Fight Aging!

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