Fight Aging!

Somatic mosaicism in tissues occurs as a result of random mutational events in stem cell populations. Stem cells accumulate mutations randomly over time, a small fraction of the continual damage to nuclear DNA that slips past the highly efficient DNA repair machinery. Those mutations spread out into tissue via the daughter somatic cells generated by the stem cells. A tissue made up of somatic cells thus exhibits an ever more complex mosaic pattern of overlapping mutations over time. Somatic mosaicism in the immune system is known as clonal hematopoiesis. This is arguably the most studied form of somatic mosaicism, as the immune cells produced by hematopoietic stem cells are readily accessible via a blood sample.

Somatic mosacism sets the stage for cancer by spreading mutations that raise the odds of any specific cancerous combination of mutations occurring in any one somatic cell. But does somatic mosaicism contribute more generally to degenerative aging and loss of function, and is this contribution large enough for us to care about? There is some evidence to suggest that this is the case, but an important role for somatic mosaicism in aspects of aging other than cancer risk is far from conclusively demonstrated at this point in time. Clonal hematopoiesis seems likely to be where that is initially proven, if it is going to be.

Ageing Through the Looking-Glass: The Different Flavours of Clonal Haematopoiesis

Clonal haematopoiesis (CH) is the presence of acquired mutations in blood cells and is a consequence of ageing that is linked to malignancy, cardiovascular disease and other diseases of ageing. CH is a reflection of genomic instability with ageing; however, there is evidence that CH may exacerbate features of normal ageing, including inflammageing and immunosenescence, and more directly contribute to disease causation. CH can manifest as mosaic loss of X or Y chromosomes, autosomal mosaic chromosomal rearrangements, or point mutations or small insertions or deletions. However, differences in CH definitions, detection methods and cohort characteristics have contributed to heterogeneous and sometimes discordant findings across studies.

It has been hypothesised that the different forms of CH may all arise from a 'common soil' of genomic instability, that is, that shared heritable and environmental factors may promote the acquisition and subsequent expansion of mutations. However, it remains largely unknown whether associations between CH and diseases of ageing reflect correlation or whether CH may directly cause disease. Here, we review the relationship between ageing and CH, including how CH develops, and how it interacts with other features of ageing including inflammageing, immunosenescence, epigenetic ageing and telomere shortening. We also review what is known about the overlap between different forms of CH and whether they make independent contributions to risk of disease.

The different forms of CH share common germline and environmental risk factors and have overlapping prevalence and disease associations, suggesting they reflect common underlying processes of ageing. CH is also associated with other biomarkers of ageing, namely accelerated epigenetic age and shorter telomere length. The presence of CH may reflect a biologically older haematopoietic system and exacerbate features of normal ageing, including inflammageing and immunosenescence, which may be important causal mechanisms explaining the association between CH and a variety of diseases of ageing. Additionally, inflammation likely also promotes further expansion of CH. Different forms of CH may work together to promote clonal expansion and synergistically promote disease including through promoting inflammation. CH may also synergise with, or be influenced by, other sources of inflammation outside the haematopoietic system, potentially including somatic mutations in other tissues or epigenetic changes. There is some evidence that different forms of CH may make independent contributions to disease risk.

The balance of microbial species making up the gut microbiome changes with age in ways that promote inflammation and other harms. Researchers can accurately map the composition of the gut microbiome using sequencing approaches, and are steadily identifying specific microbial species and mechanisms that contribute to the dysfunctions of age. A number of approaches exist to restore a more youthful gut microbiome composition, such as fecal microbiota transplantation from a young donor or flagellin immunization, but none are yet very widely used in the context of attempting to improve late life health.

Physiological and pathological changes associated with aging contribute to deteriorating disease prognosis in sepsis. However, the mechanisms by which these disturbances exacerbate inflammation remain underexplored. In this study, fecal samples were collected from aged and young septic patients and mice and subsequently transplanted into young pseudo-germ-free mice via fecal microbiota transplantation. Fecal, colon tissue, and blood samples were collected to be used 16S rDNA sequencing to characterize the gut microbiota, histopathological examination, enzyme-linked immunosorbent assay and FITC-dextran intestinal permeability assay to assess gut injury and gut barrier function.

Additionally, nontargeted and targeted metabolomics were used to identify differential metabolites in the feces of aged and young septic mice. To further validate the roles of specific bacterial strains and their metabolites in sepsis, genetically engineered bacteria were used in both in vivo and in vitro experiments.

The results showed an increased abundance of Klebsiella aerogenes (K. aero) in aged hosts, which led to elevated histamine (HA) production and exacerbated intestinal barrier dysfunction. Importantly, K. aero strains carrying a histidine decarboxylase gene variant were identified as major HA producers. Mechanistically, HA was shown to drive intestinal barrier dysfunction by inhibiting Nlrp6 expression and its subsequent binding to LC3, thereby impairing autophagy. Treatments that modulated HA levels or overexpressed Nlrp6 ameliorated inflammation in septic mice. These findings suggest that targeting the HA-Nlrp6-LC3 axis could offer a novel therapeutic approach for managing sepsis, particularly in aged populations.

Link: https://doi.org/10.1080/19490976.2026.2630475

Atherosclerosis involves the growth of fatty plaques in blood vessel walls that weaken and obstruct those blood vessels. It is a universal condition; all older individuals exhibit some degree of plaque formation. A heart attack or stroke occurs when an unstable, fatty atherosclerotic plaque ruptures and the debris blocks a vessel somewhere downstream. Interestingly, atherosclerosis is quite different in character between the sexes. Until menopause, atherosclerosis proceeds more slowly in women, and as noted here women tend to exhibit lesser degrees of plaque in later life. That does not, unfortunately, translate into a lesser degree of risk of plaque rupture.

This study evaluated health data for more than 4,200 adults (more than half of whom were women) to compare how quantity of plaque influenced the risk of major heart conditions. The study included people with stable chest pain and no prior history of coronary artery disease. Participants were randomized to undergo diagnostic evaluation via coronary computed tomography angiography (X-ray images of the heart and blood vessels) and followed for about two years.

Fewer women had plaque in their coronary arteries than men (55% of women vs. 75% of men). Women also had a lower volume of artery plaque than men (a median of 78 mm^3 among women vs. 156 mm^3 in men). Despite less plaque, women were just as likely as men to die from any cause, have a non-fatal heart attack or be hospitalized for chest pain (2.3% of women vs. 3.4% of men). In addition, women faced increased heart risk at lower levels of plaque compared to men. For total plaque burden, women's risk began to rise at 20% plaque burden, while men's risk started at 28%. With increasing plaque levels, risk rose more sharply for women than for men.

"Because women have smaller coronary arteries, a small amount of plaque can have a bigger impact. Moderate increases in plaque burden appear to have disproportionate risk in women, suggesting that standard definitions of high risk may underestimate risk in women."

Link: https://newsroom.heart.org/news/women-may-face-heart-attack-risk-with-a-lower-plaque-level-than-men

Reducing the dietary intake of calories while retaining an optimal intake of micronutrients is well established to slow aging and extend life in a number of species. In humans, studies have shown that reduced calorie intake improves health in ways that are likely result in an extension of life span. Short-lived species exhibit a greater relative extension of life as a result of calorie restriction than is the case for long-lived species. In mice, calorie restriction can produce as much as a 40% extension of life span. In humans, a few years of additional life seems the likely effect size, although the only thing we can say in certainty given the data to hand is that the benefit cannot be much larger than this. If humans robustly became centenarians given the right restrictions of diet, this would be have been well known to the peoples of the ancient world and every monastic order since then. Even a ten year gain would be hard to hide over this span of time, let alone from modern epidemiology.

From a mechanistic perspective, this smaller effect on life span in longer-lived species is likely the case because the long-lived species already benefit from a sizable fraction of the life-extending mechanisms that are indirectly triggered by a reduced calorie intake in the short-lived species. From an evolutionary point of view, the life-extending response to reduced availability of nutrients likely evolved because it raises the odds of successful reproduction following seasonal famine. A winter is a much larger fraction of a mouse life span than it is of a human life span, so the mouse has evolved to exhibit a much longer relative increase in life span than the human.

Much of the attention given to the mechanisms of the calorie restriction response is focused on autophagy, the collection of processes that recycle damaged or otherwise unwanted proteins and cell structures into the raw materials needed to synthesize more proteins. Up to a point, more autophagy improves cell function. Improved cell function means improved tissue function, greater resilience to the damage and dysfunction of aging, and thus a slowing of declines and extension of life. Autophagy is far from the only mechanism that is studied by the research community in this context, however, and today's open access paper is a review that covers a range of the others.

Molecular mechanisms underlying the lifespan and healthspan benefits of dietary restriction across species

Among numerous genetic, pharmacological, and lifestyle interventions examined over the past decades, dietary restriction (DR) remains the most robust and evolutionarily conserved strategy for extending lifespan and improving healthspan. Originally described in rodents nearly a century ago, the beneficial effects of reduced nutrient intake have since been validated in a wide range of organisms, including yeast, nematodes, flies, and mammals. While often used interchangeably, it is critical to distinguish between different nutritional interventions to avoid conceptual overlap. Caloric restriction (CR) typically refers to a chronic reduction in total calorie intake (usually 20%-40%) without malnutrition. In contrast, Chronic Dietary Restriction (DR) is a broader term encompassing the restriction of specific macronutrients (amino acid restriction, protein restriction) regardless of total calorie count. Furthermore, long-term Fasting involves extended periods without food intake, triggering distinct periodic metabolic switches that differ from the continuous physiological adaptations induced by chronic CR or DR.

Genetic and transcriptomic studies have revealed that DR induces coordinated changes in gene expression, chromatin state, and metabolic wiring, leading to a systemic shift from anabolic growth toward cellular maintenance and stress resistance. Central to these are conserved nutrient-sensing pathways - such as insulin/IGF-1 signaling, the target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and NAD+-dependent sirtuins - that function as molecular hubs linking environmental cues to transcriptional and epigenetic regulation. These pathways regulate the activity of key transcription factors and transcriptional coactivators, thereby shaping long-term gene expression programs associated with longevity.

Downstream, these pathways enhance autophagy and proteostasis, remodel mitochondrial function and redox balance, reshape immune and inflammatory networks, and induce epigenetic and transcriptional reprogramming. Recent work further highlights amino acid-specific sensing mechanisms, endocrine mediators such as fibroblast growth factor 21 (FGF21), the gut microbiome, circadian regulators, and nuclear pore-associated transcriptional plasticity as integral components of DR responses. Importantly, the physiological outcomes of DR are context dependent and influenced by genetic background, sex, age at intervention, and the type and duration of restriction. In this review, we summarize current knowledge on the genetic and molecular architecture underlying DR-induced longevity and health benefits across species, discuss implications for aging-related diseases, and outline future directions toward precision nutrition and safe translational strategies.

Researchers here make some inroads into gathering and analyzing data relating to age-related alterations in the features and contents of extracellular vesicles taken from a blood sample. Much of the communication between cells involves secretion and uptake of vesicles, membrane-wrapped packages of diverse molecules. Taking a sample of extracellular vesicles from blood is thus a merged view into any number of complex interactions between systems and organs, a sizable blob of data that emerges from an intricate, evolving set of underlying processes. Generating meaningful insight into those processes from the data is not a straightforward exercise, but some progress is being made.

Extracellular vesicles (EVs) are key mediators of intercellular communication and may reflect physiological changes during aging. We analyzed plasma-derived EVs from a healthy aging cohort stratified by age, using size exclusion chromatography, surface profiling, nanoparticle tracking, and small RNA sequencing.

The age-dependent variation in EV surface markers - including decreased CD3, CD56, HLA-A, and CD45 and increased CD14 and CD69 - supports a shift in EV immunophenotype, consistent with immunosenescence and changes in circulating immune cell populations. These changes could reflect a reduced contribution of adaptive immune cells to the pool of circulating EVs and an increased release by activated monocytes. Interestingly, recent findings have shown that EV surface antigen profiling can be used as a biomarker of aging, reflecting features of inflammaging commonly observed in older people, as well as the cardiovascular risk of individuals. Furthermore, the alterations in the surface markers of EVs could not only indicate a differential cellular origin but could also affect the uptake of these EVs by different target cells. This could ultimately influence the intercellular communication mediated by EVs during aging.

The analysis of EV-associated small RNAs revealed distinct clustering by age group, with the young cohort showing a markedly different profile compared to middle-aged and older individuals. This early divergence in the EV miRNA signature suggests that some molecular hallmarks of aging are already encoded in EVs well before late-life decline becomes clinically evident. Older individuals showed shifts in EV immunophenotype consistent with immunosenescence and displayed distinct miRNA signatures enriched in muscle-specific and metabolism-related miRNAs, including miR-206, miR-143-3p, miR-122-5p, and miR-20b-3p - linked to muscle, metabolic, and vascular function. Notably, miR-6529-5p, associated with neuroprotection, was elevated in aging.

Target gene analysis revealed involvement in aging pathways such as Ras, VEGF, and MAPK signaling. EV miRNAs and particle counts correlated with biological aging markers, including GDF-15, visceral fat, and muscle quality. These findings highlight coordinated age-related changes in EVs reflecting musculoskeletal and metabolic aging and support their potential as minimally invasive biomarkers of biological aging and functional decline.

Link: https://doi.org/10.1038/s41514-025-00321-1

Researchers here argue that cells that become senescent because errors in DNA replication produced entire extra duplicate chromosomes, a state known as polyploidy, are meaningfully different than cells that become senescent due to other forms of damage or stress. The researchers also point out that present studies do not adequately differentiate between polyploid senescent cells and those with normal chromosomes, suggesting that more work is needed here. In general, the research community is motivated to better understand the biochemistry of senescence in order to improve efforts to either selectively destroy senescent cells or alter their behavior to reduce the harmful pro-inflammatory signaling that they produce. Studies in animals suggest that therapies to control the burden of cellular senescence could produce meaningful degrees of rejuvenation in humans, but it is taking longer than expected to translate that research into the clinic.

One understudied form of cellular senescence is polyploidy-induced senescence (PIS) which was initially observed in vitro after drug-induced tetraploidization. We recently reported that polyploid uroepithelial cells in the mouse bladder are senescent over the lifespan, raising new questions about the physiological and pathological significance of polyploid, senescent cells. These senescent uroepithelial barrier cells persisted after treatment of mice with the senolytic combination dasatinib plus quercetin (D+Q). We now hypothesize that some bladder cancers, 90% of which are of urothelial origin, may arise from polyploid umbrella cells that, through loss of senescence enforcers and tumor suppressors such as p16, escaped PIS.

The idea that cancers can arise from cells escaping senescence is well established, but our observations link this specifically to polyploidization. This has important implications in the context of therapy-induced senescence (TIS). Many cancer treatments trigger senescence through replication stress and polyploidization. By contrast, naturally occurring polyploid senescent cells, such as bladder umbrella cells, appear to serve important biological functions - though they too may destabilize under chronic stress.

Not all polyploid cells are senescent, and their relationship is context dependent. Hepatocytes, for example, can be both polyploid and senescent, but polyploid hepatocytes also undergo senescence reversal and ploidy reduction divisions under stress, re-entering the cell cycle and contributing to carcinogenesis. We propose that PIS acts as a developmental timer: replication stress from endoreplication activates the DNA damage response, linking proliferation to differentiation during development, regeneration and repair. In this model, senescence is not merely a stress response but a programmed cellular fate that enforces terminal differentiation, contributes to organ structure, and preserves tissue architecture.

Link: https://doi.org/10.18632/aging.206355

In recent years, the research community has developed a number of blood tests to assess risk and progression of Alzheimer's disease, relevant to the earliest, pre-symptomatic stages of the condition. Alzheimer's disease emerges very slowly over time, a process of damage and dysfunction that builds by stages over decades. The present consensus is that these early stages are dominated by amyloid-β misfolding and aggregation with only mild cognitive impairment at worst as the result. Only later is it the case that outright neuroinflammation and aggregation of phosphorylated tau protein come into play as the primary disease mechanisms. Nonetheless, forms of phosphorylated tau circulating in blood have proven useful as a marker of disease progression even in the early stages.

Today's research materials report on the use of one of the Alzheimer's blood tests based on phosphorylated tau to construct an aging clock specifically focused on predicting the time to development of Alzheimer's symptoms. Any set of markers that change with age can be used to produce a predictive clock, given enough data from enough people. The only question is how accurate it is; more data is generally better. Here, researchers work from only one assessment in a few hundred people to produce an estimated margin of error of 3 to 4 years over a time span of 10 to 20 years of disease development to first symptoms - a decent outcome given such a limited set of data.

Blood test "clocks" predict when Alzheimer's symptoms will start

Researchers have demonstrated models that predict the onset of Alzheimer's symptoms within a margin of three to four years. This could have implications both for clinical trials developing preventive Alzheimer's treatments and for eventually identifying individuals likely to benefit from these treatments. The models use a protein called p-tau217 in an individual's blood plasma to estimate the age when they will begin experiencing symptoms of the neurodegenerative disease. Levels of p-tau217 in the plasma can currently be used to help doctors diagnose Alzheimer's in patients with cognitive impairment. These tests are not currently recommended in cognitively unimpaired individuals outside of clinical trials or research.

To identify the interval between elevated p-tau217 levels and Alzheimer's symptoms, researchers analyzed data from volunteers in two independent long-running Alzheimer's research initiatives. The participants included 603 older adults who lived independently in the community. Plasma p-tau217 has previously been shown to correlate strongly with the accumulation of amyloid and tau in the brain as shown on PET scans. The key hallmarks of Alzheimer's disease, amyloid and tau are misfolded proteins that begin building up in the brain many years before Alzheimer's symptoms develop.

The models predicted the age of symptom onset within a margin of error of three to four years. Older individuals had a shorter time from when elevated p-tau217 appeared to the start of symptoms as compared to younger participants, suggesting that younger people's brains may be more resilient to neurodegeneration and that older people may develop symptoms at lower levels of Alzheimer's pathology. For example, if a person had elevated p-tau217 in their plasma at age 60, they developed symptoms 20 years later. If p-tau217 wasn't elevated until age 80, they developed symptoms only 11 years later.

Predicting onset of symptomatic Alzheimerʼs disease with plasma p-tau217 clocks

Predicting not just if, but also when, cognitively unimpaired individuals are likely to develop onset of Alzheimerʼs disease (AD) symptoms would be useful to clinical trials and, eventually, clinical practice. Although clock models based on amyloid and tau positron emission tomography have shown promise in predicting the onset of AD symptoms, a model based on plasma biomarkers would be more accessible. Using longitudinal plasma %p-tau217 (the ratio of phosphorylated to non-phosphorylated tau at position 217) from two independent cohorts (n = 258 and n = 345), clock models were used to estimate the age at plasma %p-tau217 positivity.

The estimated age at plasma %p-tau217 positivity was associated with the age at onset of AD symptoms with a median absolute error of 3.0-3.7 years. Notably, the time from %p-tau217 positivity to onset of AD symptoms was markedly shorter in older individuals. Similar models were constructed with data from one p-tau217/Aβ42 immunoassay and four plasma p-tau217 immunoassays. These findings suggest that the time until onset of AD symptoms can be estimated using a single blood test within a margin of error that is acceptable for use in clinical trials.

Lifestyle choice relating to diet influences the pace of aging over the long term. A great deal of effort has been devoted to understanding why this is the case, focused on the specific effects of excess weight and various dietary components on metabolism. Researchers here make an effort to assess the effects of dietary choices on human life expectancy that emerge from the large amount of epidemiological data recorded in the UK Biobank. The results are in the same ballpark as the benefits to life expectancy indicated by some past large studies of the effects of moderate exercise.

Associations between healthy dietary patterns and life expectancy remain unclear. Here, we reported the prospective associations of five dietary patterns with mortality and life expectancy in 103,649 UK Biobank participants. Over a median follow-up period of 10.6 years, 4,314 total deaths were documented. Alternate Healthy Eating Index-2010, Alternate Mediterranean Diet (AMED), healthful Plant-based Diet Index (hPDI), Dietary Approaches to Stop Hypertension, and Diabetes Risk Reduction Diet (DRRD) were associated with lower all-cause mortality and longer life expectancy, with DRRD showing slightly stronger associations than hPDI.

Compared with the bottom quintile, achieving the top quintile of dietary scores was associated with 1.9 to 3.0 years of life gained at 45 years in men and 1.5 to 2.3 years in women. The life gained was longest in DRRD for males and AMED for females. The significant associations remained when accounting for genetic susceptibility. Our findings underscore the advantages of healthy dietary patterns in prolonging life expectancy, regardless of longevity genes.

Link: https://doi.org/10.1126/sciadv.ads7559

Researchers have in past years established that some degree of transmission of environmental information takes place from generation to generation. The epigenetic response to environmental factors such as abundance of food is partially passed on to offspring to result in changes in the operation of offspring metabolism. Epigenetic and metabolic reactions to abundance of food affect pace of aging and life span, and these outcomes are also changed in offspring, even when the offspring live in a different environment with different abundance of food.

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age.

This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of maternal obesity may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

Link: https://doi.org/10.64898/2026.02.04.703858

A wide variety of stem cell therapies exist at various stages of development and clinical use. A broad range of cell sources and processing techniques are unprotected by intellectual property and are thus employed by clinics both within and outside the more heavily regulated regions of the world. Stem cell therapies have long been a staple of the medical tourism industry. These first generation stem cell therapies may be widely used but do not contribute much in the way of robust data to improve our understanding of how well they work. It appears to be the case, from what little we can see, that the benefits of treatment vary notably between patients and clinics. Even similar approaches can produce very different outcomes in different hands, and it is not well understood as to why this is the case or how to improve the situation.

At the other end of the industry, companies develop their own proprietary, patented approaches to producing stem cell therapies that might have a chance of passing muster with regulatory authorities. The intellectual property and consequent monopoly on the technology used is necessary for a company to raise enough funding to conduct clinical trials, which regulators have made a very expensive process. Developing a therapy for regulatory approval tends to require directly addressing the questions of variability between patients and batches of cells, and so far stem cell therapies have done relatively poorly in clinical trials; robust and sizable benefits beyond a months-long reduction in inflammation remain elusive. Today's open access paper is, I think, largely interesting for a large table of trials and trial outcomes that illustrates that point.

A narrative review on the therapeutic potential of stem cells in neurodegenerative diseases: advances, insights, and challenges

Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. In recent years, stem cell transplantation therapy has gained attention as a promising treatment approach for neurological diseases. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

Stem cells, including embryonic stem cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells, and neural stem cells, possess distinctive regenerative properties. MSC-derived exosomes can traverse the blood-brain barrier and improve nerve cell longevity. Administration routes such as intravenous, intranasal, and direct brain transplantation are being studied. Neurodegenerative conditions such as PD, AD, HD, and ALS have been widely studied for therapeutic benefits.

This narrative review presents a current synthesis of the most recent experimental and clinical findings on stem cell-based therapies for major neurodegenerative disorders. In contrast to previous reviews that mainly concentrated on individual cell types or specific disease applications, this article combines evidence related to specific diseases, clinical trial results, and innovative technologies such as exosome therapy, nanotechnology, and CRISPR-based enhancements. It thus provides a holistic view that connects molecular mechanisms to practical applications. This review distinctively emphasizes the regulatory and ethical framework, tackling real-world challenges that have often been overlooked in earlier discussions.

Portions of the research community are concerned that the ability to preserve function in the aging brain is not progressing as rapidly as the ability to intervene in the aging of other organ systems in the body. This gives rise to articles such as the one here, which seeks to bring attention to this issue by coining a term for the healthspan of the brain specifically. The brain is complex, inaccessible, and irreplaceable in ways that are not the case for even, say, a heart, liver, or kidney. This constrains the strategies that might be developed to treat the aging of the brain, and those constraints in turn lead to concern regarding the development of future therapies.

Longevity medicine has achieved substantial gains in extending lifespan, yet these advances have not been matched by equivalent preservation of cognitive and functional capacity. As a result, many individuals now live longer while experiencing prolonged periods of cognitive decline, emotional dysregulation, sleep disruption, and loss of independence. Existing constructs, including lifespan and healthspan, insufficiently capture the central role of brain function in determining meaningful aging outcomes.

This article introduces the concept of brainspan, defined as the duration of life during which neural network efficiency remains sufficient to support autonomy, adaptive capacity, and coherent physiological and behavioral regulation. Brainspan is conceptualized as a dynamic systems property emerging from the integrated performance of cognitive, autonomic, sleep, emotional, and behavioral networks. We describe characteristic brainspan trajectories across the lifespan, identify chronic and episodic determinants of brainspan decline, discuss approaches to measuring brainspan using longitudinal, multimodal assessments, and outline implications for longevity medicine. Preserving brainspan reframes longevity from survival alone toward sustained independence, resilience, and functional agency across aging.

Link: https://doi.org/10.7759/cureus.101279

The research community appreciates that our ability to preserve function in the aging brain lags behind our ability to intervene in the age-related degeneration of other organs. The brain is also an organ in which our ability to replace tissues, either actually or in principle, is limited. It is comparatively difficult and expensive to access the brain, and structure in the brain store the data of the mind. The only practical path forward is to find ways to repair existing brain tissue without disrupting its activities and data storage. As the ability of the medical community to maintain the rest of the body advances, it will become ever more pressing to develop the means to restore function to an aging brain.

Longevity research has traditionally emphasized peripheral organ systems, metabolic optimization, and molecular aging pathways, while comparatively neglecting the central nervous system as the primary determinant of healthspan. This editorial advances the thesis that the brain functions as the rate-limiting organ of longevity. Drawing on systems neuroscience, clinical neurology, and evidence from neuropsychiatric and neurodegenerative disease, it is argued that progressive disruption of neural networks governs functional decline across multiple physiological systems, regardless of peripheral biological age.

Cognitive resilience, autonomic regulation, sleep integrity, affective stability, and behavioral capacity are centrally mediated processes that determine an individual's ability to maintain homeostasis over time. When brain function deteriorates, lifespan may persist, but meaningful healthspan collapses. A Brain-First Longevity Framework (BFLF) is proposed that prioritizes preservation and restoration of neural network function as foundational to extending durable, functional longevity. BFLF has direct implications for clinical practice, therapeutic development, and the future architecture of longevity medicine.

Link: https://doi.org/10.7759/cureus.101106

Loss of specialized cells is a feature of aging, exhibited in tissues throughout the body. There are many examples of cell types that could in principle be replaced once lost, but in practice are not replaced. The underlying reasons for this selective lack of regenerative capacity are incompletely understood. Examples of highly specialized cell types that do not regenerate include sensory hair cells in the inner ear and the podocyte cells of the kidney that are the subject of today's research materials. Interestingly, some of the cell types that regenerate poorly or not at all in mammals are in fact restored when lost in other species. While comparative biology allows for an exploration of these differences, cells are enormously complex and expanding the understanding of any specific topic in cellular biology remains a slow and difficult undertaking.

Researchers in the field of regenerative medicine are very interested in finding ways to encourage regeneration of cells and tissues that would not normally occur in our species. As yet, progress towards meaningful enhancement of human regeneration remains in its infancy, however. Despite some limited advances, the research community is not yet capable enough when it comes to controlling the behavior of cells to reliably achieve enhanced regeneration. A future in which transplanted cell and native cell behaviors can be shifted in desired ways to allow replacement of lost cells is entirely plausible, but we are not there yet.

Structural Adaptations in Aging Podocytes

The kidneys are vital organs that sustain life by filtering the blood and producing urine. This filtration process takes place in specialized structures called glomeruli, where podocytes play a crucial role by forming the filtration barrier on the glomerular surface. Mature podocytes cannot regenerate once lost, which means that the podocytes generated during fetal development must be used throughout life. It is well known that the number of podocytes decreases with age; however, lost podocytes are not replaced by newly generated cells, and continued podocyte depletion ultimately leads to loss of glomerular function. Therefore, the remaining podocytes are thought to adapt in order to preserve glomerular function despite a reduction in cell number; however, how podocytes adapt to this loss has long remained unclear.

In this study, the research team employed array tomography (AT), a technique that enables whole-cell observation of podocytes with their complex three-dimensional architecture, to elucidate age-related structural changes in podocytes in rats. As podocytes are lost, podocyte density on the glomerular surface decreases, while the volume of remaining aged podocytes increases markedly. The volume of aged podocytes was found to be approximately 4.6-fold greater, indicating compensatory hypertrophy in response to podocyte loss. In addition, areas lost through fragmentation were repaired by coverage from surrounding podocytes, during which atypical self-cellular junctions were frequently formed. These autocellular junctions are entirely absent in normal glomeruli and are considered to represent structural "footprints" of injury repair in aging glomeruli. Furthermore, although aging cells generally exhibit a decline in intracellular degradation capacity for unnecessary cellular components, podocytes were found to compensate for this functional decline by exporting such materials into the extracellular space rather than degrading them intracellularly.

Structural Plasticity of Aged Podocytes Revealed by Volume Electron Microscopy

Aged podocytes exhibited eight characteristic structural alterations: hypertrophy, pseudocystic changes, irregularity of foot processes, fragmentation, pruning of foot processes, autocellular interdigitation, release of lysoendosomal and multivesicular body contents, and an increase in lysosomal volume. Among these, hypertrophy was particularly notable - it resulted in an approximately 4.6-fold increase in podocyte volume and a 3.0-fold increase in total surface area, enabling adequate coverage of the enlarging glomerular surface. Furthermore, in areas where portions of podocytes seemed to be lost because of fragmentation, adjacent podocytes formed de novo autocellular junctions/interdigitation, thereby preventing exposure of the basement membrane. In addition, aged podocytes showed clustering of lysoendosomes and multivesicular bodies, with evidence of their exocytotic release into the urinary space. This process may compensate for the reduced intracellular degradation capacity associated with aging.

Mitochondrial dysfunction is a prominent feature of aging, particularly in tissues with high energy requirements, such as muscles and the brain. Part of the problem is that autophagy to clear out damaged mitochondria becomes less effective. Here researchers show that the distribution of mitochondria in neurons is important to the operation of autophagy and mitochondrial function. Unlike other cells, neurons have very long projections, the axons, that require a sufficiently large population of localized mitochondria for correct function. Aging impairs the mechanisms involved in ensuring that axons are sufficiently supplied with mitochondria, and this in turn impairs function in the brain.

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution.

We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.

Link: https://doi.org/10.7554/eLife.95576.5

Hematopoietic stem cells are responsible for generating red blood cells and immune cells. With age, this production of cells becomes dysfunctional in a variety of ways, contributing to the aging of the immune system. For example, production of immune cells becomes biased to myeloid cells at the expense of lymphoid cells, a change that contributes indirectly to the more inflammatory behavior of the aged immune system. Identifying specific mechanisms involved in hemotopoietic aging is the first step on the road to finding ways to reverse these issues.

Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitin-conjugating enzyme likely involved in clonal selection of HSCs, was elevated in aged murine and human HSCs. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging.

Elevated levels of Ube2g1 in young murine HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naïve T-cells, both known hematopoietic aging hallmarks. Interestingly, the ubiquitination function of Ube2g1 didn't primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired T-cell development and reduced HSC function.

Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.

Link: https://doi.org/10.3324/haematol.2025.288847