexpression in aged male mice demonstrates that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.

Link: https://doi.org/10.1038/s41467-026-73115-y

Researchers here report on a recent conference focused on bringing the viewpoint of the physics community to the study of aging. This is largely a matter of building models of aging for a variety of purposes, such as breaking down aging into different conceptual components to make more sense of the observed, somewhat confusing range of outcomes in different species, better predicting which classes of intervention may be most effective in the treatment of aging, or better understanding which aspects of cellular biochemistry are more versus less important in aging.

The first session focused on applying physics laws to understand the aging process, work on how to model three aging patterns - exponentially rising death with late slowdown, exponentially rising disease incidence with late decline, and linear decline of physiological function with age. The saturating removal (SR) model equation has damage production that rises with time (due to accumulating damage producing units) and damage removal process that saturates at high damage plus noise. This equation can explain all three aging patterns.

Furthermore, the model can analyze the shape of the survival curve to tell if geroprotective interventions act on damage production (survival scaling) or damage removal/threshold (survival steepening). Based on the SR model, longevity interventions act by reducing the damage production rate and/or increasing the damage removal rate, both of which are inherently age-dependent processes in this model. He theorized that interventions that prevent damage production will lead to scaling of both lifespan and sickspan, which leads to scaling of the lifespan curves, while interventions that increase damage removal rate can compress the sickspan, leading to the steepening of the survival curve.

Mathematical models can "find simplicity in complexity" when studying the highly intricate process of aging. By integrating diverse data and enabling in silico experiments, such models offer powerful tools to understand aging mechanisms. Researchers presented work on developing new computational tools such as the multi-scale aging model, which integrates nutrient signalling, metabolism, damage accumulation, and growth, enabling exploration of metabolic changes as the cell ages and becomes exposed to stress and protein damage. As the cell gets older, the timing and pattern of normal metabolic states change, so-called metabolic phases. By accounting for these altered patterns, the model can help guide metabolic interventions for lifespan control, by identifying points where interventions might have different effects depending on when they occur in the cell's life.

Link: https://doi.org/10.18632/aging.206378

The gut microbiome is made of thousands of microbial species, many of which conduct activities necessary to health. Our tissues have evolved to at least somewhat rely upon the molecules produced by many of these species as they process the food we eat. Unwanted species are also present, generating harmful products that trigger inflammation and tissue dysfunction. With age, the size of harmful microbial populations increase at the expense of the size of helpful microbial populations. Our health suffers as a result. Animal studies have demonstrated that restoring a more youthful composition to the gut microbiome of an old animal, such as via fecal microbiota transplantation from a young donor, can improve health and lengthen life.

The study of communication between cells has moved on from considering only single secreted molecules, one at a time, to incorporate an attempt to understand the role of extracellular vesicles. These vesicles are membrane-wrapped packages containing many different molecules. The scientific community presently categorizes vesicles by size, such as exosomes versus microvesicles. Cataloguing their contents and the factors determining size and contents is a work in progress at the earliest stage; all too little is mapped out. Vesicles are generated and taken by cells constantly. Just as this happens between our own cells, we might expect vesicles to be an important form of communication between the gut microbiome and our cells. Some of that communication will be detrimental to tissue function, as illustrated in today's open access paper.

Gut Luminal Exosomes in Young and Old Mice: Multi-Omic Characteristics and Regulation of Gut Permeability

Aging is a multifaceted process impacting physiological, genomic, metabolic, and immune functions. This study investigates the role of luminal fecal exosomes (LFEs) in age-associated metabolic dysfunction. We analyzed LFEs from the intestines of young (3-month) and old (24-month) male and female C57BL/6 mice to characterize age-related differences in exosomal proteomic and microRNA cargos. To explore interactions between LFEs and the gut microbiome, naïve young mice were gavage fed with LFEs from old donors, followed by 16S rRNA sequencing. Gut permeability in vitro and in vivo and systemic metabolic effects were assessed.

Bioinformatic analyses identified specific proteins and microRNAs linked to insulin resistance and barrier dysfunction. Heatmaps and principal component analysis revealed distinct differences in LFE profiles between young and old mice. Notably, LFEs from old mice impaired gut barrier integrity and metabolic function in young recipients, with reciprocal effects noted in older mice when receiving LFEs from young mice. Multi-omics profiling, including proteomics and microRNA sequencing, identified age-dependent and gender-related changes in LFE cargo, encompassing host- and microbiome-derived proteins and microRNAs. These age-specific profiles were associated with pathways implicated in cancer, neurobehavioral changes, and metabolic dysfunction.

Our findings highlight that LFEs from old mice are enriched with proteins and microRNAs involved in insulin resistance and gut barrier disruption. Together, these findings identify gut luminal exosomes as age-dependent mediators of microbiome-host communication that contribute to intestinal barrier dysfunction and metabolic decline.

Cyclarity Therapeutics has been processing safety data from a phase 1 safety trial of a cyclodextrin drug to bind 7-ketocholesterol, a toxic form of oxidized cholesterol that contributes to a range of conditions. The company is initially focused on atherosclerosis, the formation of fatty plaques that obstruct blood vessels and ultimately rupture to cause a stroke or heart attack. It is thought that 7-ketocholesterol may be a significant factor in the toxic environment of atherosclerotic plaques, alongside other forms of cholesterol that are also harmful to cell function in larger amounts. Recall that atherosclerosis progresses in its later stages because macrophages are called to the plaque to attempt to repair it, are overwhelmed by the plaque environment, become inflammatory, and die, adding their mass to the plaque. The field is searching for better ways to take the stress off macrophage cells and thus tip the balance towards at least a slower growth of plaque over time.

Data from a study offers the first clinical evidence that 7-ketocholesterol (7KC), a root cause of atherosclerosis, can be safely targeted and removed from the human body, marking a pivotal milestone toward moving cardiovascular treatments from managing arterial damage to achieving true plaque reversal. Results of the phase 1 trial evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of UDP-003. UDP-003 is the first clinical-stage therapeutic discovered using Cyclarity's proprietary drug discovery AI Platform which engineers cyclodextrin molecules to reverse disease and protect against future accumulation of harmful molecules and aging pathologies. These engineered cyclodextrins precisely attract and encapsulate hydrophobic molecules such as forms of cholesterol, rendering them dissolvable in water and thus destined to be purged from the bloodstream.

Most cardiovascular drugs, including statins, anti-inflammatories, and RNA-based therapies, work systemically throughout the body to alter how cholesterol, inflammation, and gene expression are regulated. In contrast, Cyclarity's UDP-003 binds directly to 7KC, a root cause of plaque buildup, then facilitates urinary excretion of it. Much like removing rust from metal, this approach directly targets a key source of damage within plaque with the goal of reversing and preventing atherosclerosis, a primary underlying cause of cardiovascular disease, and does so locally within the plaque to reduce risks of unintended systemic effects.

7KC is considered a biologically active driver of cardiovascular disease, contributing to inflammation, cell death, and plaque instability and has emerged as an important target in emerging therapies aimed at treating the disease at its root. In addition to cardiovascular disease, 7KC is implicated in Alzheimer's disease, metabolic dysfunction-associated steatohepatitis (MASH), and other age-related conditions. Cyclarity is currently enrolling patients with acute coronary syndrome (ACS) into the efficacy cohort of the ongoing Phase 1 trial, which includes pre- and post-treatment coronary CT angiography (CCTA) to assess plaque changes.

Link: https://cyclaritytx.com/cyclarity-unveils-first-ever-clinical-data-demonstrating-excretion-of-oxidized-cholesterol/

As aging emerges from the accumulation of a relatively small number of underlying forms of damage and dysfunction, we might expect even very different aspects of aging to correlate with one another. Maybe not a very tight correlation if the two aspects are far removed from one another in terms of the connection of proximate causes and their interactions, but ultimately they arise from the same roots. Here, researchers rely on the interconnected nature of aging in order to make use of retinal aging to assess bone aging. The researchers use an aging clock derived from retinal imagery and show that greater predicted age correlates with greater loss of bone mineral density and risk of fracture resulting from the progression of osteoporosis.

Osteoporosis is a common condition that weakens bones and raises the risk of fractures, especially in older adults. However, many individuals are not diagnosed until after a fracture occurs, in part because the standard diagnostic test, Dual-energy X-ray Absorptiometry (DEXA), is not always readily accessible. We therefore investigated whether retinal photographs, taken from the back of the eye, could help identify people at higher risk of osteoporosis. This possibility arises from the idea that the retina may reflect the body's overall biological aging.

Hence, we used an artificial intelligence-derived age marker, RetiAGE, to estimate retinal biological age and test the association between retinal age and osteoporosis. In the Singapore study of 1,965 older adults, older retinal biological age was associated with lower bone mineral density (BMD), lower BMD T-scores, and higher fracture risk scores. In the UK Biobank study of 43,938 participants, older retinal biological age also predicted a higher risk of developing osteoporosis over time, even after accounting for major risk factors. These findings suggest that retinal biological aging may reflect broader aging processes related to skeletal health. Retinal imaging may therefore provide a simple, non-invasive, and accessible way to support opportunistic screening for osteoporosis risk.

Link: https://doi.org/10.1371/journal.pdig.0001360

Ken Scott and Helga Sands have been features of the longevity industry conference circuit for about as long as there has been a longevity industry; I first met Ken at at the big Undoing Aging conference in Berlin in 2019, just before COVID started up, and he became one of the early investors in Repair Biotechnologies, the company I co-founded with Bill Cherman. Ken is an enthusiastic self-experimenter for personal gain in health and very much an advocate for something better than the present medical regulatory system, particularly when it comes to the long span of years that it takes for therapies to move from laboratory to clinic. Ken is now in his 80s and not one to be patient; there is a powerful argument there for some form of improvement in terms of the right to try and the primacy of patient choice when considering any balance of risk versus reward in access to new medical technologies.

Ken and Helga recently launched the KHL Foundation, a medical tourism concern that seeks to expand the availability of gene therapies that are already deployed or under development. These are relatively safe approaches to gene therapy that have emerged from the efforts of Bioviva and competitors such as Triple Helix, alongside newer developers such as Unlimited Bio and others. These companies are largely focused on the use of local injections of viral vectors, as that minimizes the potential for adverse immune reactions, and on a few genes and proteins known to robustly produce benefits in animal models: klotho, follistatin, telomerase, and so forth. This seems a growing market, and I expect it to continue to expand in much the same way that the stem cell industry expanded, for better or worse. Few companies will publish data, it will be hard to distinguish high quality versus low quality clinics, but over time a few companies will take what has been learned, pay the regulatory costs, and bring the best approaches to clinics in the US and Europe. Meanwhile, for anyone who doesn't want to wait, there is medical tourism.

KHL Foundation

The KHL Foundation, founded by Kenneth Scott (b. 1942) and Helga Sands (b. 1938), is dedicated to making proven rejuvenation therapies available now for people over 60 who refuse to age on schedule. We founded the KHL Foundation because we believe that people over 60 deserve access to the best scientifically grounded rejuvenation therapies available today, not ten or twenty years from now. We test therapies on ourselves. We partner with trusted clinicians. We share results openly. And we move with the insouciance of youth, because we know how precious time is.

The Rejuvenation Cocktail delivers three carefully selected gene therapies that target the core mechanisms of aging. Each gene enhances one of the pillars of vitality - muscle, mind, and metabolism - to restore youthful performance and resilience. Results are designed to be long lasting, with effects that will persist for 15 to 20 years. Klotho is often called the longevity gene. It supports neuronal health, maintains vascular flexibility, and reduces inflammation. Follistatin suppresses myostatin and activin - both limit muscle growth. Increasing its levels enhances muscle regeneration. Sirtuin 1 is a master regulator of mitochondrial function and cellular energy. The treatment includes same day intramuscular injections of follistatin gene therapy and intranasal application under local anesthetic of klotho and sirtuin 1 gene therapies.

The composition of the gut microbiome changes in detrimental ways with age, leading to increased production of inflammatory metabolites and reduced production of beneficial metabolites. There is ample evidence for this to contribute to aspects of aging. Rejuvenation of the composition of the gut microbiome via various approaches has been shown in animal studies to improve health and extend life span. A human trial has started for fecal microbiota transplantation from young donors to old patients, but it will take a few years for data to be published. The study noted here describes a quite different approach to the problem, which is the use of ultrasound to bias the gut microbiome composition; it used only a small number of mice, and it is entirely unclear as to how ultrasound might produce this outcome. So: interesting, but more research needed.

This study employed a natural ageing mouse model to investigate whether noninvasive low-intensity pulsed ultrasound (LIPUS), a therapeutic ultrasound, delivered to the abdomen, could alleviate age-related muscle deterioration and whether its effects were linked to gut microbiota modulation. C57BL/6 mice were maintained until 92 weeks of age, after which abdominal LIPUS stimulation was administered for 8 weeks. At 100 weeks, both forelimb and hind limb grip strength were assessed prior to euthanasia.

Naturally aged mice exhibited sarcopenia-like characteristics, including impaired muscle performance, reduced myofiber diameter and decreased muscle weight (n = 6). Age-related renal impairment promoted the accumulation of advanced glycation end products (AGEs) in skeletal muscle, triggering pro-inflammatory signalling cascades characterized by elevated COX-2, phosphorylated NF-κB, NLRP3, IL-1β, and Caspase-1 (n = 5-6). LIPUS treatment significantly improved muscle strength (forelimb and hind limb grip strength, n = 6) and muscle mass (n = 6), while suppressing inflammatory mediators (n = 5-6).

Gut microbiota analysis showed that LIPUS increased microbial diversity (n = 5-6) and altered taxonomic composition, enriching anti-inflammatory taxa such as Lactobacillus, Bifidobacterium, Faecalibaculum and Coriobacteriaceae_UCG_002 (n = 6). Correlation analysis indicated that these LIPUS-enriched taxa were positively associated with enhanced muscle performance. These data suggest that LIPUS mitigates sarcopenia in naturally aged mice by restoring muscle integrity and attenuating inflammation, possibly via gut microbiota regulation.

Link: https://doi.org/10.1002/jcsm.70291

Age-associated B cells are a problematic subset of the B cell population of immune cells that emerges in later life. In recent years researchers have uncovered various ways in which these cells contribute to the pathology of specific age-related conditions. The existence of age-associated B calls makes clearance of B cells an interesting topic; there are ways to destroy the entire B cell population in the body, which then reconstitutes itself within a few weeks minus any senescent or age-associated or other problem B cells. Unfortunately there doesn't appear to be any meaningful effort underway to bring such immune clearance approaches to the clinic. Studies so far remain preclinical, meaning assessments in animal models of age-related disease, and looking over correlations in human data. That said, one strong focus that may give rise to clinical efforts is the contribution of age-associated B cells to autoimmune conditions.

Age-associated B cells (ABC) are a unique subset of antigen-experienced B cells that were first identified in old female mice. ABC have both physiological and pathological roles in humans and they are important in the progression of some immune disorders, chronic infections, and even in the aging process. These cells are differentiated from other B cell subsets by the expression of transcription factors T-bet and surface markers such as CD11c+, CD21/CD35-, CD23-.

ABCs are heterogeneous cell populations that are involved in the development of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis by producing inflammatory cytokines and autoantibodies, antigen-presenting to T cell, and developing a specific humoral response and memory. Discovering the exact function of ABCs and their related regulatory factors can be effective in introducing them as therapeutic targets and diagnostic biomarkers. In this manuscript, we aimed to explain the role of these cells and their function in autoimmune diseases so that by reviewing past studies, a new window can be opened towards a better therapy approach of mentioned autoimmune diseases, in the future.

Link: https://doi.org/10.1186/s12979-026-00564-w

The immune system declines with age, and this causes more than just a progressive failure to adequately defend against infectious pathogens. The immune system is deeply involved in normal tissue function, maintenance, and regeneration. It is also responsible for destroying senescent and potentially cancerous cells throughout the body. Thus immune decline both degrades tissue function and increases the risk of cancer. Researchers tend to bucket aspects of immune aging into two broad categories, immunosenescence and inflammaging. Immunosenescence is the loss of capacity, while inflammation is a continual overactivation of the immune system, placing it in a state of chronic, unresolved inflammatory signaling.

There are obviously sex differences in the pace and structure of degenerative aging. In our species, women live longer but suffer greater disability. Given that the immune system touches on so much of heath and tissue function, we might expect to find a catalog of specific differences in immune system aging between the sexes. This is indeed the case. Today's open access paper provides a tour of what is known on this topic. It is possible that comparisons between the sexes might teach us useful things about aging, but equally the causes of aging are the same from individual to individual. The differences lie in the way in which damage spirals out into interacting webs of dysfunction and further damage. A therapy that targets an underlying cause of aging should be useful to all older individuals, though it is certainly possible that it will be more useful for some categories of individual than for others.

The problem with one-size-fits-all medicine: Biological sex and the aging immune system

The immune system can be divided into two categories: innate and adaptive. Innate immune cells (e.g., neutrophils, macrophages, and dendritic cells [DCs]) release cytokines and pro-inflammatory mediators that coordinate the immune response and protect the host. By contrast, the adaptive immune system provides a targeted and long-term defense against pathogens. While innate responses are rapid and general, adaptive immunity is slower and highly specific.

Like other biological systems, the immune system undergoes age-related functional decline. Indeed, the latest hallmarks of aging recognized by the field now include chronic inflammation as a distinct hallmark, recognizing its crucial role in aging phenotypes. Changes in the immune system can both promote or restrain aging across multiple organs. Two main characteristics of immune aging are 'immunosenescence' and 'inflammaging'. Together, these processes promote the development of age-associated diseases (e.g., atherosclerosis, dementia, osteoarthritis). Understanding hallmarks of immune aging is critical, as they influence both life span and healthspan.

In addition to shared age-related changes, sex differences further shape immune aging. Sex differences lead to divergent patterns of life span and healthspan between males and females. Overall, females tend to live longer than males, yet experience more age-related and immune-related diseases, whereas males are more likely to develop severe outcomes from infections. This discrepancy, in which females outlive males but spend more years in poor health, is referred to as the 'morbidity-mortality' paradox. One potential driver of sex differences in disease susceptibility and health outcomes is maternal-fetal microchimerism, which has been shown to modulate the immune system. However, sex differences in disease susceptibility and health outcomes are thought to be mainly driven by the effect of sex chromosomes (XX versus XY) and/or sex hormones on the immune system.

Indeed, the X chromosome contains many immune genes, some of which escape X inactivation with aging, contributing to stronger immune responses in females. By contrast, the Y chromosome encodes relatively few immune genes, which contributes to sex differences in immune system robustness. Reflecting this difference in copy number, females generally produce more cytokines than males regardless of age. Sex-steroid receptors are expressed broadly in immune cells, though absolute levels vary. Estrogens exert both pro-inflammatory and anti-inflammatory effects, depending on concentrations, whereas androgens suppress immune activity.

With aging, females maintain adaptive immune responses more effectively than males, suggesting that the female immune system has higher baseline activity, with stronger expression of adaptive versus innate immune pathways. Conversely, aging males rely more heavily on innate immunity, which may partly explain heightened innate responses but poorer outcomes following infections and vaccinations. This sex difference may be due to overall higher levels of testosterone in males, which has been shown to have important impacts the immune system over time. However, while stronger immune responses provide protection in females, they also increase autoimmunity risk with age. Sex differences in immune aging highlight how differences in both adaptive and innate immunity shape lifelong susceptibility to infections and age-related diseases, emphasizing the importance of sex as a biological variable in both immunological research and clinical care.

Far too little research into infectious disease and the development of vaccines and other approaches to therapy employs old animals. It is accepted that infectious disease becomes worse with age and treatments become less effective, and then left to the smaller aging research community to see if anything can be done about it. Here, for example, is an example of research in which scientists attempt to build an incrementally better picture as to what exactly is going wrong in the aging immune system, in the specific context of a single infectious disease, tuberculosis. Matters move slowly.

Aging profoundly impairs immune competence, a phenomenon termed immunosenescence, rendering older adults (≥60 years) highly vulnerable to infectious diseases such as tuberculosis (TB). Clinically, older adults exhibit reduced vaccine effectiveness alongside heightened susceptibility to TB, with epidemiological data indicating 2-3 times higher TB incidence and up to four times higher mortality than younger patients. Despite this growing burden, current TB research predominantly employs young adult mouse models (6-8 weeks old, equivalent to ~18-year-old humans), which do not adequately capture the immune landscape of older hosts. Evidence from studies suggests that old mice exhibit higher bacterial burden, delayed CD4+ T cell responses, and altered immune activation compared to younger counterparts. However, the impact of immunosenescence on bacterial clearance dynamics, immune cell phenotypes, and host responses during TB treatment remain largely unexplored.

Here, we monitored the immunopathology, frequency, and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with TB and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks post infection, mycobacterial load in tissues (lung, spleen, and liver) of old (17-19 months old) and aged (31 months old) C57BL/6 mice was similar to that of young (2-4 month old) mice. However, at two weeks post-treatment, older mice showed a slower rate of TB clearance in the lungs. TB-infected old mice had higher splenic T-follicular cytotoxic (TFC)-like cells, and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase, and prostaglandin E synthase), suggesting impaired mitochondrial function.

Collectively, these findings suggest that age-associated immune alterations may disrupt immunometabolic pathways, thereby contributing to the delayed TB clearance. Targeting immunometabolic dysfunction therefore represents a promising strategy to enhance TB treatment efficacy and reduce disease burden in older populations.

Link: https://doi.org/10.18632/aging.206374

Given access to a large body of biological data from people of various ages, creating an aging clock from that data is fairly straightforward and costs relatively little in time and funding. Thus clocks are proliferating, a new one published by an academic research group every few months. Most will vanish into obscurity. The problem is not the lack of a perfect clock for any given situation, but the lack of understanding as to how any given clock will react to a novel potential approach to slowing or reversing aging. The real potential value of clocks is not risk estimation for patients, but rather the rapid assessment of potential therapies to treat aging. But that latter use is challenging when one can't trust that a clock will in fact react appropriately and correctly judge the degree to which aging has been slowed or reversed.

Identifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether mid-life metabolomic ageing is associated with incident dementia and its age of onset and assessed joint associations and interactions with APOE genotype and dementia polygenic scores. In the UK Biobank, plasma metabolites were quantified at baseline. Metabolomic age (MileAge) delta reflects the difference between metabolite-predicted and chronological age. Dementia was identified via health records.

Amongst 223,496 participants, 3,976 developed dementia. A higher MileAge delta was associated with higher hazards of all-cause, unspecified and vascular dementia (hazard ratio, HR = 1.61) and earlier onset. Key metabolites were lipids, lipoproteins, and amino acids. MileAge delta and genetic risk were jointly associated with dementia. Individuals with a high MileAge delta and two APOE ε4 alleles had a 10.30-fold higher all-cause dementia risk. Thus metabolomic ageing and genetic risk likely represent independent biological pathways contributing to dementia risk.

Link: https://doi.org/10.1002/alz.71280

The integrated stress response in cells acts to reduce protein synthesis while enhancing maintenance activities. A number of sensors for different forms of cell stress all converge on activation of the integrated stress response. These stresses include lack of nutrients, the presence of viral material, and too many unfolded proteins cluttering up the endoplasmic reticulum, among others. The degree of activation of the integrated stress response is important: mild activation is generally beneficial, but too much activation will produce apoptosis, the cell destroying itself in programmed cell death.

Like other stress response systems in the cell, some studies show that manipulation of the integrated stress response can modestly slow aging and extend life in short-lived species. Thus there is considerable research interest in the manipulation of the integrated stress response as a basis for therapy. A number of drugs capable of promoting or suppressing the integrated stress response exist already, and others are in development. The challenge in targeting the integrated stress response lies in the threading the needle of settling on enough activation to be useful, but not too little activation or too much activation, either of which can be harmful. What constitutes the right level of integrated stress response activation may vary between cell types in a tissue, between different tissues, and between individuals. Thus integrated stress response targeting drugs tend to have unpleasant side effect profiles.

Today's open access research paper illustrates this challenge in the move between laboratory species. The authors report that flies react quite differently to manipulation of the integrated stress response than nematode worms. Given the present state of medical technology, I do not think that we should be confident in the emergence of a very safe therapeutic approach to the adjustment of integrated stress response activity intended to slow aging. That is not to say it is impossible, it is just more difficult than would be cost-effective to attempt in the environment of what is readily possible today.

Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly

Recent progress in geroscience suggests that targeting broad aspects that underlie the biology of aging could prevent many age-related diseases simultaneously. One such treatment is the activation of stress response pathways. Recently, activation of the integrated stress response (ISR) orchestrated by the transcription factor ATF4 has been studied. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNA interference) of dATF4 extends lifespan.

We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity.

Despite the failure to produce any useful approach to therapy based on upregulation of sirtuin 1 expression, and an entirely unhelpful hype cycle that came and went associated with those efforts, research into sirtuin 1 continues apace. In the example here, researchers connect sirtuin 1 expression to the improved metabolism following exercise. As is usual in matters of cellular biochemistry, connecting specific benefits to specific mechanisms is challenging; a great deal changes with exercise, and it has hard to say which of those changes are more versus less important.

Sirtuin 1 (SIRT1) was initially identified as an enzyme that deacetylates histones and suppresses gene activity. Since then, its roles have expanded considerably, and it is now recognized as a multifunctional protein conserved across various organisms. Despite increasing interest, it remains essential to clarify how exercise-induced changes in SIRT1 counteract multiple hallmarks of aging, as well as the full scope of SIRT1's impact on different physiological systems. This review highlights recent findings on the short- and long-term effects of exercise on SIRT1 signaling in both rodents and humans during aging. We explore the molecular pathways activated in various tissues, providing insight into the specific biological functions of SIRT1 within aging cells.

Optimal levels of SIRT1 help maintain homeostasis and a biochemical environment conducive to healthspan, influencing biological processes such as mitochondrial dynamics, metabolic pathways, tissue remodeling, autophagy, inflammatory responses, and redox balance. This indicates that SIRT1, a pleiotropic molecule, orchestrates multiple responses throughout aging. SIRT1 may act as a dynamic sensor for exercise benefits and protect against aging by maintaining genomic integrity. Different exercise protocols (acute and chronic) and modalities (aerobic, resistance, and combined training) can increase messenger RNA levels, activity, or protein levels of SIRT1 in various vital organs (adipose tissue, hippocampus, heart, liver, bone, and skeletal muscle) of aged animals and older adults, promoting health. Taken together, these observations support the notion that SIRT1 functions as a potential exerkine, and understanding its role in exercise-induced adaptations offers new insights into non-pharmacological strategies to enhance longevity.

Link: https://doi.org/10.1007/s10522-026-10442-z

Nerves are made up of bundled axons, the long connections between neurons, and so regeneration following injury involves new axons finding their way across the area of damage as they regrow, a process hampered in mammalian species by the formation of scar tissues. The antibody NG101 has long been known to promote regrowth of nerve tissue following damage. It has been a long road from the initial discovery a few decades ago to a recent clinical trial in patients with spinal cord injury. That trial allowed more data to be gathered on the regeneration process via imaging approaches, and researchers made use of the opportunity to examine in more detail as to how NG101 enhances regeneration in humans. Unlike animal studies where histology and dissection of nerve tissue is possible, human studies must rely on imaging, and those imaging techniques must be developed as trials progress.

One promising therapeutic strategy to enhance axonal plasticity is the inhibition of Nogo-A, a potent neurite growth suppressive membrane protein in central nervous system (CNS) myelin and neuronal membranes. Preclinical studies show that NG101, a humanized monoclonal antibody targeting Nogo-A, promotes axonal sprouting and functional recovery. Recent exploratory findings from a phase 2b clinical trial suggest that NG101 may also improve upper extremity motor function in participants with motor incomplete cervical spinal cord injury (SCI), supporting the translational potential of Nogo-A inhibition.

To better understand how Nogo-A inhibition influences structural recovery in human SCI, and to sensitively track potential regenerative effects, objective in vivo biomarkers are needed. Cross-sectional cord area (CSA) is a robust macroscopic marker of spinal cord atrophy, reflecting structural loss from axonal degeneration and demyelination, secondary to traumatic SCI and correlating with clinical impairment. Microstructural imaging provides reproducible metrics such as magnetization transfer saturation (MTsat), which is sensitive to myelin content and enables detection of demyelination and remyelination of spinal fiber tracts.

No study has yet assessed how macro- and microstructural Magnetic Resonance Imaging (MRI) biomarkers respond to a targeted neuroregenerative treatment in acute cervical SCI, or how these measures can be combined to optimize trial design. In this study, we investigated whether CSA and MPM-derived indices can track NG101-induced structural effects. Compared to placebo, NG101-treated participants exhibited faster lesion volume reduction and a slower decline of CSA and MTsat in the corticospinal tracts and dorsal columns. Crucially, multimodal stratification incorporating MRI and electrophysiological measures substantially enhanced the detection of clinical treatment effects. These findings suggest NG101 slows trauma-induced progressive macro- and microstructural degeneration or promotes fiber sprouting.

Link: https://doi.org/10.1038/s41467-026-71412-0

The primarily alternative to epigenetic clocks and other omics clocks to assess biological age is the use of aging clocks constructed from clinical chemistry, physical, and other simple measures, such as result from the Klemera-Doubal Method or Phenotypic Age. Examples of suitable measures include specific metabolite levels in serum, blood count data, morphometry based on waist circumference, blood pressure, grip strength, and so forth. The construction of a clock proceeds in much the same way regardless; data is assembled from a large study population of different ages, and machine learning approaches are employed to discover algorithmic combinations of data that predict chronological age. Where the predicted clock age is higher than chronological age, it is said that this person exhibits accelerated aging. The advantage of simple measure clocks versus omics clocks is that the data used is easier to theorize on; if one sees that an individual has a higher predicted age because their blood pressure increased, for example, one can form a hypothesis quite quickly and easily. When the cause is a different prevalence of DNA methylation on seven CpG sites on the genome, well, that is largely inscrutable.

That said, given the way in the which a clock is produced, a great deal of work is required in order to understand how it actually behaves, and whether it actually reflects biological age in any useful way. This is the case regardless of the type of underlying clock data. For early clocks, the discovery process has been underway for quite some time now, and it remains an interesting open question as to the degree that we should trust or can make good use of clock data in assessing interventions thought to affect aging. The uncertainty runs the other way as well, in that perhaps some of the results produced by clocks might cause us to question how we define biological age or what we might think a priori is a useful intervention. Most clocks have quirks that are distinct from these points, such as the relative insensitivity to physical fitness exhibited by first generation epigenetic clocks. In today's open access paper, researchers note that a short change of diet can move the biological age predicted by the Klemera-Doubal Method clock by a couple of years. Is this meaningful? A limited quirk? Something that should cause us to question the clock more broadly? These sorts of questions remain hard to resolve.

Short-Term Dietary Intervention Alters Physiological Profiles Relevant to Ageing

Ageing is a complex process influenced by modifiable factors such as diet, which may accelerate or decelerate physiological decline. While chronological age increases uniformly, biological ageing varies between individuals, reflecting differences in health status and the resilience of biological systems. The Klemera-Doubal Method (KDM), a composite biomarker-based index often used as an estimate of biological age, has been associated with morbidity and mortality in large cohorts. This study examined whether dietary manipulation of protein source and macronutrient composition affects KDM estimates in older adults.

We analysed data from the Nutrition for Healthy Living study, a dietary intervention trial involving 104 participants aged 65-75 years. Participants were randomised to one of four diets: omnivorous/high-fat (OHF), omnivorous/high-carbohydrate (OHC), semi-vegetarian/high-fat (VHF) or semi-vegetarian/high-carbohydrate (VHC). KDM-derived δAge (the difference between KDM-age and chronological-age) was calculated before and after a 4-week intervention.

The OHF group, most like participants' baseline diets, showed no meaningful change in δAge. Compared to OHF, participants in the OHC group showed a significant reduction in δAge. The VHF and VHC groups showed similar reductions in δAge, relative to OHF, though not all reached statistical significance. KDM-derived δAge appears responsive to dietary change within 4 weeks and may offer a useful proxy for evaluating shifts in physiological status. Caution is warranted in interpreting such changes as evidence of biological age reversal as observed shifts may reflect acute physiological responsiveness to dietary inputs rather than altered ageing trajectories. Longer-term treatment would be needed to assess changes in age-related disease risks.

With advancing age the composition of the gut microbiome changes in detrimental ways and the immune system becomes progressively incapable. These two aspects of aging do not happen in isolation from one another. The relationship between the aging of the gut microbiome and aging of the immune system is likely bidirectional. The immune system is responsible for gardening the gut microbiome, suppressing the populations of undesirable microbes, and so loss of immune function enables the growth in number of pathogenic microbes. At the same time, however, the populations of undesirable microbes can dysregulate immune function, such as via secretion of metabolites that provoke chronic inflammation. Thus gains in health are possible by either improving immune function or restoring a more youthful gut microbiome composition.

Aging is associated with systemic immune remodeling and disease susceptibility, but its impact on intestinal mucosal immunity, particularly changes in M cells, remains largely unknown. This study aimed to investigate how aging alters intestinal mucosal immune phenotypes, specifically follicle-associated epithelial cells (FAE) and the gut microbiota, and to identify interconnected pathways that may be exploited to maintain intestinal immune function in the elderly. Using intestinal tissue from young and aged mice, this study assessed manifestations of intestinal epithelial aging, changes in immune cells in the lamina propria, and microbial composition.

Aging was associated with increased expression of senescence-associated secretory phenotype (SASP) markers (IL-1β, TNF-α, p16) and decreased levels of tight junction proteins (Occludin, Tricellulin), suggesting epithelial barrier dysfunction. Aged mice exhibited decreased Naïve Th cells, increased Effector Th and Th17 subsets, and decreased fecal Immuoglobulin A. Microbiome analysis revealed enrichment of inflammatory bacteria, such as Desulfovibrio and Candidatus_Saccharimonas, and elevated dysbiosis indices. RNA sequencing of FAEs revealed 578 differentially expressed genes, including downregulation of Gp2 and Ccl28, indicating impaired M cell function. Association analysis between microbiome changes and mucosal immune aging revealed that enrichment of key inflammatory bacteria may contribute to impaired M cell function and dysregulated intestinal mucosal immunity.

These findings reveal a multi-layered disruption of intestinal homeostasis during aging-comprising barrier function, immune imbalance, FAEs dysfunction, and shifts in specific microbial taxa -leading to increased susceptibility to pathogens. Targeting these age-related pathways may provide strategies for maintaining intestinal immunity in the elderly.

Link: https://doi.org/10.1111/acel.70533

Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Overly reactive and senescent microglia are implicated in the development of neurodegenerative conditions, producing sustained inflammatory signaling while failing in their normal portfolio of tasks related to tissue maintenance and support of neurons. Here, researchers extend this line of thought to the aging of the retina and the progressive blindness of macular degeneration. To what degree are microglia a contributing cause of pathology in retinal degeneration? It is hoped that future strategies developed to address microglial dysfunction in the context of conditions such as Alzheimer's disease may have broader application.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults. Advanced AMD comprises an atrophic ("dry") form characterized by retinal pigment epithelium (RPE) and photoreceptor degeneration and a neovascular ("wet") form driven by choroidal neovascularization (CNV). Beyond genetic predisposition and environmental stressors, chronic dysregulation of innate immunity is increasingly recognized as a convergent mechanism linking drusen/Bruch's membrane alterations to outer retinal cell death and pathological angiogenesis.

Retinal myeloid cells - including resident microglia and, in specific disease contexts, recruited monocyte-derived macrophages - can support homeostasis by clearing lipids and cellular debris, yet may also exacerbate inflammation, matrix remodeling, and neovascularization. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia and other myeloid cells that regulates phagocytosis, lipid handling, migration, survival, immunometabolism, and inflammatory tone. Recent retinal studies suggest that TREM2-associated programs can restrain lesion expansion in outer retinal degeneration models and modulate CNV severity in experimental neovascularization; however, interpretation remains limited by disease stage, anatomical niche, and the difficulty of cleanly separating microglia from infiltrating macrophages in vivo.

Here, we synthesize current evidence on retinal myeloid contributions to dry and neovascular AMD, provide an updated mechanistic framework for TREM2 signaling, and discuss therapeutic strategies and translational challenges for targeting TREM2 in AMD.

Link: https://doi.org/10.3389/fopht.2026.1804578

The accumulation of senescent cells with age is clearly an important aspect of degenerative aging. Senescent cells contribute to chronic inflammation and disrupt tissue structure and function. Of the early senolytic treatments shown to clear a fraction of senescent cells in the tissues of aging, only the dasatinib and quercertin combination has undergone initial clinical trials in human patients, and even there the trials are small and the doses relatively low. Data is promising but not conclusive. The field has moved past the initial interest in clearance without actually implementing that initial interest, albeit a number of companies are working towards clinical trials for their varied senolytic strategies. Meanwhile the research is more focused on understanding differences between senescent cells and has, perhaps, become overly cautious about deploying therapies in advance of building a much more comprehensive map of senescent cells and their activities.

It is true that scenarios could exist in which blunt clearance of senescent cells will cause harms alongside benefits. For example, where senescent cells are a part of the structure of an unstable atherosclerotic plaque. Clearing those cells may tip the plaque over the edge and into fragmentation under the next incidence of pressure stress. There are no doubt other age-related circumstances in which clearance of senescent cells fails the cost-benefit test. How common are these scenarios? It seems to me that no-one is much interested in finding out, and researchers are more focused on generating the groundwork for a next generation of therapies to emerge over the next few decades. Those therapies don't yet exist, but first generation senolytics do exist. A little more thought given to the evaluation of the cost-benefit of their use seems needed, and absent.

Cellular senescence: from pathogenic mechanisms to precision anti-aging interventions

Cellular senescence, characterized by a state of stable cell-cycle arrest, has evolved from an initial observation in in vitro experiments to a central theoretical pillar for understanding systemic aging and age-related pathological processes. The traditional research paradigm primarily relies on a suite of consensus biomarkers for the identification of senescent cells. Among the most representative are the cyclin-dependent kinase inhibitors p16INK4a and p21CIP1, the activity of senescence-associated beta-galactosidase (SA-β-gal), and DNA damage. By adopting a biomarker-based definitional model, we gain a critical instrument to map the landscape of senescent cell accumulation, offering preliminary insights into its mechanistic associations with dysfunction across multiple organ systems.

In fact, senescent cells are not a homogeneous group but exhibit profound functional heterogeneity. Senescent cells with similar molecular phenotypic characteristics, regulated by their cell origin, tissue microenvironment, and induction background, may have vastly different or even opposite effects on tissue homeostasis. For example, senescent glial cells in the brain have been proven to be key factors driving neuroinflammation and cognitive decline, but senescent pancreatic β cells display superior insulin secretory capacity relative to younger cells, representing a distinct functional shift during the aging process. This insight has catalyzed a pivotal paradigm shift: moving beyond rudimentary "senescence profiling" to a mechanistic dissection of the functional trajectories of discrete senescent subpopulations. Emerging evidence increasingly highlights that certain senescent cohorts are not merely deleterious bystanders but active rheostats of tissue homeostasis, characterized by profound context-specificity and functional pleiotropy.

Current molecular markers, while useful for identification, fail to discriminate between functionally distinct senescent subpopulations. Consequently, the focus of research is shifting from "identifying the senescent state" to "evaluating functional pathogenicity," prioritizing the targeting of cell clusters that actively disrupt tissue homeostasis or drive specific disease ontologies. This shift necessitates an evolution in senolytic strategies toward "non-toxic precision clearance," requiring intervention tools to act as molecular scalpels capable of distinguishing deleterious cells from neutral or even beneficial ones. The future of this field is pivoting toward a profound integration of precision clearance and prospective intervention.

Elucidating the inductive mechanisms of cellular senescence constitutes the cornerstone for implementing effective clinical interventions, centered on a "prevention-over-cure" paradigm. The primary objective is upstream intervention: maintaining genomic stability, mitigating oxidative damage, and modulating canonical pro-senescent signaling axes (e.g., p53/p16) to delay the onset of the senescence program and restrict the systemic accrual of senescent cells. Elucidating the molecular triggers of cellular senescence is not only fundamental to understanding the core biological laws of life but also provides the precision targets required for homeostatic maintenance. The paradigm of senescence intervention is undergoing a fundamental transformation from a crude "anti-state" approach to a sophisticated "systemic management" framework.

Platelets play a vital role in blood clotting. A population of hematopoietic cells known as megakaryocytes spawn platelets by pinching off parts of their membrane and cytosol, forming what are essentially mini-cells that lack some of the usual components, such as a nucleus, but retain many of the others, such as mitochondria. As such platelets are capable of many of the functions of a full cell, such as secreting factors that influence other cells. Unfortunately, platelets become problematic with age in ways that contribute to greater inflammatory behavior and increased risk of the inappropriate clotting of thrombosis. Researchers here identify a specific protein, HuR, that regulates inappropriately inflammatory behavior in platelets in aged tissues. Suppressing HuR in only the platelets of aged mice reduces inflammation, burden of cellular senescence, and loss of physical and cognitive function characteristic of aging.

Aging involves morphological and functional changes across different organs, but how these changes are linked among the different organs remains to be elucidated. Here, we uncover a central role of platelets in systemic aging. In response to physiological or pathological stimuli, platelets synthesize and release many different growth factors, cytokines, chemokine, vasoactive substances, and other bioactive factors. During aging, platelet reactivity generally increases, even though the number of platelets decreases. As components of the blood, platelets penetrate the entire body, permitting platelets to affect the entire body. However, the role of platelet activation and platelet-secreted pro-inflammatory factors (PSPF) in aging is unclear.

In aged mice, the levels of platelet-secreted pro-inflammatory factors (PSPF) increased greatly in the serum and platelets, leading to a diffuse increase of platelet infiltration in the brain, liver, lung, kidney, and aortic root. The RNA-binding protein HuR/ELAVL1, a major regulator of RNA metabolism, promoted the production of PSPF in platelets. Platelet-specific deletion of HuR reduced the expression of PSPF in platelets, alleviated platelet infiltration in the brain, liver, lung, kidney, and aortic root, and delayed systemic aging. By using single-nucleus sequencing, platelet-specific HuR ablation was found to alleviate p53 and pro-inflammatory signaling pathways in liver, lung, and brain tissues in aged mice. Our findings highlight a role of platelets in coordinating aging traits across organs.

Link: https://doi.org/10.1038/s41467-026-72481-x

Researchers here report an surprising, interesting, but not immediately useful discovery relating to the interaction of the immune system with wound healing in aged skin. Regeneration in aged skin is impaired, and non-healing wounds are one consequence of this impairment. The researchers found that priming aged skin with a dose of lipopolysaccharide, a toxic bacterial product that the immune system reacts to, improves skin regeneration after later injury. In the real world injuries are hard to predict ahead of time, so a better understanding how the observed changes in immune cell behavior provoked by this intervention are regulated is required in order to develop a form of therapy that usefully recreates the effects.

Tissue repair is often hampered during aging. Worldwide, chronic wounds in elderly present a major challenge to the medical and socioeconomic infrastructure of societies. A comprehensive understanding of how the aging innate immune system impacts wound homeostasis is lacking. Here we employed the approach of immune modulation to restore disrupted wound repair in aged mice skin. We found that a short pulse of bacterial lipopolysaccharide (LPS) before wounding markedly accelerate tissue repair in aged mice, which - if non-primed - exhibit a defective epidermal wound closure. LPS priming induces rapid sealing of wounds, immune cell activity, keratinocyte responsiveness and their differentiation towards a newly reconstituted wound epithelium.

Structural elements such as neutrophil extracellular traps (NETs) composed of DNA and membrane protrusions derived from LPS-activated neutrophils and macrophages, respectively, reinforce physical skin barrier in aged wounds. The physical barrier established by LPS-primed innate immune cells subsequently facilitates epithelial tongue migration and adhesion of extracellular matrix (ECM)-producing mesenchymal cells. Collectively, this not only prevents the invasion of pathogens into the restoring skin tissue after injury, but also averts the persistence of low-grade inflammation associated with aged wounds. These findings underscore the benefit of immune cell priming in promoting cellular interactions between innate immune cells and epithelial cells that consequently restores physical skin barrier and promote tissue repair.

Link: https://doi.org/10.1186/s12979-026-00570-y

Programs of scientific research are ever short of funding, and this profoundly steers both the operation of these individual programs, as well as the standards for various fields of research that emerge via consensus and collaboration. Consider that the primary driving force behind most choices in the use of animal models of disease is the matter of reducing cost and time. Artificial models that turn out to have too little a connection to the real condition, or that mislead research in ways that sabotage progress, emerge time and time again because of the imperative to run studies more rapidly and at a lower cost. Young animals with forms of damage or toxicity or genetic disability are used to replicate the phenotypes of diseases that develop slowly in genetic normal old individuals. Assumptions about mechanisms are baked into the animal models. Alzheimer's disease and many cancers are the most prominent examples of conditions in which the well-established models are highly artificial and often questionable in comparison to the real conditions they are mimicking, but these are by no means the only examples.

Today's research materials provide an example of the sort of gap in knowledge that can arise when only young mouse models are used in work on cancer, a predominantly age related condition. Melanoma is a very well studied form cancer, and at this point once of the least threatening given recent advances in immunotherapy. Nonetheless, while the way in which melanoma risk changes with age in humans is well characterized, little investigation has taken place in mice to attempt to understand why this pattern of incidence exists - as that research requires a greater cost in time and funding in order to use old mice. Thus when researchers do in fact find that funding, they tend to discover new information. Melanoma is a relatively well controlled cancer in the grand scheme of things, but consider the many other far worse forms of cancer in which this same story is playing out over the years with different details.

Older Mice May Offer New Insight Into Cancer and Aging

Cancer risk increases with age and is often more aggressive and difficult to treat in older adults. However, fewer than 10% of mouse studies use aged animals, with most relying on mice roughly equivalent to humans in their early 20s. This discrepancy is one potential reason so many cancer drugs that show promise in preclinical models go on to fail in human trials. New research suggests melanoma behaves differently with age. The data showed cancer spread was the lowest in young mice, peaked in middle-aged mice, and declined in very old mice.

Researchers suggest that a key factor involves a specific group of immune cells called gamma delta (γδ) T cells, which act like early warning guards that help prevent cancer from spreading. Young and very old mice had more of these protective immune cells, and their cancer was more likely to stay dormant or spread less. Middle-aged mice had fewer γδ T cells, and their melanoma was far more likely to spread to organs like the lungs and liver. The study also showed that melanoma cells themselves can actively weaken the immune system as animals age. In middle-aged mice, melanoma released certain molecules that shut down or exhaust γδ T cells, allowing previously quiet cancer cells to "wake up" and spread aggressively. Notably, when researchers removed γδ T cells from young and very old mice, melanoma spread increased, suggesting these immune cells normally help keep the cancer in check. By contrast, blocking immune-suppressing signals restored immune protection and reduced cancer spread, but only in middle-aged mice.

Abstract 2072: Role of the aging on the ᵧδ; T-cells in metastatic cutaneous melanoma progression.

Melanoma incidence, metastasis, and mortality are significantly associated with age. Interestingly within the clinic, melanoma incidence is low in young adults, peaks between ages 65-79, and decreases thereafter (79+). This phenomenon has never been studied as pre-clinical studies predominantly focus on young (8-week-old) mouse models. Here, syngeneic melanoma cells have been injected into C57Bl/6 young (8 weeks), aged (12 months) and geriatric (18-24 months) male mice. Spleen, lungs, and liver have been collected to analyze metastasis and immune infiltration by flow cytometry. Histological analysis has been performed to quantify the number of metastases and to determine different immune markers (e.g. CD45, CD8, CD4).

Our data highlighted that middle aged mice had significantly increased γδ T cell infiltration in the metastatic lung and liver relative to young and geriatric mice, which had less metastasis. Based on this, we used a γδ T cell mouse model of depletion coupled with depletion antibodies against gamma delta in young and geriatric mice respectively. Our preliminary data indicated that upon reactivation in middle-aged mice, melanoma cells secreted PROS1, which drives cancer proliferation. Its effects on the immune system within our model have not been studied. We overexpressed PROS1 in melanoma cells, injected them, and analyzed metastasis and γδ T cell infiltration. Our data shows that middle-aged mice have significantly increased lung and liver metastasis relative to young mice. Interestingly, geriatric mice have lower levels of metastasis, replicating what is seen in the clinic.

Age induced decrease of γδ T cell infiltration in middle-aged mice, induced largely by PROS1 secretion from melanoma cells, promotes aggressive metastases. Adoptive treatment with γδ T cells or use of a PROS1 inhibitor may be a viable therapeutic option for metastasis in elderly individuals.

Epigenetic clocks are typically created from bulk epigenetic data from immune cells in blood samples taken from a population of various ages. Machine learning techniques derive algorithmic combinations of DNA methylation status at hundreds or thousands of CpG sites on the genome that tightly correlate with chronological age or mortality risk. There are certainly other ways to go about the task, but this describes most of the earlier and more mainstream clocks. Interestingly, this approach produces clocks that do not appear to be all that sensitive to physical fitness, despite what we know about the correlations between physical fitness and life expectancy. This probably says something interesting about our biochemistry, but we do not know yet know what that interesting thing is.

Physical activity reduces the risk of mortality and age-related chronic diseases, yet its association with biological age measured by DNA methylation (DNAm) clocks remains unclear. This systematic review and meta-analysis aims to evaluate the association between physical activity and biological age measured by DNAm clocks.

We identified 44 studies that were included in a systematic review comprising 145,465 participants with mean ages ranging from 24.1 years to 78.5 years. Across studies, higher levels of physical activity were generally associated with lower DNAm age, although many individual associations did not reach statistical significance. Seven cross-sectional studies contributed to the meta-analysis. Each one standard deviation (SD) higher in metabolic equivalent of tasks (MET)-minutes per week was associated with 0.03 SD lower Horvath epigenetic age acceleration (EAA) and 0.09 SD lower GrimAge EAA. No statistically significant association was observed for Hannum EAA or PhenoAge EAA.

Higher physical activity is significantly associated with lower biological age as measured by Horvath EAA and GrimAge EAA. However, evidence is predominantly from cross-sectional studies, limiting causal inference. Future longitudinal studies and clinical trials using standardised, objectively measured physical activity are warranted to clarify dose-response relationships, and to determine whether physical activity can causally modify ageing trajectories, thereby informing precision strategies for healthy longevity.

Link: https://doi.org/10.1016/j.lanhl.2026.100835

The work noted here might be taken as a companion piece to a recent paper on eusociality as a driver of the evolution of exceptional longevity in a wide variety of clades, not just mammals. Here, researchers take a broad look across mammalian species that exhibit a variety of different type of social organization, and find a correlation with species longevity. While thinking about this, one might also look at the evidence for mating strategies to drive the evolution of longevity; one might think that social organization has a large impact on mating strategy. At root, one might ask how all of these various parameters and their outcomes affect the trade-off between growth and maintenance in individuals; as a rule, species that mature faster can achieve reproductive success more reliably in an uncertain environment, but at the cost of a shorter life span and less opportunities to reproduce over time.

Extrinsic mortality, largely driven by predation, imposes strong selective pressures on ageing and longevity. Body size is perhaps the most important factor: larger mammals generally face fewer predators, allowing them to allocate more resources to maintenance and repair, thereby extending their lifespans. Comparative analyses of bats and marsupials similarly support reduced environmental vulnerability as a driver of longer lifespan. Furthermore, lifespan is correlated with other traits, including age at maturity and parental investment, consistent with the trade-off between energy allocation for reproduction and cellular repair. Increasingly, behavioural factors such as sociality are recognised for their impact on lifespan dynamics, adding another dimension to our understanding of longevity evolution.

Social groups protect their members from predation and starvation. Reduced risk of death from such extrinsic causes is expected to promote the evolution of longer lifespans. Since group-living similarly aids predator avoidance, resource defence, and foraging efficiency, we might expect a positive relationship between group-living and lifespan in comparative analyses. However a broad-scale quantitative study of 253 mammalian species failed to detect this relationship. To investigate this unexpected lack of support, we present a re-analysis of the topic, expanding the sample size to include a greater diversity of mammal species.

We analysed maximum recorded lifespan, body mass, and social organisation data for 1,436 mammal species using Bayesian phylogenetic comparative methods, confirming that group-living and pair-living species exhibit longer lifespans than solitary species after controlling for body mass and phylogeny. Pair-living species showed slightly longer lifespans than group-living species (though credible intervals overlapped), while body mass slopes did not differ substantially among social categories and activity period showed weak associations with lifespan. These results provide independent corroboration of recent findings linking sociality to longevity in mammals and suggest that while group-living may reduce predation risk, pathogen transmission costs in larger groups may constrain longevity benefits. Our findings, based on the largest comparative dataset analysed to date, strengthen the evidence that social organisation is a key factor shaping mammalian life-history evolution alongside body size and ecological adaptations.

Link: https://doi.org/10.1002/ece3.73587

Researchers have established a number of interventions in short-lived species that extend life as a result of degrading the function of a cellular component, usually the mitochondria. Some forms of degraded function induce the cell to increase maintenance activities and otherwise alter its behavior to produce a net benefit to function, resistance to damage, and other line items that combine to reduce the level of age-related dysfunction in tissues and thereby extend life span. Where alterations touch on aspects of the complex processes of gene expression in the cell nucleus, the full effects on cell function are usually unclear. Tinkering with the machineries of gene expression typically has sweeping effects on cellular biochemistry, and it is usually a surprise to find that breaking something in the nucleus yields an increase in life span.

The first step in gene expression is the production of RNA, a step known as transcription. RNA molecules in the cell nucleus are produced by structures that read gene sequences in the genome and assemble the matching RNA piece by piece from the raw materials of nucleotide molecules. An RNA molecule is finalized by giving it a 5` structure at one end and a 3` structure and poly(A) tail of trailing adenine nucleotides at the other. This decoration is managed by a different set of machinery than that responsible for reading and assembling RNA. One of these molecular machines is the Integrator, and in today's open access paper researchers report that degradation of Integrator function results in slowed aging in nematode worms. They believe that this occurs because the chain of cause and consequence spreading out from impaired RNA 3` processing in the cell nucleus leads to mild mitochondrial dysfunction, and thus an improved cell maintenance. Given the breadth of changes, however, this has to be taken as an initial suggestion rather than an answer to the question.

Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing

Identifying strategies to mitigate age-related physiological decline remains a central challenge. During ageing, the transcriptome undergoes extensive remodelling, but how this affects organismal health and lifespan is not well understood. The Integrator complex plays a central role in RNA polymerase II transcription and RNA 3` end processing. Surprisingly, we find that depletion of most Integrator subunits specifically in adults extends lifespan and healthspan in the nematode C. elegans. We show that loss of the catalytic subunit INTS-11 disrupts 3′ end formation of small nuclear and spliced leader RNAs, impairing trans-splicing and promoting outron retention in a subset of transcripts enriched for spliceosomal and nucleocytoplasmic transport genes.

These RNA-processing defects lead to altered levels of endogenous small interfering RNAs (siRNAs), which are required for the longevity and healthspan benefits of INTS-11 depletion. In parallel, outron retention disrupts nuclear-encoded mitochondrial gene expression and protein production, inducing mitochondrial dysfunction and promoting lifespan extension. We also demonstrate that loss of INTS-11 perturbs transcription elongation at genes where Integrator is present at promoters, and that upregulation of enhancer elements within intragenic regions can affect the expression and isoform usage of nearby genes. Together, our findings identify Integrator as a key upstream regulator of non-coding RNA transcription, which in turn impacts protein-coding gene expression and mitochondrial function to shape the ageing process.

All cells release and take up extracellular vesicles. This includes the bacteria present in the body, both the beneficial commensal species resident in various locations such as mouth and gut and the undesirable invasive pathogens. An extracellular vesicle is a lipid membrane wrapped package of molecules; much of the communication that takes place between cells consists of vesicle contents. Here, researchers theorize on the involvement of bacterial vesicles in the development of neurodegenerative conditions, particularly Alzheimer's disease. A body of evidence suggests a connection between infection, particularly persistent infections, and risk of neurodegenerative conditions. The underlying mechanisms remain a topic of ongoing research, with the side-effects of chronic inflammatory reactions of the immune system as one point of focus, but it seems likely that bacterial signaling has other, less immediately evident consequences.

Alzheimer's disease is a complex neurodegenerative condition characterized by progressive cognitive decline, neuroinflammation, metabolic dysregulation, and abnormal protein deposition. While genetic factors and amyloid-beta-focused hypotheses have been extensively investigated, they fail to fully account for the prolonged prodromal phase or the early susceptibility of olfactory and limbic regions. Emerging evidence suggests chronic peripheral and mucosal infections may influence disease risk; however, mechanisms by which microbial activity outside the central nervous system contributes to persistent neuropathology remain poorly understood.

This review explores the emerging concept that bacterial outer membrane vesicles act as mobile, lipid-rich vectors linking peripheral microbial reservoirs to neuroimmune and metabolic dysfunction in the aging brain. We discuss evidence suggesting vesicles originating from oral, olfactory, and upper airway niches can access the central nervous system via vascular routes and direct neural pathways, including olfactory and trigeminal nerves, where they influence glial and endothelial cell function.

We also propose the Accumulative Vesicle Load Hypothesis, which describes how cumulative lifetime exposure to bacterial vesicles shapes disease onset, anatomical vulnerability, and progression, and incorporates components of other hypotheses proposed for Alzheimer's disease. This offers a system-level perspective for early diagnosis and upstream therapeutic strategies, including minimally invasive vesicle profiling in nasal fluid, saliva, blood, and cerebrospinal fluid. This work is a conceptual review that summarizes current evidence in a hierarchically organized manner and proposes a testable model; it does not assert causality where direct human evidence is currently limited.

Link: https://doi.org/10.3390/cells15080690

The study noted here is one of many to show that the effects of lifestyle choice and environmental exposure far outweigh the effects of genetic variants when it comes to late life survival. Yes, there are a few very rare genetic variants and mutations that produce effect sizes of at least several years, but for the vast majority of individuals mortality risk in old age is overwhelmingly determined by lifestyle and environment. Did you stay relatively thin and relatively fit? Were you unlucky in your exposure to infectious pathogens, particularly persistent infections? Did you self sabotage by smoking? And so forth.

In this prospective cohort study of 1,545 participants aged 80 years and older from the China Hainan Centenarian Cohort Study, we investigated the independent and joint associations of modifiable risk factors and genetic predisposition with life expectancy. A weighted modifiable risk factor score (MRFS) based on 11 factors and a polygenic risk score (PRS) for longevity were constructed.

A favorable modifiable risk factor profile (low MRFS) was associated with a 40.7% lower death risk (hazard ratio, HR = 0.593) compared with high MRFS. Genetic predisposition to longer lifespan (high PRS) conferred a 13.0% lower risk (HR = 0.870). Participants with both low MRFS and high PRS had the lowest mortality (HR = 0.544), with a borderline significant multiplicative interaction. Life expectancy gains from a low MRFS were more pronounced in those with high PRS (6.92 years at age 80) than low PRS (5.35 years).

In conclusion, among the oldest-old Han Chinese, favorable modifiable risk profiles and genetic predisposition independently and jointly contribute to substantially longer life expectancy. Importantly, an unfavorable modifiable profile may largely negate genetic longevity benefits, emphasizing the critical role of managing these factors even in advanced age and irrespective of genetic inheritance.

Link: https://doi.org/10.1038/s41514-026-00393-7

Researchers have in recent years undertaken considerable effort to demonstrate that the biochemistry of obesity overlaps with the biochemistry of Alzheimer's disease. Setting aside motivations relating to linking two large pools of research funding (obesity researchers would love to be able to write Alzheimer's grants, and vice versa), it is certainly possible to point to a great many interesting findings in this context: circulating choline; microglial lipid accumulation; changes in extracellular vesicle profiles; links between visceral fat specifically and protein aggregation in the brain; the commonality of insulin resistance to both conditions; and so forth. From a cellular biochemistry point of view, it looks quite compelling.

Inconveniently, however, the epidemiological data from large study populations just doesn't support as direct a role for obesity in Alzheimer's risk as it does for, say, type 2 diabetes. Type 2 diabetes is very, very clearly a consequence of being overweight for the vast majority of patients, and losing that weight makes the condition go away. GLP-1 receptor agonists produce involuntary calorie restriction and weight loss, and have positive effects on patients with type 2 diabetes. So does voluntary calorie restriction achieved without the use of fancy modern drugs. GLP-1 receptor agonists do not slow the progression of Alzheimer's disease, however. To my eyes the question is more one of why so many obese people do not go on to develop Alzheimer's disease, particularly given the existence of so many plausible connecting mechanisms evaluated by the research community in recent years.

From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease

The number of individuals aged 65 and older will grow significantly over the next few years. This demographic shift is expected to increase the economic burden on society and, importantly, to elevate the prevalence of age-associated disorders such as Alzheimer's disease (AD), a neurodegenerative condition characterized by memory impairment and progressive cognitive decline. According to estimates from the Alzheimer's Society, 11% of individuals over the age of 65 in the U.S. are diagnosed with AD. At the same time, obesity - a chronic condition characterized by excessive fat accumulation and a major driver of metabolic disorders such as type 2 diabetes, liver disease, and cardiovascular disease - has risen markedly across the lifespan. Notably, its prevalence among older adults nearly doubled from 22% to 40% between 1988 and 2018.

Growing evidence indicates that obesity and AD are mechanistically linked through overlapping metabolic disturbances that contribute to structural and functional alterations in the brain and increase the risk of cognitive decline. Based on the evidence presented in this review, AD and obesity share convergent metabolic disturbances that often emerge early, preceding overt clinical manifestations. Key shared mechanisms include mitochondrial dysfunction, with coordinated impairments in the TCA cycle and electron transport chain leading to reduced adenosine triphosphate (ATP) production and excessive reactive oxygen species (ROS) generation; oxidative stress, which damages macromolecules and promotes pathological cascades such as amyloid-β aggregation and tau phosphorylation in the brain; dysregulation of adipokine signaling in adipose tissue; and systemic metabolic inflammation, linking peripheral energy imbalance to neurodegenerative vulnerability.

Given the concurrent rise in both conditions, elucidating their shared metabolic mechanisms has become increasingly important. This review focuses on the interplay between mitochondrial dysfunction, oxidative stress, and lipid dysregulation as converging mechanisms that connect peripheral metabolic imbalance to neurodegeneration. Furthermore, because adipose tissue functions as an endocrine organ, these systemic alterations can influence central nervous system (CNS) function. Accordingly, this review examines how adipose tissue dysfunction influences neurodegeneration, emphasizing the role of metabolic health in shaping cognitive decline.

Cardiovascular disease and cancer receive much of the public and scientific attention devotes to causes of human mortality, but it might surprise many people to know just how prominent respiratory conditions are in the list of causes of death. The various forms of damage and dysfunction accompanying aging predispose the lungs to all of the common fatal respiratory conditions, and incidence rates increase with age, even when the cause of disease is external, such as respiratory infections. Here, researchers take a tour of the present state of research into the aging of the respiratory system. Unlike past years, such a review now usually contains a discussion on the development of means to target mechanisms of aging and their potential relevance to the treatment of age-related conditions. It is a welcome change.

The respiratory system undergoes substantial ageing-related changes. The loss of function comes with a reduced adaptability to the ever-changing demands of the body, and more importantly, to an increase in disease states, such as sleep apnoea. The reduction in defences such as mucociliary clearance, coughing, and macrophage function causes increased respiratory infections. A reduction in autophagy, alongside replicative senescence and with chronic inflammation, contributes to age-related diseases such as COPD and pulmonary fibrosis. Sequential spatial analysis of biopsies or resection samples in individuals with airway disease will reveal altered structural and immune cell interactions associated with pathophysiological changes.

Much of what we know about lung ageing comes from the study of ageing in other systems or later-onset diseases, rather than a direct assessment from lung tissue sampled across all time periods of the life course from healthy individuals. The inference from other organ systems is particularly evident in the epigenetics and comes mainly from studies on blood cells or individuals with respiratory disease, rather than from studies on healthy lung tissue. In parallel, much of the genetic and molecular mechanisms are drawn from studies using tissue from individuals with COPD. Although COPD might represent a form of accelerated lung ageing, whether the mechanisms that underlie COPD are entirely replicative of normative ageing of the lung remains uncertain and cannot be elucidated without further study. Furthermore, a large proportion of our current understanding of lung ageing comes from animal models rather than human populations, and several areas of great importance remain almost completely unexplored. For example, research on the ageing of the mucociliary system in humans is restricted to only three studies, with one dating back to 1979.

Advances in genetic studies such as GWAS and whole-genome sequencing have been revolutionary in understanding the complexities of molecular alterations associated with diseases, and in uncovering new molecular targets. However, distinguishing which associations arise from direct effects of biological ageing on an organ system and which arise indirectly through other ageing-related pathologies is difficult. For example, GWAS on lung function found associations with genes that are related to confounding factors such as cancer and hypertension and genes related to environmental stressors, in addition to biological factors such as adult body size and BMI; whether these associations are genuine or arise due to overmatching remains to be elucidated.

Drugs that target the ageing process (senotherapies) could be of clinical value in treating respiratory diseases. Senotherapies include drugs that reduce the development of cellular senescence (senomorphics) and those that result in removal of senescent cells from lung tissue (senolytics). Several senotherapies have shown promising results in experimental models of age-related lung diseases, but only few clinical studies have been reported to date. Clinical studies of geroprotective therapies in lung diseases are challenging because the slow progression in these diseases is difficult to measure in clinical trials. However, changes in markers of senescence, such as p16INK4a and p21CIP1, and SASP mediators, are feasible. There is a need to know clinical biomarkers of lung ageing to identify the most suitable individuals for clinical trials and to monitor anti-ageing interventions.

Link: https://doi.org/10.1016/j.lanhl.2026.100842

Researchers continue to identify compounds that marginally affect aging in short-lived species. The Interventions Testing Program at the NIA continues to show that most of these have no effect on life span when rigorously assessed in mice. The few points of comparison we do have between mice and humans suggest that effects on life span in mice resulting from manipulation of metabolism become much smaller in humans. Long lived species do not have the same flexibility in metabolic determination of the pace of aging as exists in short lived species. This entire branch of longevity science, focused on exercise mimetics, calorie restriction mimetics, and other similar approaches, should not be expected to deliver meaningful results to human medicine in terms of years of life gained. Nonetheless, these efforts persist.

Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.

This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction. We analyzed age-stratified muscle transcriptome data from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. Subsequently, myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction.

Celastrol, a bioactive triterpenoid, was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6%, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.

Link: https://doi.org/10.1016/j.jare.2026.01.079

Evidence suggests that one of the major components of muscle aging is degeneration of neuromuscular junctions, the structures linking the nervous system to muscle fibers. Absent the signaling from nervous system to muscle, muscles will degenerate. That signaling is necessary for muscle tissue maintenance and growth. Thus a loss of function in neuromuscular junctions will contribute to the characteristic age-related loss of muscle mass and strength that leads inexorably to the line in the sand that marks the conditions known as sarcopenia and dynapenia. Can the degeneration of neuromuscular junctions be reversed to any great degree? Today's open access paper provides animal study evidence for photobiomodulation to achieve this goal, though it must be said that the broader context surrounding the widespread clinical use of photobiomodulation suggests caution in taking this data at face value.

Photobiomodulation as practiced by clinicians largely means low-level red laser light therapy. There is some debate over the degree to which red wavelengths penetrate tissues and may thus still be as beneficial in larger animals as it is assessed to be in smaller animals. This form of treatment is thought to improve mitochondrial function, though it is still a mystery as to how exactly this works. Sadly, while researchers can and do publish interesting mechanistic papers on what might be going on under the hood, we largely know the bounds of the possible for photobiomodulation. People undergo this sort of therapy in large numbers, and have done so for a long time. It simply isn't possible in this sort of an environment to hide very large effect sizes on, say, muscle function. One has to assume that effects on health and tissue function in humans, while quite interesting, are small to vanishing in the practical sense.

Ultrastructural Signs of High Functional Activity of Neuromuscular Synapses in Aging Rats After Photobiomodulation

Aging is characterized by progressive degeneration of neuromuscular junctions (NMJs), which significantly contributes to muscle weakness and the development of sarcopenia. Photobiomodulation (PBM), a non-invasive therapeutic method based on the use of low-intensity light, has shown promising results in mitigating muscle degeneration in both experimental and clinical studies. The aim of this study was to evaluate the ultrastructural effects of photobiomodulation on neuromuscular junctions and skeletal muscle fibers in the vastus lateralis muscle of aged rats using light and transmission electron microscopy. Male Wistar rats (18 months old, body weight 650-800 grams, n = 10) were subjected to photobiomodulation of the right vastus lateralis muscle (650 nm wavelength, 6 J/cm^2, four consecutive daily sessions of 3 min each). The contralateral left limb served as an untreated control.

Muscle samples were analyzed by light and transmission electron microscopy. Histological examination revealed typical age-related changes in control muscles, including variability in muscle fiber diameter, centrally located nuclei, and an increased volume of connective tissue. Ultrastructural analysis confirmed signs of skeletal muscle aging, such as myofibril fragmentation, sarcomere disorganization, lipofuscin accumulation, and tubular aggregate formation. Morphometric analysis of neuromuscular junctions after photobiomodulation showed an increase in the number of active zones on the presynaptic membrane, elongation of the postsynaptic membrane, and a reduction in the width of the synaptic cleft. In addition, mitochondrial hyperplasia was observed in presynaptic terminals, while the total number of synaptic vesicles decreased.

These findings indicate a compensatory reorganization of neuromuscular junctions and suggest that photobiomodulation can enhance their functional activity in aged skeletal muscle.

Sleep apnea is correlated with cardiovascular disease, among other conditions. It induces a state of hypoxia in tissues when regular breathing is interrupted. Here, researchers induce a similar degree, duration, and intermittency of hypoxia in mice to examine the effects it has on vascular tissue. They find that this sort of hypoxia exposure increases the burden of senescent cells in the vasculature, alongside worsened measures of cardiovascular dysfunction. The researchers further show that clearing senescent cells from the vasculature improves cardiovascular function in the mice exposed to intermittent hypoxia, suggesting that this strategy should be tried in human patients.

Obstructive Sleep Apnea (OSA) is a pervasive cardiovascular risk factor linked to accelerated aging and systemic inflammation. Intermittent hypoxia (IH), a hallmark of OSA, induces cardiovascular decline, yet the underlying tissue-specific and systemic epigenetic mechanisms and the role of cellular senescence in the pathophysiology of OSA and associated cardiovascular disease (CVD) remain poorly understood. Here, C57BL/6J male mice were exposed to IH or room air (RA) for durations ranging from 7 to 210 days. Genome-wide DNA methylation profiling was conducted on left cardiac ventricle and peripheral blood mononuclear cells (PBMCs) samples. Epigenetic age acceleration (EAA) was calculated using a multi-tissue epigenetic clock. Furthermore, p16-reporter and targeted ablation mouse models were utilized to assess the role of p16Ink4a-mediated senescence in IH-induced vascular dysfunction.

Chronic IH exposures significantly increased systolic and diastolic blood pressure and altered endothelial function. Both left cardiac ventricle and PBMCs exhibited an early peak in EAA at 7 days of exposure, differing in the trajectory in longer exposures. Pathway analysis linked these epigenetic changes to cardiac dysfunction and cellular senescence, specifically highlighting Cdkn2a gene, which encodes the p16 protein, a marker of cellular senescence. Immunofluorescence confirmed increased p16 expression in aortic endothelial cells following IH. Remarkably, systemic ablation of p16-expressing cells reversed IH-induced hypertension and restored coronary flow reserve to control levels.

Our findings provide initial evidence that p16Ink4a-mediated cellular senescence is a primary driver of OSA-induced cardiovascular morbidity and that targeting the senescent endothelium can revert vascular dysfunction, thereby establishing a novel mechanistic framework for cellular senescence as a therapeutic target in OSA.

Link: https://doi.org/10.21203/rs.3.rs-9371471/v1

Researchers have been arguing for some years that microgravity exposure as a model of aging in order to assess potential means of treating aging as a medical condition. The eternal challenge for the scientific community is that funding is scarce, time is money, and it takes a long time for animals to become old. The use of alternative forms of damage and dysfunction that are faster to induce is widespread, and arguably a problem in that these models are not in fact aging and thus may lead researchers to incorrect conclusions. Will microgravity be any better in this respect? Only time will tell.

Spaceflight and microgravity profoundly affect human physiology and have been proposed to recapitulate key features of biological aging, yet the underlying mechanisms remain incompletely understood. Here, we performed whole-genome transcriptomic profiling to define immune cell alterations associated with both natural aging and simulated microgravity. Leveraging the longitudinal nature of the Stanford 1,000 Immunomes Project, we compared peripheral blood mononuclear cells (PBMCs) exposed to rotating wall vessel bioreactor with matched samples collected up to 9 years later from the same individuals. We quantified changes across aging hallmarks, molecular pathways, gene modules, cellular energetics, disease risk, and vaccine-response signatures.

Microgravity-induced transcriptional closely tracked subject-level aging trajectories spanning across disease risk domains including those affecting the metabolic, musculoskeletal, and circulatory systems, and multiple aging hallmarks involving nutrient sensing, intrinsic capacity, chronic inflammation, proteostasis, cellular senescence, and metabolic regulation. Independent validation using Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH) profiling confirmed these observed metabolic adaptations and revealed reduced mitochondrial dependence with minimal compensatory glucose dependence across immune cell subsets, features that strongly parallel aging biology. Consistent with previous findings, longitudinal changes indicated that close of 1/3 of participants do not follow population trajectories but these can be partly predicted with simulated microgravity exposure.

Together, this within-donor framework establishes simulated microgravity as a scalable and experimentally tractable platform to model aspects of biological aging in humans and accelerating the prioritization of candidate countermeasures for spaceflight and aging on Earth.

Link: https://doi.org/10.64898/2026.03.03.709404

Partial cell reprogramming as a basis for rejuvenation therapies is an area of great interest in the research and development communities. It has received greater funding in recent years than any other part of the field, with the founding of Altos Labs and a number of other unusually well-funded biotech companies. Reprogramming involves expression of some or all of the Yamanaka factors. Full reprogramming of a somatic cell slowly transforms that cell into a pluripotent stem cell, a recreation of the process of early embryonic development. Partial reprogramming for a shorter period of time only restores youthful epigenetic patterns of gene expression without changing cell state, and this, if it can be made to work in a living organism, is the basis for potential rejuvenation therapies.

The challenges of partial reprogramming, at least until people find a viable small molecule approach that seems safe enough to develop as a therapy, are the challenges of gene therapy, which is to say near entirely a matter of how to deliver the therapy in way that sufficiently controls degree and duration of gene expression. A given tissue can be made up of many different cell types that all need different approaches to partial reprogramming. Current gene therapy vectors struggle with effective delivery to many tissue types. Control over location and duration of expression is thus a major area of innovation in the field, a problem to be solved piece by piece. Today's open access paper is an interesting example of a novel approach to induced expression of a gene therapy, in that the induction occurs via pulsed electromagnetic fields rather than use of small molecules.

Scientists Prolong the Life of Mice With Invisible Energy Fields, New Study Shows

Researchers have established a method for inducing cellular reprogramming with electromagnetic fields (EMFs). Complete cellular reprogramming can cause cancer and early mortality, so the researchers implemented cyclic cellular reprogramming. To do so, they genetically engineered aged mice to activate cellular reprogramming genes in response to EMFs. They applied the EMFs cyclically to induce cyclic cellular reprogramming. The researchers then assessed the survival of the mice up until they were 108-weeks-old, which is roughly equivalent to the human age of 70.

The researchers found that over 75% of the reprogrammed mice lived to 108-weeks-old. Only about 60% of untreated mice survived until 108-weeks-old. To be thorough, the researchers also monitored normal-aged mice that were not genetically engineered. The survival rate for these mice was even lower, at about 50%. These findings suggest that EMF-induced cyclic cellular reprogramming can prolong the lifespan of aged mice. The researchers also found that EMF treatment countered certain aspects of aging in the engineered mice. The aorta, which thickens with age, was restored to normal thickness. Additionally, the treatment improved skin thickness and liver cell numbers, which decline with age, and it rejuvenated the spleen and kidneys. There were also signs of reduced senescent cells, which are cells that can accumulate with age and promote inflammation and tissue damage. The mice also become visibly younger, with less of a hunched back, better grooming, and a reduction in gray hair.

They started by asking a simple question: which genes naturally respond to EMFs? In mouse brain tissue, they identified one gene in particular - called Lgr4 - that could be activated and deactivated quickly. They then focused on the gene's promoter, a stretch of DNA that modulates when a gene turns on or off. From this region, they chose a specific sequence and named it Ei, short for "EMF-inducible DNA element." However, this did not explain how the EMFs actually trigger this switch. To find out, the researchers looked at what was happening inside cells. Their experiments suggested that EMFs interact with a protein called Cyb5b, setting off a chain reaction that releases calcium ions (Ca2+). Remarkably, the released Ca2+ oscillated at a frequency that activates the Ei switch.

Electromagnetic field-inducible in vivo gene switch for remote spatiotemporal control of gene expression

Gaining precise control of gene expression is crucial in biomedical applications. However, spatiotemporal precision remains challenging. Here, we present a remotely controlled in vivo gene switch responsive to electromagnetic fields (EMFs) that enables precise spatiotemporal activation of target genes. We uncovered the EMF-inducible gene switch activation mechanism via a CRISPR-Cas9 screen, identifying cytochrome b5 type B (Cyb5b) as an essential mediator likely acting as an EMF sensor. The EMF-inducible gene switch was activated by rhythmic oscillatory calcium dynamics rather than generic calcium influx, defining a precisely tuned and bio-orthogonal induction mechanism.

Functionally, EMF activation of the Oct4-Sox2-Klf4 (OSK) cassette induced in vivo partial reprogramming in aged mice, conditional expression of human mutant amyloid precursor protein (APP) for Alzheimer's disease (AD) modeling recapitulated pathological features, and EMF-mediated Tph2 expression restored serotonergic activity and ameliorated depressive-like behaviors in Tph2-mutant depression mice. Overall, a remotely controlled EMF-inducible gene switch represents a versatile and effective biomedical platform.

Our perception of the passage of past time appears to change with age. Studies suggest that when looking back at recent personal history in later life time appears to have passed more rapidly than it did in youth. One potential explanation for this is that people recall less of what happened in later life than they do in earlier life, or that the storage or retrieval of experiential memory becomes otherwise more compressed. Studies of recall suggest that we remember something like 2% of our experience; we're all ghosts of ourselves in that sense. Does this tiny fraction become even smaller with advancing age, and if so, why does this occur? The author of this paper offers a testable hypothesis connected to age-related declines in energy metabolism in the brain.

A year of chronological time is typically assumed to represent comparable experiential encoding across individuals and age groups. This assumption is rarely examined. Yet subjective reports across adulthood consistently suggest that extended periods - months and years - are often remembered as having "passed quickly," particularly in later life. Importantly, this phenomenon does not imply a change in objective time but reflects differences in how time is encoded and reconstructed. Time-perception research distinguishes moment-to-moment passage-of-time judgments from retrospective duration judgments, and evidence indicates that long-interval judgments rely heavily on memory structure rather than internal clock mechanisms.

I introduce the concept of experienced longevity, defined as the amount of lived time subjectively contained within a fixed chronological interval. Within the present framework, this construct is operationalized through experiential density, defined as the number and distinctiveness of event units segmented, encoded, and later retrievable per unit of chronological time. I propose that age-related biological changes - particularly declines in mitochondrial efficiency, increased vascular stiffness, and reduced nitric oxide-mediated neurovascular coupling - may constrain the brain's capacity for high-fidelity updating during ongoing experience. By limiting event segmentation and episodic distinctiveness, these neuroenergetic constraints may increase the probability of retrospective temporal compression.

I term this framework the Neuroenergetic Constraint Model of experienced longevity. In this framework, experienced longevity is the broader aging-related construct, experiential density is the proximate memory-level property through which it is expressed, and retrospective temporal compression is the downstream subjective outcome expected when that density is reduced.

Link: https://doi.org/10.3389/fnagi.2026.1815030

Greenland sharks can live for at least a few centuries, and are thus of interest in the study of the comparative biology of aging. Here, researchers take a first step in examining the cellular biochemistry of aging in this species. As a rule, aquatic species are less well investigated in this regard than is the case for land animals, and most land animals are less well investigated than mammals. One never knows what might be discovered, of course, though it remains the case that efforts to bring beneficial mechanisms from a long-lived species into a short-lived species are in their infancy. Developing therapies based on the biochemistry of a long-lived species has yet to happen, so it is hard to predict just how great a utility this research will provide over time.

The Greenland shark (Somniosus microcephalus), with a lifespan estimated around 300 years, represents a unique model for studying vertebrate longevity. Here, we characterize its cardiac aging profile and compare it with two other species: the deep-sea shark Etmopterus spinax and the short-lived teleost Nothobranchius furzeri.

Histological analysis revealed extensive interstitial and perivascular fibrosis throughout the ventricular myocardium of S. microcephalus, affecting both compact and spongy layers of both sexes. This fibrotic pattern was absent in E. spinax and N. furzeri, suggesting it is a specific feature of S. microcephalus. We also observed extreme lipofuscin accumulation within cardiomyocytes of S. microcephalus, which correlates at the ultrastructural level with the abundance of damaged mitochondria and the presence of strikingly enlarged lysosomes filled with electron-dense material of likely mitochondrial origin. Additionally, in the myocardium of S. microcephalus we found abundant deposition of the oxidative stress marker 3-nitrotyrosine.

Remarkably, despite showing multiple canonical markers of aging such as fibrosis, lipofuscin accumulation, and oxidative stress, S. microcephalus individuals appeared healthy and physiologically uncompromised at the time of capture. These findings suggest that S. microcephalus has evolved resilience to molecular and tissue-level aging signs and hallmarks, supporting sustained cardiac function over centuries and offering new insights into the mechanisms of extreme vertebrate longevity.

Link: https://doi.org/10.1111/acel.70505

The immune system becomes dysfunctional with age. On the one hand it becomes overly active and inflammatory, a state known as inflammaging. Many of the forms of cell and tissue damage characteristic of aging can provoke the immune system into an inflammatory response. One example is the increasingly well studied mislocalization of mitochondrial DNA and nuclear DNA fragments within the cell. This mislocalized DNA triggers sensors that evolved to detect viruses and bacteria, leading to cells alerting the immune system with inflammatory signaling. When that mislocalized DNA is a constant feature of a sizable population of dysfunctional cells, the consequent inflammatory signaling never ceases. Chronic unresolved inflammation alters cell behavior for the worse, and is damaging to tissue structure and function.

While constantly on alert, the aged immune system also becomes less capable, the state known as immunosenescence. It falters in its vital tasks of defense against infectious pathogens, maintenance of tissues, and destruction of senescent and potentially cancerous cells. The immune system becomes increasing populated by exhausted, senescent, and malfunctioning immune cells. In the brain, specialized populations of immune cells such as microglia are vital to the ongoing function, maintenance, and change of synaptic connections between neurons, and these tasks are also impaired by immune aging. Thus the complex aging of the immune system contributes to the onset and progression of neurodegeneration in a range of ways beyond the obvious issues of chronic inflammation and incapacity, as researchers note in today's open access paper.

Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications

mmunosenescence, together with chronic low-grade inflammation known as inflammaging, reflects the age-associated decline in immune competence, characterized by coordinated functional, structural, and metabolic alterations rather than a sudden failure. These changes include remodeling of lymphoid tissues, shifts in immune cell composition and dysregulation of immune responses, ultimately reducing the ability to respond to novel pathogens. As a consequence, older adults are more susceptible to infections, autoimmunity, cancer and neurodegenerative diseases (NDDs). NDDs represent a major challenge of population aging due to their rising prevalence, inter-individual variability and the lack of disease-modifying therapies. These disorders are characterized by the gradual loss of neurons, which progressively impairs motor, sensory, and cognitive functions.

Growing evidence suggests that immunosenescence and inflammaging are not merely secondary consequences of neurodegeneration but actively contribute to disease susceptibility, progression and therapeutic resistance. Systemic immune aging and immune dysfunction within the central nervous system (CNS) converge to establish a persistent pro-inflammatory milieu that may disrupt neuronal homeostasis and contribute to neurodegeneration. Emerging data also indicate that age-related alterations in peripheral immunity can influence neuroimmune crosstalk and may modulate disease onset and progression.

Despite compelling evidence that immune aging is a key driver of neurodegenerative diseases, several conceptual and translational challenges remain. A major limitation is the lack of validated, disease-relevant biomarkers that reliably capture immunosenescence and inflammaging in humans. Immune aging is a multidimensional process encompassing cellular senescence, altered immune repertoire diversity, metabolic dysfunction and chronic inflammatory signaling, yet most clinical studies rely on isolated markers or systemic inflammatory readouts.

Another critical challenge lies in bridging mechanistic insights from basic immunology and neurobiology with clinical trial design. Preclinical models have convincingly demonstrated that immunosenescence and inflammaging actively shape glial dysfunction, blood-brain barrier integrity, and neuronal vulnerability. However, most clinical interventions are initiated at symptomatic stages, long after immune-driven neuroinflammatory loops are established. This temporal mismatch likely contributes to the limited efficacy of immune-modulating and senescence-targeting therapies in human neurodegenerative diseases. Translational strategies must therefore prioritize early intervention windows, stratification of patients by immune-aging phenotypes, and a clearer distinction between systemic and CNS-compartment-specific immune dysfunction.

Glycation arises from the interaction of sugars with proteins, decorating proteins with additional structures that alter their function. Advanced glycation endproducts (AGEs) are a broad class of glycated proteins. The presence of AGEs is a form of stress on cells and systems in the body; some forms drive chronic inflammation through interaction with the receptor for AGEs (RAGE), while other forms alter the structural properties of the extracellular matrix by cross-linking collagen and other molecules to restrict their motion. Relatively little work has taken place on ways to address the problem of excessive AGEs in aging and age-related disease, unfortunately. Compared to more popular topics in the life sciences, the study of AGEs, and particularly their interactions with the extracellular matrix, remains underfunded and gives rise to little in the way of efforts to produce therapies to tackle this aspect of aging.

Biological molecules seldom act alone. Within the crowded environment of a cell, proteins, lipids, and nucleic acids are constantly surrounded by sugars and metabolites that test their stability and shape. Among these interactions, glycation stands out as a subtle yet far-reaching reaction, linking the routine chemistry of metabolism to the gradual story of molecular aging. Often described as the Maillard reaction, glycation is a spontaneous nonenzymatic process in which simple sugars or their reactive derivatives attach covalently to amino acid residues such as lysine, arginine, and cysteine. The resulting adducts evolve into Amadori compounds and eventually into advanced glycation end products (AGEs), which alter protein conformation, solubility, and biological activity.

In living systems, glycation proceeds slowly but accelerates with age, becoming a hallmark of molecular aging. Beyond structural damage, AGEs act as signaling molecules by binding to the receptor for advanced glycation end products (RAGE). This interaction triggers oxidative stress, inflammation, and tissue remodeling that contribute to chronic disease. Clinically, glycation serves as both a biomarker and a therapeutic target. Measurements such as glycated hemoglobin and glycated albumin provide indicators of metabolic control, while pharmacological and nutritional strategies aim to limit AGE formation, disrupt crosslinks, or block receptor-mediated signaling

This review synthesizes the molecular pathways of AGE formation, their structural diversity, and the biological factors influencing glycation kinetics. Advances in analytical detection methods - including fluorescence spectroscopy, LC-MS/MS, and immunochemical approaches - are highlighted for their role in monitoring AGE accumulation. Particular attention is given to the contribution of glycation to diabetes, cardiovascular disease, neurodegeneration, and cancer, alongside emerging therapeutic strategies to limit AGE formation or block AGE-RAGE signaling. Glycation thus represents a central mechanism in human disease pathogenesis and an emerging therapeutic frontier.

Link: https://doi.org/10.3390/diseases14040137

Stem cells support tissues by generating a supply of daughter somatic cells to replace losses. A broad body of evidence points to reduced muscle stem cell activity as a major contributing cause of age-related loss of muscle mass and strength. Other evidence suggests that this stem cell population remains capable; when old muscle stem cells are removed from the aged tissue environment for assessment, they appear to be as capable as young muscle stem cells. Researchers are now interested in establishing how an aged environment interacts with muscle stem cells to reduce their activity, with an eye to developing therapies to interfere in specific mechanisms as they are uncovered.

Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes.

Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.

Link: https://doi.org/10.64898/2026.04.10.717808

The collective influence on aging of insulin, insulin-like growth factor (IGF-1), growth hormone, and the receptors for these signal molecules is well studied. It is arguably the most well studied area of cellular biochemistry and metabolism in the context of aging, a central set of mechanisms that regulate the evolved trade-off between growth and maintenance, and which is strongly influenced by the equally well studied intervention of calorie restriction. Numerous animal studies have demonstrated that interfering in various specific parts of this collection of signaling processes is capable of at least modestly slowing aging. In the case of the growth hormone receptor, genetic engineering to cause life-long loss of function produced what remain the longest lived mouse lineages to be generated in the laboratory. These dwarf mice live up to 70% longer than unmodified peers.

Humans with Laron syndrome exhibit essentially the same loss of function and dwarfism, but while they may prove to be more resistant to some age-related diseases, they unfortunately do not exhibit a sizable increase in life span. The same is true for the practice of calorie restriction; humans may gain a few years, but clearly not the 40% extension of life span that has been observed in mouse studies. The evolution of mechanisms relating to growth, maintenance, and availability of food has led to a great plasticity of life span in short-lived species, but not in long-lived species. The health benefits resulting from the practice of calorie restriction in humans are considerable relative to what can be achieved using near all existing forms of medicine, but fall far short of our aspirations for the future.

Nonetheless, the development of calorie restriction mimetic drugs is a major focus in the research and development communities, an attempt to indirectly interfere in the regulation of growth versus maintenance by provoking some of the same reactions as take place in an environment of a reduced calorie intake. Another area of interest is the development of drugs that interfere more directly with the IGF-1 signaling involved in regulating growth versus maintenance. Today's open access paper is an example of a proof of concept study aimed at inhibition of the IGF-1 receptor, using drug candidates that would not be suitable for further development due to their side-effect profiles. They nonetheless produce a modest slowing of aging in mice.

Small-molecule IGF1R inhibitors extend healthspan in a mouse model

Antagonistic pleiotropy of the IGF-1 signaling cascade is well recognized, as it promotes growth and development at younger ages and delays aging later in life. The goal of this study is to test in a mouse longevity experiment whether orally delivered small-molecule IGF1R inhibitors have promise as an anti-aging therapy. C57BL/6 mice (25 male and 25 female mice per treatment) were treated with selective IGF1R inhibitors, picropodophyllin (PPP) or 5-[3-(phenylmethoxy)phenyl]-7-[trans-3-(1-pyrrolidinylmethyl)cyclobutyl]-7H-pyrrolo[3-d]pyrimidin-4-amine (NVP-ADW742), via powdered diets starting at 13 months of age, and physiological and behavioral parameters, as well as survival, were assessed.

Both compounds protected both sexes from short-term memory decline; reduced systolic blood pressure in males and pulse rate in both sexes; rescued declining glucose tolerance in males; and abolished grey hair development, reduced frailty, and protected against decline in grip strength in female mice. There were no sex differences in survival curves within groups. No significant differences between groups were observed in the Kaplan-Meier analysis of survival. However, the survival curve in the NVP-ADW742 group was "squarer" than in controls, indicating a 93-day longer healthspan. PPP treatment was associated with toxicity (gastrointestinal bleeding). Additional analysis of the drug likeness of NVP-ADW742 demonstrated potential cardiotoxicity and brain bioaccumulation.

To conclude, small-molecule IGF1R inhibitors hold promise as a therapy that may improve human health span and lifespan; however, both molecules tested in this study have side effects that may outweigh their anti-aging effects.

Naked mole-rats live very much longer than other similarly sized rodents, and exhibit very little age-related decline until very late life. Researchers use this species as a point of comparison to attempt to better understand mechanisms of aging that might be targeted in mice and humans. Here, for example, the focus is on naked mole-rat skin structure. As is the case for other organs, old naked mole-rat skin doesn't exhibit the evident signs of aging observed in old mice and humans. Why is this the case? A first step is to catalog the structural and biochemical differences as best possible; given a reasonably comprehensive catalog, deeper investigations can then proceed.

Naked mole-rats are extremely long-lived rodents with a lifespan of up to 40 years, during which cellular and tissue aging is rarely observed. In this study, we analyzed the extracellular matrix (ECM) of naked mole-rat skin at the molecular level to elucidate the molecules involved in anti-aging and their localization. Raman spectroscopy and Fourier transform infrared spectroscopy were applied to investigate the hierarchical structure of the ECM, showing that, whereas the epidermis of aged mice had thinned, the epidermis of naked mole-rats became thickened and hyaluronic acid (HA) was distributed under the basement membrane. Furthermore, naked mole-rat skin had a regular skin texture and flexibility, allowing the maintenance of a youthful appearance.

Hyaluronic acid in naked mole-rats characteristically exists as clusters (chain HA) in skin tissue, where it is thought to permit moisture retention and maintain elasticity, contributing to the skin's youthful appearance. These results suggested that not only the density of ECM but also its spatial distribution and topographic properties are important for skin anti-aging. Our findings may contribute to the elucidation of skin disease pathology, the development of therapeutic gel scaffolds, and the control of aging.

Link: https://doi.org/10.3390/gels12040303

Long-lived naked mole-rats are eusocial: like ants and bees, they live in colonies led by a queen that is the only female that reproduces. Naked mole-rats are extremely long-lived in comparison to other similarly sized mammals, and this tendency towards greater longevity shows up in many other eusocial species. It crosses evolutionary clades and ecological niches, which might lead one to ask what exactly it is about eusociality that promotes longevity. Here, researchers offer a hypothesis based on modeling.

Animals such as bees, ants, wasps, termites, and naked mole-rats live in colonies in which a single queen is the only female reproductive, an arrangement known as eusociality. Eusocial animals are known for their remarkably long lifespans. It has been argued that longevity becomes selected when queens are shielded from "external mortality". While such protection may contribute, we find a deeper reason: the eusocial reproduction strategy itself inherently creates selection for long lifespans.

Lifespans typically reflect two processes: the baseline risk of death and the rate at which this risk increases with age. Each is a parameter in the Gompertz mortality equation. We show that the mathematical properties of eusocial reproduction lead to slowly-growing, older populations where selection acts more strongly on the rate at which risk increases than on the baseline risk. In addition, we show that channeling reproduction through a single female also selects for longevity, which we term the "queen effect". Thus, the dynamics of eusocial reproduction select for longer lifespan. More broadly, these results show that reproductive structure and population growth dynamics can fundamentally shape selection on lifespan, with implications outside eusocial systems as well.

Link: https://doi.org/10.1101/2025.03.25.645350

The article that I'll point out today is primarily intended to explain to a layperson the recent history of partial reprogramming as an approach to the treatment of aging and age-related disease. The article clearly exists because the leadership at Altos Labs wants to attain a higher profile in the public eye. Altos was created in 2022 or thereabouts and funded with the immense sum of $3 billion, a sizable fraction of all biotech investment in that year. Thus the usual reason for increased publicity, meaning the desire to raise further funding from investors, seems less likely.

It is perhaps the case that there is some pressure behind the scenes to show results, particularly now that Life Biosciences has commenced a first human trial of a very narrowly focused use of partial reprogramming for optic nerve injury or degeneration. Biotech is a slow business, however, in which fifteen years between initial research and clinical approval is entirely normal. Nonetheless, one might imagine that more knowledgeable types might look back at the history of the Ellison Medical Foundation and Calico Life Sciences and express some concern that perhaps large amounts are once again being spent to, as yet, no evident good. This is of course all speculation, but we shall see.

Longevity Science Is Overhyped. But This Research Really Could Change Humanity

When a woman gets pregnant, she has been carrying her egg cells since birth. The sperm that joins with the egg to form a zygote might have been just a few months in the making, but it inherits markers of age from the man who produced it. It only follows that the zygote would also show signs of age - and at first it does. But then a mysterious metamorphosis begins: the cells of the zygote begin to reverse that damage, shaking off the metaphorical (epigenetic) dust that the parents accumulated on their DNA. After two weeks, the cells of the embryo are back to a kind of ground zero of youth. Recreating this rejuvenation is one of the newest and most promising developments in longevity research.

Over the past 20 years, they have learned how to trigger rejuvenation in the lab, achieving a series of breakthroughs that have made that future feel tantalizingly close. Scientists have taken skin cells from 90-year-olds and restored them to youth in a petri dish. They have rejuvenated diseased mice, turning their gray hair back to black and strengthening their muscles. Rejuvenation sounds just as sci-fi as any of the ideas coming out of the longevity field, and yet there's widespread agreement among scientists that the research has extraordinary potential. The most vehement disagreements are not over whether cellular aging can be reversed, but how far scientists can push it. Will it work in humans? Will its use be limited to targeted interventions that cure specific diseases? Or could it ever be safe enough to enable full-body rejuvenation - to help humans look and feel younger, or to stop them from aging in the first place?

Some of the answers to those questions are likely to come from Altos Labs, a secretive biotech company. With $3 billion in investment at its founding in 2022, Altos is thought to have been the single largest biotech start-up launch. A would-be Manhattan Project for longevity science, Altos is responsible for one of the biggest migrations of academics to industry in recent years, luring marquee names in the field with million-dollar salaries and the promise of near-unlimited funding. Among its competitors, Altos has earned a reputation as a black box.

In 2006, Shinya Yamanaka identified four unusual genes that are active in early embryonic development. He introduced them into the skin cells of older mice in a petri dish and watched and waited. Over the course of two weeks, the skin cells transformed, becoming something close to embryonic stem cells. The original Yamanaka factors are now considered just one of many potential ways that scientists could trigger rejuvenation. Altos and a handful of other start-up biotech companies are competing to find the safest version. Altos is conducting research on rejuvenation in the kidney, the heart, and the liver, which are often the first organs to fail as we age. The hope is that in fixing whatever organ is aging first, scientists could give someone a longer, healthier life, with everything essentially winding down at the same time, making for a mercifully brief period of decline.

Some varieties of hydra are immortal, in the sense that mortality rate and measures of function do not change over time. A hydra is in essence a sophisticated bundle of stem cells, somewhat analogous to an early embryo, capable of replacing any of its component parts. Are there aspects of hydra cellular biochemistry that could be introduced into more structured, sophisticated species to extend life? One view is that hydra-like strategies for longevity are incompatible with a central nervous system that retains information. Another view is that this point doesn't rule out all of the potentially interesting biochemistry in this species. Certainly, researchers have already started to move genes and other aspects of cellular biochemistry from long-lived species to short-lived species, such as from naked mole rats to mice, in order to test the bounds of the possible.

Hydra vulgaris ("Hydra") exhibits negligible senescence due to continuous self-renewal and stem cell cycling, contrasting sharply with short-lived, eutelic rotifers that exhibit rapid aging and fixed somatic cell numbers post-development. These organisms therefore represent extremes on the spectrum of invertebrate lifecycles and offer a unique opportunity to test whether patterns of gene expression associated with repressed senescence in Hydra can delay senescence in aging-prone animal models. We hypothesize that introducing Hydra-like gene expression profiles into rotifers (e.g., Brachionus manjavacas) via genetic manipulation will extend healthspan and reduce age-related mortality, providing proof-of-principle for effective manipulation of conserved anti-aging mechanisms.

While translation to humans remains highly speculative at this early stage, the rotifer-Hydra model provides a proof-of-principle framework for discovering targets potentially more relevant to mammalian aging than those from other invertebrate systems. If Brachionus manjavacas can, at least to some extent, exhibit more negligible senescence via transfer of relevant Hydra-like gene expression patterns, this would constitute the required proof-of-principle for the overall concept. It is a long leap from rotifers to geroprotective strategies for humans, but without the initial step from Hydra to rotifer, nothing else would likely be possible. Therefore, we posit that Hydra to rotifer, considered long term, is of relevance to the question of aging, senescence, and geroprotective strategies for humans.

Link: https://doi.org/10.18632/aging.206370

Lung fibrosis is challenging to treat and largely irreversible. There have been signs that clearance of senescent cells can improve the condition, but this has yet to move beyond early human safety trials. Here researchers take a more traditional approach to assessing and then tinkering with the expression of specific genes to produce a reduction in fibrosis in animal models. After finding that ID1 and ID3 exhibited elevated expression in some lung cells, they showed that reducing expression via a variety of means caused some degree of reversal of fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease in which scar tissue builds up in the lungs, making it increasingly difficult to breathe. Existing therapies can slow disease progression but do not stop or reverse it, and most patients survive only three to five years after diagnosis. The research combined analyses of human lung tissue and cells from patients with IPF with several experimental models in mice. The team found that ID1 and ID3 levels are elevated in diseased lung fibroblasts - cells that drive the formation of scar tissue.

When both proteins were inhibited, fibroblast activation was significantly reduced, limiting the processes that lead to pulmonary fibrosis. The researchers tested multiple strategies to block ID1 and ID3, including a small molecule drug and a targeted gene therapy approach. Across these approaches, inhibition of the proteins not only slowed disease progression but also reduced established pulmonary fibrosis in mice and improved lung function. The study also sheds light on how these proteins contribute to disease. ID1 and ID3 regulate fibroblast growth through cell cycle pathways and promote scarring through MEK/ERK signaling - key mechanisms underlying pulmonary fibrosis.

Link: https://www.eurekalert.org/news-releases/1125917

The blood industry is enormous, a long-standing component of the medical industry and one of the largest areas of focus for regulators. Blood is donated and sold in immense amounts, processed and separated into countless different fractions, and those fractions used in equally immense amounts. A sizable research and development community views the contents of human blood in much the same way as others view libraries of small molecules: a domain in which the focus is on discovery of potential new uses in medicine.

Since the modern resurrection of heterochronic parabiosis studies, in which an old mouse and young mouse have their circulatory systems linked, the role of alterations in blood contents with age has been a growing topic of interest. Evidence strongly suggests that old blood is harmful, while less robust evidence suggests that specific factors in young blood might be favorable. For example, one novel approach to therapy under development involves clearing circulating TGF-β while increasing circulating oxytocin, a little from both sides. There is, however, a great deal of ongoing research into many different approaches to improving health in old people by manipulating the circulating contents of the bloodstream.

Blood as the mirror and modulator of aging: mechanistic insights and rejuvenation strategies

Aging arises not only from intrinsic cellular decline but also from systemic alterations in circulating factors that govern tissue maintenance and regeneration. Recent multi-omics advances - including plasma proteomics, metabolomics, and single-cell immunomics - highlight blood as both a mirror and a modulator of organismal aging. Circulating proteins and metabolites reflect not only chronological and biological age but also organ-specific aging trajectories, serving as robust predictors of healthspan, longevity, and disease risk. Beyond their diagnostic value, blood-borne components actively dictate the tempo of aging by shaping immune remodeling, metabolic homeostasis, and interorgan communication.

Youthful circulation, defined as the blood-borne systemic environment of young individuals, promotes tissue homeostasis and regeneration and, when experimentally transferred via heterochronic parabiosis or young plasma transfer, induces transcriptomic, metabolic, and epigenetic rejuvenation across multiple tissues. Specific fractions - such as small extracellular vesicles, plasma proteins, and metabolites - restore mitochondrial function, suppress inflammation, and extend lifespan in animal models. Conversely, reducing pro-aging factors through plasma dilution or therapeutic plasma exchange mitigates age-associated decline and shows translational promise in neurodegenerative disease. Collectively, these insights position blood as a central regulatory axis of aging.

Human epidemiological data robustly indicates a trade-off between risk of cancer and risk of neurodegenerative conditions. Why is this the case? While all too little is understood of the precise details, at the high level it is thought that this is a reflection of the degree to which tissue maintenance activities decline with age. The less work undertaken by stem cells, the less cell replication in general, the lower the risk of a potentially cancerous combination of mutations occurring. But without that ongoing maintenance, the loss of tissue function accelerates, and neurodegenerative conditions are one of the more prominent outcomes. In essence one is forced to choose between cancer or regeneration. Not all species face that choice, of course. Some, like naked mole rats, can have their cake and eat it too; their cancer suppression mechanisms are so exceptionally effective that individuals can maintain youthful levels of regeneration and function well into late life without any downsides.

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune-stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons.

Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration.

Link: https://doi.org/10.3390/ijms27072989

Inflammation in the brain is thought to be important in the progression of neurodegenerative conditions, disruptive to cell and tissue function. Understanding why the other features of neurodegenerative disease activate chronic inflammation in the brain is a necessary first step on the long road to the development of therapies capable of selectively suppressing this harmful inflammation while only minimally interfering in the normal, necessary inflammatory response to pathogens and injury.

The protein called STING normally functions as part of the immune system's early-warning system. In the brains of people with Alzheimer's, the team discovered that STING undergoes a chemical modification known as S-nitrosylation (or SNO, a reaction involving sulfur, oxygen, and nitrogen) that promotes its overactivation. Blocking this chemical change to STING in a mouse model of the disease decreased neuroinflammation.

Over three decades ago researchers discovered the S-nitrosylation process, in which a molecule related to nitric oxide (NO) binds to a cysteine amino acid in proteins, producing "SNO" and thus regulates the protein's function. SNO, which can be triggered by aging, neuroinflammation, and environmental toxins such as air pollution and wildfire smoke, disrupts a variety of different proteins in the body.

In this new study, the team focused on the protein STING, which was previously linked to Alzheimer's inflammation. They pinpointed exactly where on STING an S-nitrosylation reaction occurred, homing in on one specific building block of the protein: cysteine 148. When cysteine 148 is S-nitrosylated, they discovered, STING clusters into larger complexes and triggers inflammation. The team found high levels of the chemically modified form of STING (called SNO-STING) in postmortem brain tissue from Alzheimer's patients, in human brain immune cells grown in the lab and exposed to Alzheimer's proteins, and in a mouse model of the disease.

In laboratory experiments, the team showed that the clumps of proteins found in the brain in Alzheimer's - including amyloid-beta and alpha-synuclein - can themselves trigger the S-nitrosylation reaction in STING. This finding suggests that inflammation occurs in a cycle: initial protein clumps, coupled with environmental influences and aging, could cause inflammation that generates NO, driving S-nitrosylation of STING, which in turn drives more inflammation.

The researchers then engineered a version of STING lacking cysteine 148 so it couldn't be S-nitrosylated. When this modified protein was introduced into a mouse model of Alzheimer's, brain immune cells showed significantly less inflammation, and critically, the connections between nerve cells (called synapses) were protected from degradation. This preservation of synapses is known to correlate with protection from the cognitive decline of dementia.

Link: https://www.scripps.edu/news-and-events/press-room/2026/20260423-lipton-alzheimers.html

Since the discovery that adult mice generate new neurons in the brain, and thus the brain is not wholly reliant upon structures and cells created during development, there has been considerable debate over whether or not this adult neurogenesis exists and is important in humans. This is in part a logistics problem: the human brain is inherently hard to study. It is in part a methodological problem, in that human neurogenesis appears to be different enough from mouse neurogenesis in its details to challenge researchers. Much of the debate of the past fifteen years has focused on whether the tools are working in the way that they are claimed to work, and whether human data actually reflects what those who present it think it reflects. Nonetheless, the present weight of data and scientific consensus support a role for neurogenesis in the maintenance of the aging brain.

So we come to the question of why some people exhibit molecular pathology characteristic of Alzheimer's disease, such as the generation of protein aggregates that can be visualized via imaging approaches, but do not suffer extensive cognitive decline as a result. There is a school of thought that suggests that these individuals have more efficient or greater levels of neurogenesis, capable of compensating for losses. Or that their neurogenic mechanisms are in some way more resistant to the damage of aging. This ties in to the high level concepts of cognitive resilience and cognitive reserve, created by clinicians and researchers seeking to describe the observed differences in the cognitive outcomes of neurodegeneration from individual to individual. Whether differences in neurogenesis are indeed important in this context remains an unanswered question; today's open access paper is an example of ongoing work aimed at developing better tools to obtain better data and thus come to a conclusion.

Not all Alzheimer's leads to dementia

Why do some people experience memory loss and cognitive decline as Alzheimer's builds up in their brain, while others stay mentally sharp? This question lies at the heart of new research into "cognitive resilience", a phenomenon that is gaining attention in neuroscience. "Around 30 percent of older adults who develop Alzheimer's disease never experience its symptoms. We really don't know why. That's a big mystery, and a very important one."

One possible explanation is that resilient brains are better at repairing themselves during Alzheimer's. This idea is linked to a process called adult neurogenesis, which refers to the birth of new neurons in the adult brain. It has been well-established in other animals, but its existence in humans has been debated for years. To study this, researchers used human brain tissue from the Netherlands Brain Bank, which collects and stores donated brain samples for research. They included brains from control donors with no brain pathology, Alzheimer's patients, and individuals with Alzheimer's pathology who remained resilient to developing dementia.

The team found what they were looking for: so-called "immature" neurons. These cells resemble young, not fully developed neurons. While the team had expected to find much more of these cells in the resilient group than in the Alzheimer's patients, the difference was not as big as expected. Instead, the team found that the key difference lies in how the immature neurons behave. "In resilient individuals, these cells seem to activate programs that help them survive and cope with damage. We also see lower signals related to inflammation and cell death."

Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer's pathology and cognitive resilience

An attractive approach to treating Alzheimer's disease (AD) could involve harnessing the brain's endogenous regenerative potential to restore function in the degenerating hippocampal network. This strategy presumes the occurrence of adult hippocampal neurogenesis (AHN) in the human brain and the functional integration of newly generated granule cell (GC) neurons into the hippocampal formation. Reconstructing the molecular and cellular signatures of immature hippocampal GC neurons may not only offer novel targets for brain repair and regeneration strategies in the AD human brain but also directly probe the question of whether human AHN contributes to a lifelong buildup of cognitive reserve. This reserve may, in turn, confer resilience to cognitive decline or AD-related dementia later in life.

Despite its therapeutic appeal, identifying and profiling putative neurogenic populations in the adult human brain has not been trivial; beyond reflecting technical roadblocks, this also hints at some potentially unique attributes of these cells. Although single-nucleus RNA sequencing (snRNA-seq)-based studies have identified cells with immature neuronal characteristics in the adult human hippocampus, methodological discrepancies have led to substantial debate in the field. Recently, we examined experimental and computational variables that may confound the results and conclusions of such approaches. Building on these insights, we here establish a refined experimental and computational framework aimed at reliably identifying neurogenic populations in the aged human brain, while minimizing biases inherent to marker-based preselection.

Our findings reveal that immature neuronal signatures persist into adulthood, with some of them potentially arising postnatally. Although these cells present some transcriptional similarities to their fetal counterparts, they also appear to have acquired unique features that may enable them to adapt to the complex adult niche microenvironment. Our findings suggest that the presence of these immature neuronal populations may actively contribute to maintaining homeostasis within the aged human hippocampus and to cognitive resilience in AD.

Researchers here show that fecal microbiota transplantation from young mice to old mice suppresses age-related increase in MDM2 expression and reduces risk of liver cancer. The balance of microbial populations making up the gut microbiome changes with age in ways that promote chronic inflammation and reduce the production of beneficial metabolites. Fecal microbiota transplantation is one of the few approaches that can make a permanent change to the composition of the gut microbiome, rejuvenating it when the donor is younger than the recipient. Numerous animal studies have shown improved health and extended live to result from this restoration of a youthful gut microbiome, and the work here is another example of the same, focused on the health of the liver.

Researchers collected fecal samples from eight young mice and transplanted them back into the same mice when they were older, a process called fecal microbiota transplantation, or FMT. The eight controls received sterilized fecal slurry, and a small group of similar young mice provided additional baseline data. None of the mice with the restored microbiome developed liver cancer by the end of the study, while liver cancer was found in 2 out of 8 aging controls. The mice with the restored microbiome also saw reduced inflammation and less liver damage.

At the conclusion of the in vivo study, the researchers conducted a comprehensive analysis of the liver tissue. They identified differences in MDM2, a gene already known to play a role in liver cancer. MDM2 protein levels were low in young mice, high in untreated older mice, and suppressed in treated older mice, making them more like young mice. "Restoring a more youthful microbiome can reverse several core features of aging at both the molecular and functional level, including inflammation, fibrosis, mitochondrial decline, telomere attrition, and DNA damage." The research grew out of an earlier cardiac study, which found that microbiome changes could improve heart function. When analyzing tissues at the end of that study, the team noticed an even more dramatic effect on the liver, which prompted deeper investigation.

Link: https://www.eurekalert.org/news-releases/1124997

Some evidence suggests that deubiquitylases are relevant to aging. These enzymes remove ubiquitin from proteins; recall that the decoration of a protein with ubiquitin enables it to be broken down into raw materials for further protein synthesis by a proteasome. Alongside autophagy, the ubiquitin-proteasome system is one of the important processes by which a cell maintains quality control and otherwise manages its contents. Managing which proteins are flagged by ubiquitin necessarily involves removal, not just addition, and thus the existence of deubiquitylases. Here, researchers provide evidence for rising levels of oxidative stress in the aging brain to impair the activity of deubiquitylases. As is usually the case in these matters, it is unknown as to the relative importance of this issue versus all of the other problems produced by age-related change in the operation of cellular biochemistry.

Among the cellular mechanisms governing proteostasis, the ubiquitin-proteasome system (UPS) plays a central role in signaling, stress responses, and protein degradation by attaching ubiquitin to lysine residues of specific target proteins. Within the UPS, ubiquitin ligases and deubiquitylases (DUBs) act antagonistically to modulate protein fate and signaling pathways dynamically. Altering DUB activity has been linked to lifespan in nematodes, and dysregulation of specific DUBs in humans leads to several neurodegenerative diseases, such as spinocerebellar ataxia and Parkinson's disease. However, a systematic understanding of how DUB functions is altered in the aging brain, the mechanisms driving these changes, and the consequences of altered DUB activity at the molecular level are still lacking.

Here we used activity-based proteomics to profile cysteine protease DUBs in aging mouse and killifish brains. We identified a subset of DUBs that progressively lose catalytic activity with age despite stable protein abundance. Mechanistically, oxidative stress impaired DUB function through thiol oxidation, whereas antioxidant treatment with N-acetylcysteine ethyl ester (NACET) restored activity in aging brains. In human induced pluripotent stem cell-derived neurons, global DUB inhibition and targeted inhibition of USP7, one of the most strongly age-affected DUBs, partially recapitulated ubiquitylation changes observed in aged brains. Temporal analysis in mice further revealed that DUB inhibition precedes proteasome decline during brain aging. Together, these findings identify redox-sensitive DUBs that lose activity with age and suggest impaired deubiquitylation as an early, potentially reversible driver of proteostasis decline in the aging brain.

Link: https://doi.org/10.1038/s41467-026-71921-y