Fight Aging!

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

The aging of the oral microbiome is relatively understudied in commparison to the present interest in the aging of the gut microbiome, but there is still a fairly sizable literature on the topic. There is clear evidence for a relationship between the oral microbiome and age-related disease, which one will largely find in the context of the potential effects of inflammatory gum disease on cardiovascular and neurodegenerative conditions, where researchers are interested in the leakage of microbes and their metabolites into the bloodstream via injured gums. The literature is not consistent when it comes to effect sizes, however; it is unclear as to how much of a problem this is.

Today's open access paper presents a different focus on the oral microbiome, more akin to work on the gut microbiome. The authors are concerned with the effects of the oral microbiome and its metabolites on the harmful behaviors of senescent cells. Obviously one can mount a good argument for effects in the mouth and the role of cellular senescence in inflammatory gum disease, but going beyond that it is interesting to think about the possible size of the effect of the oral microbiome on senescent cell behavior elsewhere in the body. Again, the effect size are uncertain, however. Mechanisms might be plausible, but equally they may not as much of an issue as other problems in the aging body. Whether this is the case remains to be concretely determined.

Oral microbiome-SASP-aging axis: mechanisms and targeted intervention strategies for age-related diseases

Cellular senescence is a fundamental hallmark of aging. Triggered by diverse stressors, this process is defined by irreversible cell cycle arrest and the development of a complex senescence-associated secretory phenotype (SASP). The accumulation of senescent cells exerts harmful effects on the tissue microenvironment, including promoting inflammation and tissue dysfunction, thereby playing a unique role in systemic metabolic dysfunction and various age-related pathologies.

The oral microbiome is hailed as the second largest microbial community in the human body and serves as the 'second gut' microbial reservoir for human aging. It features a highly diverse ecosystem comprising bacteria, fungi, and viruses. To date, it has been discovered that the oral microbiome significantly influences host systemic and oral health by modulating metabolic and immune pathways. Recent attention has focused on the crosstalk between cellular senescence and oral microbiome dysbiosis and its consequences for host health.

While evidence indicates that the oral microbiome can accelerate disease progression by stimulating SASP-mediated systemic chronic inflammation, the intricate nature of their interactions and their collective impact on host aging remain unclear. Here, we first explore the correlation between the oral microbiome and aging. Then, we systematically summarize how the oral microbiome promotes the progression of aging-related diseases through the secretion of SASP components to induce chronic inflammation. Finally, we discuss the efficacy of therapeutic measures targeting the SASP in diseases.

The immune system is full of specific examples of what is known as antagonistic pleiotropy, the evolution of systems that are beneficial in youth but become harmful in old age. B cells serve a useful but not absolutely vital role in the immune system; one can survive without B cells if necessary, at the cost of diminished immune responsiveness. Unfortunately, aging brings a growing population of dysfunctional, harmful age-associated B cells that aggravate loss of immune function and age-related disease more generally. Destruction of B cells is readily achieved in animal models, either temporarily or permanently. Temporary clearance of B cells in mice is beneficial, removing the age-associated B cells and replacing them with more functional B cells, while here researchers show that permanent life-long removal of B cells in mice slows aspects of immune aging and improves late-life health.

Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span.

We uncovered a role for B cell-intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.

Link: https://doi.org/10.1126/sciimmunol.adv7615

Researchers here provide evidence for circulating oligodendrocyte myelin glycoprotein (OMG, and the expected joking reference is made in the paper's title) to correlate with the state of neurodegeneration in the aging brain. Interestingly, further investigations indicated that OMG is actively protective, not just a marker of protection, and thus one can envisage efforts to increase its expression in the brain as a basis for future therapies to make the brain more resilient to the damage of aging. That process of development is ever a long one, of course, and it is hard to predict timelines for moving from identification of a target to a viable approach to therapy.

After identifying oligodendrocyte myelin glycoprotein (OMG) as a central nervous system (CNS)-specific protein whose levels in peripheral circulation were inversely associated with cortical amyloid-β deposition in two community-based cohorts, the current study leveraged high-throughput plasma proteomic data from over a dozen independent cohorts to characterize OMG's role in Alzheimer's disease and other age-related dementias. We found lower plasma OMG levels among individuals with dementia, compromised brain structure (measured with MRI), and multiple sclerosis (MS). Additionally, individuals with lower plasma OMG were at elevated risk for future dementia and faster cognitive decline.

Using its multi-cohort, cerebrospinal fluid (CSF) proteomic signature, we demonstrated that higher OMG abundance is reflective of broader neuronal and oligodendroglial mechanisms that primarily promote the maintenance of axonal structural stability, along with cell adhesion, synaptic functioning, and proteostasis. Having identified similar structural- and axonal-integrity pathways in OMG's conserved brain tissue proteomic signature, we used genetic inference techniques to show that the cis regulation of OMG abundance across biofluids and brain tissue is causally implicated as protective against multiple neurodegenerative diseases.

Link: https://doi.org/10.1186/s13024-025-00921-1

Cytomegalovirus is a form of herpesvirus that is prevalent in the human population. As is the case for other herpesviruses, the immune system struggles to clear cytomegalovirus from the body. It becomes a persistent infection. Few people make it to late life without being infected, at least judging by those regions of the world where there is good data on cytomegalovirus prevalence. Cytomegalovirus infection typically goes unnoticed and produces no evident symptoms, at least in the vast majority of individuals who have a normally functioning immune system. But evidence suggests that the presence of cytomegalovirus infection has a corrosive effect on the immune system in late life. Ever more cells become specialized to focus on cytomegalovirus at the expense of populations needed to conduct other activities.

Researchers have correlated the presence of cytomegalovirus with risk of various age-related diseases, but it is unclear as to whether (a) cytomegalovirus infection selects for individuals with more dysfunctional immune systems and thus a higher burden of inflammation to drive the onset and progression of age-related diseases, or (b) cytomegalovirus is actively contributing to disease progression in some way, whether via promoting immune dysfunction and inflammation, or some other mechanism or mechanisms. It is also unclear as to how great a contribution is provided to disease progression by cytomegalovirus, if it is indeed providing a meaningful contribution. These sorts of questions are hard to definitively answer in human medicine. The most feasible approach is probably to develop the means to clear cytomegalovirus from the body, and see how the uninfected fare versus the infected over the long term.

Human cytomegalovirus infection and cognitive decline: insights from population and experimental studies

Human cytomegalovirus (HCMV), a ubiquitous DNA betaherpesvirus, is capable of persistent infection and immunomodulation, particularly in immunocompromised and elderly hosts. Emerging evidence links HCMV to neurodegenerative diseases through its multifaceted immunomodulatory effects. This review summarizes key viral architectures and mechanisms, epidemiological trends, and experimental data supporting HCMV's role in cognitive decline.

The association between HCMV infection and cognitive impairment has been explored across multiple large-scale studies, though findings remain heterogeneous. In the Sacramento Area Latino Study on Aging (SALSA), a prospective cohort of 1,204 older Mexican Americans (mean age 70.3 ± 6.8), higher HCMV IgG levels - but not HSV-1 - were significantly associated with accelerated cognitive decline over four years, independent of age, sex, education, income, and comorbidities. Postmortem and in vitro studies further implicate HCMV in neurodegenerative processes. In a PCR-based analysis, HCMV DNA was detected in 93% of brain specimens from patients with vascular dementia, compared to 34% of age-matched controls. In AD patients, HCMV seropositivity has been associated with increased neurofibrillary tangle (NFT) burden and elevated interferon-γ levels in cerebrospinal fluid (CSF) - a cytokine detected only in seropositive individuals .

Animal studies have also provided mechanistic insights into how cytomegalovirus infection may contribute to neurodegeneration. In vitro, murine CMV (MCMV) infection induces tau pathology in mouse fibroblasts and rat neuronal cells, dependent on late viral gene expression but independent of glycogen synthase kinase 3β (GSK3β) activity - suggesting an alternative pathway for tau phosphorylation. In vivo, repeated systemic MCMV infection in mice has been shown to elevate neuroinflammatory markers, disrupt mitochondrial function, increase oxidative stress, and impair cognitive performance.

While a causal role for HCMV in neurodegeneration remains unproven, future studies - particularly those leveraging antiviral therapies or vaccines aimed at preventing AD and vascular dementia - may clarify whether the virus functions as an etiological contributor. Additional approaches, including probiotics or fecal microbiota transplantation that influence HCMV latency and reactivation, also warrant close investigation as potential strategies to mitigate cognitive decline in susceptible populations.

The failure of anti-amyloid-β immunotherapies to more than slightly slow the progression of Alzheimer's disease has not much dented the amyloid cascade hypothesis, just clarified that amyloid-β becomes unimportant to disease progression once at the stage of sizable tau aggregration, neuroinflammation, and loss of cognitive function. The consensus continues to be that amyloid aggregation is the originating cause of Alzheimer's disease, the pathology that sets the stage for what comes later. That hypothesis will be confirmed or disproven in the years ahead as anti-amyloid-β immunotherapies are deployed in ever earlier stages of the condition. There may be other approaches to obtaining useful data, however. Here, researchers note that an existing drug, levetiracetam, reduces amyloid-β production in the brain, which will in turn reduce misfolding and aggregation of amyloid-β. This suggests the potential for a trial to directly assess its ability to delay or prevent Alzheimer's disease.

Amyloid-β (Aβ) peptides are a defining feature of Alzheimer's disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ42 in the SV lumen.

Levetiracetam (Lev) is a US Food and Drug Administration-approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ42 levels by reducing amyloidogenic APP processing in an SV-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway.

Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Brains from patients with Down syndrome also displayed presynaptic protein accumulation before the occurrence of substantial Aβ pathology, supporting the hypothesis that protein accumulation is a relevant pathogenic event in amyloid pathology. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.

Link: https://doi.org/10.1126/scitranslmed.adp3984

Academic research is, as a rule, always short of funding. Researchers are consistently strongly motivated to find less costly approaches to animal studies. One aspect of this pressure is that the standard, most widely used animal models of disease tend to be the ones that can be created as rapidly as possible, using various toxic, damaging strategies to reproduce aspects of aging in relatively young mice. Time has its own cost, and budgets don't stretch to waiting around for mice to get old. Thus in this modern era of enthusiasm for targeting the mechanisms of aging, the research community finds itself in the position of knowing too little about how aging interacts with disease processes.

Mouse models of Parkinson's disease (PD) are invaluable for advancing our understanding of the disease, and there is much hope that their use will help develop new therapeutic interventions. PD is a complex multisystem disorder characterized by a spectrum of motor and non-motor symptoms, and numerous mouse models have been developed to study its various aspects. While age is the primary risk factor for PD, the role of biological aging in PD is still unclear, and it is often overlooked in the design and application of these models. This omission risks missing critical insights into disease mechanisms and opportunities for the development and translation of novel interventions, in particular as aging biology is emerging as a therapeutic target.

The International Network for Parkinson's Disease Modelling and AGEing (PD-AGE), funded by the Michael J. Fox Foundation for Parkinson's Research, was established to address critical gaps in our understanding of the role of aging in PD. Its creation was prompted by a workshop that brought together leading experts in PD modeling and aging who collectively highlighted the need for a systematic investigation into how aging contributes to PD.

To achieve its goals, PD-AGE was divided into four working groups, each focusing on different models. Here, we report on the working group that focused on approaches using mouse models and conducted a series of workshops to build consensus on prioritizing models of aging and PD, experimental approaches, and the standardization of protocols for their characterization. The result is a comprehensive roadmap for selecting optimal models, defining relevant measurements, and harmonizing protocols.

Link: https://doi.org/10.1038/s41531-025-01239-x

The immune system is a very complex array of interacting cell populations, constantly changing over time. The inflammatory response is similarly complex, arising from many different inciting events and cascades of signaling and interaction between various immune cell types. Thus there are no simple measures of inflammation, no matter that the medical community has certainly tried very hard to make that goal a reality. Or perhaps it is better to say that simple measures of, say, one signaling molecule (in practice often C-reactive protein), paint a limited picture of what is actually going on. Sometimes that limited picture is useful, sometimes it is misleading.

Today's open access paper is a good illustration of the limits of what one can learn from a single marker, or two related markers. Circulating C-reactive protein and IL-6 are linked mechanistically in that C-reactive protein rises in response to IL-6. These are also the most commonly used measures of inflammation, so the research and medical communities have a fair grasp on the limitations. Nonetheless because they are commonly assessed markers, there is a tendency to continue to use them, as then at least there is a large body of existing data to compare against.

Peripheral inflammation in a Canadian cohort of neurodegenerative conditions: Occurrence, determinants, and impact

"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration. Interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.

We found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts - 36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.

In conclusion, peripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.

Imaging of atherosclerotic plaque, particularly via CT scan, has improved immensely over the past decade in its ability to quantify plaque and discern plaque composition, particularly with advances in machine learning approaches to analysis. Here, researchers demonstrate that plaque volume correlates with risk of severe cardiovascular events. The volume of softer, more fatty plaque also correlates with risk, much as one might expect. It is these less stable plaques that are more likely to fragment, leading to a downstream blockage. Imaging will become more important as cardiovascular therapies improve to point of being able to produce rapid stabilization or even regression of plaque, capabilities that do not currently exist. The best that can be done with the present standard of care, focused on lowering LDL cholesterol, is a slowing of plaque growth and some degree of stabilization over years of sustained use.

Despite the increasing use of coronary computed tomographic angiography (CCTA) in patients with known or suspected coronary artery disease (CAD), comparatively little is known about its predictive value for adverse events or clinical applicability of volumetric plaque analysis. This post hoc analysis involved a prospective randomized clinical trial conducted across 193 clinical sites in North America. Participants were symptomatic outpatients without known CAD who were randomized to receive CCTA. Core laboratory-based quantitative plaque measures including total plaque volume (TPV), calcified (CPV) and noncalcified (NCPV) plaque volume, low-attenuation plaque volume (LAPV), total plaque burden (TPB), and noncalcified plaque burden (NCPB), normalized with vessel volume.

The primary outcome was major adverse cardiovascular events, MACE (composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina). Among 4,267 patients, the mean age was 60.4 ± 8.2 years; 2199 patients (51.5%) were female and 2068 (48.5%) were male. Higher total plaque volume (≥87 mm), total plaque burden (≥35%), and noncalcified plaque burden (≥20%) were associated with an increased risk of MACE, independent of atherosclerotic cardiovascular disease risk, statin use, 50% or more stenosis, coronary artery calcium score, and high-risk plaque.

Link: https://doi.org/10.1001/jamacardio.2025.5520

Partial reprogramming involves the short-term expression of Yamanaka factors to restore youthful epigenetic control over nuclear DNA structure and gene expression. The primary challenge is to avoid accidental full reprogramming of cells into induced pluripotent stem cells, or otherwise losing necessary cell state, in a tissue environment in which different cell types require different degrees of exposure to pass various reprogramming-related thresholds. Interestingly, much of the present development of partial reprogramming as a basis for rejuvenation therapies has converged on the central nervous system as a target. For example, here researchers are interested in the neurons that encode memory, and find that partial reprogramming can improve memory function in aged mice.

Partial cellular reprogramming has emerged as one of the most promising strategies in regenerative medicine. Cyclic expression of the four Yamanaka factors (Oct4, Sox2, Klf4, and cMyc - OSKM), or a partial combination thereof (OSK), holds the potential to orchestrate rejuvenation of cellular function in aging while at the same time preventing changes in cell identity and tumorigenesis.

Memories are encoded in sparse neuronal ensembles termed engrams, which are found in different brain regions, with specific contributions to recall during memory consolidation. Thus, engrams in the hippocampus, and in particular in the dentate gyrus (DG), are predominantly important for learning and recent recall, whereas engrams in the medial prefrontal cortex (mPFC) become gradually more relevant for remote memory expression. Importantly, during physiological aging and in mouse models of Alzheimer's disease (AD), engram impairments interfere with memory recall, suggesting that engram dysfunction may underlie age- and disease-related memory decline.

Here, we report that partial reprogramming of engram neurons - bona fide memory trace cells - by OSK-mediated gene therapy reversed the expression of senescence-related and disease-related cellular hallmarks in aged mice and models of Alzheimer's disease (AD), re-established aberrant epigenetic-transcriptional patterns pertaining to synaptic plasticity, and counteracted AD-typical neuronal hyperexcitability. Importantly, irrespective of the brain area targeted or the behavioral paradigm employed, engram reprogramming also recovered learning and memory capacities to levels of healthy young animals, suggesting cognitive rejuvenation. These results posit that partial reprogramming of specific cell populations in the brain can be exploited for cognitive restoration in aging and disease.

Link: https://doi.org/10.1016/j.neuron.2025.11.028

APOE is a component of the low density lipoprotein (LDL) particles that carry cholesterol from the liver to where it is needed in the body. Lowering circulating LDL-cholesterol levels to modestly slow the progression of atherosclerosis is the primary approach taken in cardiovascular medicine; in recent years, new forms of LDL-lowering therapy such as PCSK9 inhibitors have been used to dramatically reduce LDL-cholesterol to far below normal levels with no immediately apparent prohibitively negative effects on patients.

In today's open access paper, researchers show that elevated APOE levels are a feature of old age and negatively affect bone regeneration, likely by suppressing the creation of osteoblast cells responsible for producing bone extracellular matrix structures. A near complete elimination of APOE production in the liver (which will also have the consequence of dramatically reducing LDL-cholesterol in circulation) improves the regeneration of fractures in old mice. There is clearly still a sense of caution in making permanent changes of this nature, despite ongoing development such as Verve Therapeutics' gene-editing PCSK9 inhibition therapy.

Neutralizing hepatic apolipoprotein E enhances aged bone fracture healing

In our previously published study, we demonstrated that circulating ApoE levels increase with age in patients and in mice and that by using liver targeted AAV to deliver siRNA for ApoE we decreased circulating ApoE levels and increased bone deposition and mechanical stability of healed tissue. However, the potential negative impact on a patient's cardiovascular health resulting from the permanent lowering of ApoE precludes this therapeutic strategy. Therefore, in the current study we aimed to use a neutralizing antibody against ApoE which would be cleared from the body by immune cells.

In this study we identified the mechanism of action by which hepatic ApoE inhibits fracture healing and identified a translatable non-invasive therapeutic intervention to improve aged bone repair. We knocked out hepatic ApoE expression in mice - this decreased levels of circulating ApoE and increased bone deposition and tissue mineral density within the fracture callus. Using tissue culture models, we found ApoE inhibits bone marrow stem cell to osteoblast differentiation and activity by binding to the cell-surface receptor Lrp4 and inhibiting Wnt/β-catenin signaling. Moreover, the same mechanism of action was identified during ApoE-induced inhibition of human bone marrow stem cells.

Finally, aged wildtype mice underwent tibial fracture surgery and were treated with a neutralizing antibody for ApoE 3 days post-injury which decreased levels of circulating ApoE and significantly improved fracture healing.

Atherosclerosis is the largest cause of human mortality, a growth of fatty plaques in blood vessel walls that narrow and weaken vessels. The structure and composition of plaques can vary considerably between people and within one individual. The most dangerous plaques are those with more fat and less structural material, as these are prone to rupture, leading to a downstream blockage and a heart attack or stroke. A plaque is a toxic environment that draws in macrophage cells that attempt to repair the lesion, but instead are overwhelmed, killed, and add their mass to the plaque. Initially, circulating monocyte cells arrive at a plaque and turn into macrophages, but in later stages an almost cancerous process causes smooth muscle cells in the vascular wall to turn into macrophages to further accelerate plaque growth and instability. Here, researchers find a way to potentially interfere in this process, and thus greatly reduce the formation of unstable plaques that are prone to rupture.

Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood.

Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation via an intermediate "stem-endothelial-monocyte" cell state. Integrated gene regulatory network inference and in silico perturbation modeling identified interferon regulatory factor 7 (IRF7) as a master transcriptional regulator orchestrating this specific pathogenic transition.

Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. In vivo, ApoE knockout mice challenged with a high-fat diet exhibited robust upregulation of IRF7 in aortic plaques, which co-localized with macrophage markers. Crucially, SMC-specific knockdown of Irf7 significantly attenuated atherosclerotic plaque progression, reduced necrotic core formation, and enhanced fibrous cap stability. Mechanistically, Irf7 silencing preserved the contractile SMC phenotype and inhibited the accumulation of pro-inflammatory SMC-derived macrophage-like cells within the lesion.

Link: https://doi.org/10.1093/pcmedi/pbaf039

The creation of engineered immune cells equipped with what are known as chimeric antigen receptors (CARs) can in principle be used to target any distinctive population of cells or extracellular materials for selective destruction. First introduced as a treatment for leukemia, this remains a very expensive form of therapy, and so is not as widely developed for new uses as might otherwise be the case. Nonetheless, a steady stream of proof of concept studies exists, such as the example here in which CAR technology is applied to target protein aggregates in the context of Alzheimer's disease.

Alzheimer's disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8+ cells, CD4+ T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging.

Here, we sought to exploit the beneficial properties of CD4+ T cells while circumventing the need for T cell receptor and peptide / major_histocompatibility_complex antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4+ T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4+ T cells into the brain parenchyma and leptomeninges.

In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4+ CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the central nervous system, paving the way for future development of cellular immunotherapies for neurodegenerative disease.

Link: https://doi.org/10.1073/pnas.2530977123

The retina at the back of the eye is the one part of the central nervous system that can be readily visually inspected, including the state of the network of blood vessels that supports it. Capillary networks of tiny blood vessels are dense and actively maintained; as the character of angiogenesis changes for the worse with aging, these networks become less dense and exhibit other signs of damage. Thus imagery of the retina provides a lot of data that can be employed to, for example, produce aging clocks, or act as a proxy measure for other forms of vascular and nervous system aging.

For retinal imagery to be usefully employed as a proxy measure of any specific aspect of vascular aging or central nervous system aging, or specific form of age-related damage, a robust correlation must first be demonstrated. Thus we have papers such as today's example, in which researchers establish links between retinal imagery characteristics and vascular and brain aging. One might expect this to inform efforts to further advance retinal imaging as a relatively low cost diagnostic tool, a way to better establish risk and the need for more costly forms of assessment in older people.

Cross-organ analysis reveals associations between vascular properties of the retina, the carotid and aortic arteries, and the brain

Doctors often use eye scans to check for signs of heart and brain disease, but the exact link between the tiny blood vessels in the eye and those in major organs is unclear. We aimed to systematically map similarities between blood vessels across the entire body. We compared vascular image-derived phenotypes from the brain, carotid artery, aorta, and retina, using UK Biobank sample sizes ranging from 18,808 to 68,740 participants. We examined phenotypic and genetic correlations, as well as common associated genes and pathways.

Here we show that white matter hyperintensities are positively correlated with carotid intima-media thickness (r = 0.03), lumen diameter (r = 0.14), and aortic cross-sectional areas (r = 0.09), but negatively correlated with aortic distensibilities (r ≤ -0.05). Arterial retinal vascular density shows negative correlations with white matter hyperintensities (r = -0.04), intima-media thickness (r = -0.04), lumen diameter (r = -0.06), and aortic areas (r = -0.05), while positively correlating with aortic distensibilities (r = 0.04). Significant correlations also persist after correcting for hypertension.

In summary, we found strong connections with the health of retinal blood vessels mirroring the health of the brain and major arteries. This suggests that some of the same factors influence vessel health across the body. This suggests that an eye scan could be a fast, non-invasive way to get a complete snapshot of a person's overall cardiovascular and brain health. These findings could help doctors identify health issues, such as early artery stiffness or brain aging, much sooner.

Aging is an accumulation of cell and tissue damage, combined with the dysfunctions resulting from that damage. Damaged systems lose function in a haphazard, random fashion that, averaged out over time and across many systems, tends to be proportional to the burden of damage. This is the case whether the system is a simple mechanical device, an organ, or a human. In aging humans and animals one thus observes correlations between most different examples of lost and degraded function, including those that cause mortality.

We assessed the population distribution of age-related functional impairments (ARFIs) and their associations with mortality and life expectancy (LE). We included 12,906 participants (mean age: 62.6 years) from the China Health and Retirement Longitudinal Study. Visual impairment, hearing impairment, cognitive impairment, sleep disorder, depressive symptoms, and disability in activities of daily living (ADL) were assessed. Cox proportional hazards models were used to estimate the associations of ARFIs with all-cause mortality. Life expectancy at age 50 was estimated by the presence and number of key ARFIs.

The six ARFIs exhibit distinct distributions by ages and provinces across China. During the 9-year follow-up, ADL disability, cognitive impairment, and depressive symptoms are independently associated with 64%, 41%, and 20% higher risks of mortality, corresponding to LE losses of 4.45, 3.08, and 1.59 years at the age of 50 years. A greater number of key ARFIs is associated with higher mortality risk in a dose-response manner (hazard ratios: 1.23 for one, 1.42 for two, and 1.86 for three) and greater LE loss (1.63 years for one, 3.37 for two, and 4.96 for three).

Link: https://doi.org/10.1038/s43856-025-01350-3

Evolution optimizes for reproductive success, and thus it should be no surprise to find that reproductive organs influence the entire body, and thus their aging has sizable effects on the aging of other organs. Researchers here review the mechanisms of aging that act to degrade structure and function of the testes, and in turn affect the production of androgens that influence tissue function elsewhere in the body.

The testis, a male-specific organ, plays a critical role in maintaining spermatogenesis and androgen production. As men age, testicular function declines, compromising not only reproductive capacity but also overall health and quality of life. Testicular ageing is characterized by progressive degeneration of the seminiferous epithelium and interstitial compartments, leading to endocrine dysfunction, impaired spermatogenesis, and heightened risk of age-related disease.

Although mechanistic insights are advancing rapidly, most therapeutic studies remain rooted in reductionist single-cell models that overlook the integrated dynamics of the testicular microenvironment. In reality, testicular ageing reflects a coordinated decline of germ cells, Sertoli and Leydig cells, and their niches. This process is driven by interconnected mechanisms, including oxidative stress, defective DNA repair and autophagy, dysregulated endocrine homeostasis, impaired protein quality control, and aberrant activation of ageing-related signalling pathways, which act synergistically.

Testicular ageing is accompanied by a progressive collapse of energy metabolism. Impaired fatty acid utilisation, reduced glucose uptake, and widespread mitochondrial dysfunction collectively drive metabolic remodelling that deteriorates the testicular microenvironment. Moreover, senescent somatic cells acquire a senescence-associated secretory phenotype (SASP), releasing pro-inflammatory cytokines such as IL-6 and IL-1β, while testicular macrophages adopt a pro-inflammatory state that recruits adaptive immune cells. Together, these changes establish a chronic inflammatory microenvironment that reinforces cellular senescence and accelerates testicular ageing.

Priorities for future research include clarifying cell-microenvironment interactions, establishing non-invasive biomarkers for early detection, and resolving metabolic pathways that may guide senolytic strategies. As therapeutic paradigms evolve, emerging interventions - particularly stem-cell-based approaches - may extend beyond the limits of conventional pharmacology to enable more precise and effective mitigation of testicular ageing.

Link: https://doi.org/10.1080/07853890.2026.2624183

The peptide industry has been growing for some years now, becoming more vocal and visible. It occupies a similar space to the supplement industry, and seems likely to provoke many of the same battles with regulators such as the FDA. Peptide use is characterized by the same lack of rigorous supporting data that attends supplement use, and for many of the same reasons. The lines in the sand dividing peptide from drug are just as arbitrary as those dividing supplement and drug, and just as driven by funding and the high cost of regulatory compliance. Peptides that can be effectively monopolized via intellectual property become drug candidates, as only with that monopoly is it possible to raise enough funding to engage with regulators and run clinical trials. Peptides that cannot remain on the outside, without the robust human data needed to support greater interest.

Against the background of this broader context of a growing market for the use of peptides, you might recall that the peptide FOXO4-DRI was one of the early potential senolytic therapies to be validated in animal studies, back in the mid-2010s. FOXO4-DRI interferes in the interaction between FOXO4 and p53 that normally inhibits apoptosis of senescent cells, and thus results in the selective destruction of senescent cells with very little impact on other cells. Clearance of senescent cells is well demonstrated to improve health in aged animal models, but only relatively small clinical trials of a few senolytic small molecules have yet taken place to validate use in humans.

A company, Cleara Biotech, was formed to commercialize the early academic work on FOXO4-DRI, and appears to still be a going preclinical concern focused more on the FOXO4-p53 interaction than on FOXO4-DRI per se. Other groups have since become involved, such as Numeric Biotech, and it has long been the case that anyone so minded can just up and buy FOXO4-DRI for personal use from any number of peptide sellers. It is unclear as how many people are choosing to do that, and certainly we'll never see any sort of useful data resulting from that use. Meanwhile, academic research groups continue to work with FOXO4-DRI as a tool to explore the FOXO4-p53 interaction in the context of cellular senescence as a driver of degenerative aging.

FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway

Endothelial cell dysfunction during aging is a key driver of vascular aging and related diseases; however, effective strategies to selectively eliminate senescent endothelial cells and restore vascular function remain lacking. FOXO4-DRI, a novel peptide-based intervention, specifically disrupts the interaction between FOXO4 and P53, thereby inducing apoptosis in senescent cells. This study innovatively focuses on the mechanism by which FOXO4-DRI induces apoptosis in senescent endothelial cells, demonstrating that it functions by activating the p53/BCL-2/Caspase-3 signaling pathway to promote selective apoptosis of these cells. FOXO4-DRI significantly improves vascular function and delays vascular aging.

This study aims to analyze the vascular function and aging status of the aorta in naturally aged mice and progeroid model mice following FOXO4-DRI injection. Additionally, it investigates changes in endothelial cell function in senescent endothelial cells induced by oxygen-glucose deprivation (OGD), as well as the protein expression and interaction in the FOXO4-P53 signaling pathway. To assess the impact of FOXO4-DRI on endothelial cell senescence, the senescent endothelial cells were treated with FOXO4-DRI, followed by immunofluorescence and Western blotting experiments.

Injection of FOXO4-DRI in both naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function. Additionally, we found that FOXO4-DRI alleviates endothelial cell senescence induced by OGD, thereby enhancing endothelial cell function. Through co-immunoprecipitation (CO-IP) experiments, we discovered that FOXO4-DRI prevents the binding of FOXO4 to P53, facilitating the phosphorylated P53 nuclear exclusion, which subsequently trigger BAX and cleaved caspase-3, leading to the apoptosis of senescent cells. Ultimately, this mechanism achieves the goal of inhibiting vascular aging.

There are so many detrimental age-related changes in gene expression that it will always be possible to pick out any one gene exhibiting altered expression and spend years on research and development aimed at fixing this one specific issue. Restoring youthful expression of any one gene in any one tissue is an achievable goal for present day medical research and development, though costs and regulatory hurdles remain challenging. Expression can be increased via gene therapy vectors, or reduced via various approaches, such as small interfering RNA, that attack some part of the process of gene expression. The most productive future will not be one of picking through thousands of changes one by one, however, but instead a matter of attempts to restore youthful gene expression more generally, for most or all genes, through some form of reprogramming. Still, the one by one approach remains the primary focus of the research community, as this example illustrates, though at least researchers now tend to favor regulatory genes that influence the expression of large numbers of other genes.

O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.

While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.

Link: https://doi.org/10.1002/cbic.202500774

Researchers here provide evidence for glycogen produced by the gut microbiome to contribute to age-related neurodegeneration. A mutation associated with amyotrophic lateral sclerosis and frontotemporal dementia appears to make the inflammatory consequences of microbiome-derived glycogen worse, thus potentially explaining its relevance to disease. But the prevalence of the microbes involved in the production of glycogen in the gut microbiome of patients with these conditions suggests that every older person is impacted by this mechanism to some degree, with that degree being dependent on the exact composition of the gut microbiome. This is one of a range of studies showing at least some correlation between gut microbiome composition and specific age-related conditions, and as illustrated here, researchers are starting to move beyond correlation to explore the mechanisms responsible.

Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation.

Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.

A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.

Link: https://doi.org/10.1016/j.celrep.2025.116906

The composition of the gut microbiome, the relative sizes of the various microbial populations, changes with age in ways that promote chronic inflammation and dysfunction throughout the body. The production of beneficial metabolites decreases, while microbes capable of provoking a constant inflammatory reaction increase in number. Studies of fecal microbiota transplantation have demonstrated that the unfavorable composition of the gut microbiome in old animals can be rejuvenated via the introduction of donor material from young animals. One treatment produces lasting rejuvenation, though presumably the processes of aging will slowly degrade the gut microbiome over time, just as they did before. Health is improved and life span increased.

Fecal microbiota transplantation sees enough use in medicine for researchers and clinicians to broadly understand the safety profile of the treatment, and for a body of work to have evolved regarding best practices for sourcing, screening, storing, and using donor material. But the most common use case, to treat C. difficile infections in which hostile bacteria have overrun the intestine, is not focused on older people, and donors do not necessarily tend to be younger people. Clinical trials that do provide evidence specifically for the use of young donor material to treat old patients are thin on the ground. So it is good to see that at least one group is making the effort to run such a trial; we might expect to see results in a few years.

Aging Resilience Through Microbiota Optimization and Regulation (ARMOR)

It has been proposed that changes in the gut microbiota in aging individuals, known as gut dysbiosis, contribute to sarcopenia. Species diversity decreases, and bacterial representation is altered, which could impair muscle function through various pathways, such as mitochondrial dysfunction, chronic inflammation, and disruption of protein synthesis. Muscle function loss is strongly associated with cognitive and metabolic impairment in older adults.

Recently, it has been demonstrated that fecal microbiota transplantation (FMT) is an effective procedure for modulating gut microbiota and has proven highly effective in managing cases of Clostridium difficile-associated chronic diarrhea. The main objective of this project is to carry out FMT from young, physically active donors to a cohort of older adults to evaluate its effect on muscle, cognitive, and metabolic function.

Why donors who exercise? There is growing evidence that gut microbiota diversity is increased in young, physically active individuals. The FMT is planned to be administered through lyophilized microbiota capsules. By restoring microbial diversity, it is expected to improve the quality and function of skeletal muscles, leading to greater cognitive and metabolic resilience.

Randomized, double-blind, placebo-controlled trial of fecal microbiota transplantation from young physically active donors to promote resilient aging: clinical trial protocol (ARMOR study)

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength in older adults, is a key determinant of frailty and functional decline. Affecting up to 15% of individuals aged 65-80 years and more than 50% of those over 80, sarcopenia not only compromises physical autonomy but also increases the risk of metabolic dysfunction and cognitive decline. Emerging evidence suggests that age-related gut microbiota dysbiosis contributes to these impairments by reducing microbial diversity and altering host metabolic signaling, leading to chronic inflammation and mitochondrial dysfunction. The present study aims to evaluate the safety, tolerability, and preliminary efficacy of oral fecal microbiota transplantation derived from young, physically active donors administered to older adults, focusing on outcomes related to functional autonomy, muscle performance, metabolism and cognition.

This is a double-blind, randomized, placebo-controlled clinical trial involving community-dwelling adults aged 65-84 years. Participants will be randomized 1:1 to receive either FMT capsules or placebo following a short course of oral rifaximin (or placebo). Assessments will be performed at baseline and at 4, 8, and 20 weeks post-intervention. The primary outcomes are safety and tolerability, as well as changes in the Global Index of Functional Autonomy (GDLAM battery) and muscle strength. Secondary outcomes include gait speed, body composition (DXA), metabolic biomarkers, gut microbiota composition (shotgun metagenomics), cognitive performance, and psychological well-being.

By restoring microbial diversity and function, FMT from young, active donors may enhance muscle quality, cognitive resilience, and metabolic health in older adults. This study introduces a novel, non-invasive therapeutic approach based on lyophilized and encapsulated microbiota, offering a feasible and scalable strategy to promote healthy aging.

Aging is by far the greatest cause of human suffering and mortality. Yet is it in human nature to resist every change whether or not it is beneficial. It is also in human nature to accept what is. So the development of means to treat aging in order to prevent the present toll of suffering and death will be resisted, and then these means will come into being, exist, and be accepted. Along the way, a lot of ink will be spilled on why we should or should not make the world a better place in this way. Such is the way of things. Ignoring the debate to focus on building rejuvenation biotechnologies is probably the fastest way to create (a) therapies for aging that most people will choose to use and (b) a world in which most people accept this state of affairs as a good thing.

Humanity has long sought to mitigate the challenges of ageing and extend the span of healthy life. But for centuries, a story of resignation shaped the moral imagination: ageing and death were inevitable, so ethics concerned how best to accept them. This narrative is crumbling. Over the past few decades, biogerontology has revealed that ageing is not immutable. Lifespan has been extended by tenfold in nematodes and by 50% in mice. Cellular reprogramming, senolytic drugs, and genetic insights suggest that at least parts of the ageing process can be modified.

Due to the profound implications of such progress, ethical debate has followed close behind. However, most discussions have been dominated by consequentialist framings: balancing hoped-for benefits (e.g., reduced healthcare costs, productivity gains) against feared harms (e.g., overpopulation, inequality, loss of meaning). Both critics and advocates tend to treat longevity as a matter of projected outcomes, reducing the ethical question to a contest of demographic forecasts. What remains underexplored is a deeper foundation: whether anti-ageing research is justified independent of its consequences, rooted instead in duties, autonomy, and the intrinsic value of life itself.

We seek to further this discussion by grounding the case for longevity research not only in outcomes but also in respect for autonomy, self-ownership, and the intrinsic value of life itself. On this basis, we address three kinds of critiques: philosophical appeals to "naturalness", societal concerns about resources, justice, and stagnation, and individual worries about meaning and boredom, showing that none provide decisive objections. Beyond rebuttal, we highlight neglected benefits: longevity research drives technological integration like the Apollo program, affirms the priority of existing persons over abstractions, and liberates individuals from rigid age-based expectations. The moral baseline must flip: the burden now falls on defenders of forced ageing to explain why preventable suffering should continue.

Link: https://doi.org/10.1016/j.arr.2026.103054

The supporting cells of the brain are collectively known as glia. This category includes astrocytes, microglia, and oligodendrocytes, among others, cells that are responsible for maintenance of an environment in which neurons can function, or directly aiding neuron function in various ways. Researchers here discuss how age-related changes in the interactions between neurons and glia may both arise from neurodegeneration and drive neurodegeneration. Manipulating some of these interactions can slow aging and extend life span in flies.

Aging is often discussed as something that happens inside cells: DNA is damaged, mitochondria stop working, and proteins are misfolded. But aging also changes how cells communicate with each other. For example, neurons in the brain rely on neighboring cells, called glia, for nutrients, waste handling, and local repair. Dysregulation of the interactions between neuron and glia is considered a hallmark of brain aging, but the consequences of disrupting neuron-glia communications are still being uncovered.

Researchers compared glial cell-surface proteomes in young (5 day) and old (50 day) flies to examine how signaling molecules are regulated in the aging brain, and identified a set of 872 proteins that exhibited age-specific differences in abundance. Proteins that became more abundant with age were enriched for functions related to localization and transport, which supports the idea that older brains may need stronger homeostasis and trafficking control. In contrast, many proteins that became less abundant with age were associated with synapse organization, axon guidance, and related processes.

The researchers chose 48 genes that exhibited the greatest changes between the glial surface proteomes of young and old flies, and tested whether manipulating these genes in adult glia altered lifespan. One candidate from the screen, a cell adhesion protein called DIP-β, was found to extend lifespan in both males and females when overexpressed in glia. Older flies with higher levels of DIP-β in their glia also climbed better than controls, suggesting improved late-life function in addition to longer lifespan. Analysis suggested that DIP-β overexpression was associated with increased signaling between glia and neurons, and between glia and fat cells, with prominent shifts in a number of signaling pathways (such as the TGF-beta, Wnt, FGFR, and EGFR pathways). This is an appealing model because it connects a surface protein found in glia to broader tissue coordination during aging.

Link: https://doi.org/10.7554/eLife.110158

Nuclear DNA is surrounded by transcriptional machinery, protein structures that will attempt to transcribe any gene sequence they encounter. Where DNA is compacted into regions of heterochromatin by being spooled onto histones, genes are silenced because their sequences are hidden from transcriptional machinery. Whether a given stretch of DNA is compacted or not is determined by epigenetic mechanisms, largely decorations (such as methyl groups) attached to DNA and histones that alter their structural behavior. A general feature of aging is a loss of heterochromatin and increasing expression of genes and other sequences that are usually silenced in youth. This leads to, for example, the expression of transposons that can drive DNA damage and inflammation, but also disruption and change in normal cell function.

Some time ago, researchers established a way to visualize whether or not a given region of DNA is compacted into heterochromatin. Flies can be genetically engineered with suitably placed genes that change the color of some of their features, such as eye segments, depending on whether or not they are expressed. Thus just by looking at the fly, researchers will know whether or not the region of DNA containing the inserted gene is compacted. A number of different fly lineages have been constructed over the years, as researchers needed a solution for one region or another. This approach is called position effect variegation.

Today's open acccess paper is a discussion of position effect variegation as a tool to inspect changes in DNA compaction into heterochromatin that occur with age and their correlation with high level outcomes such as mortality risk and longevity. Since increased loss of heretochromatin appears to correlate with longevity in flies, position effect variegation could be used to build aging clocks (in flies at least) that primarily reflect alterations to DNA structure rather than other mechanisms.

Position effect variegation (PEV) as an aging clock: visualization of age-dependent loss of heterochromatin and longevity associated with enhanced heterochromatin

The heterochromatin loss model of aging suggests there is an age-dependent reduction in epigenetic factors that form and maintain the heterochromatin state of chromosomes. Position Effect Variegation (PEV) can visually report phenotypes of heterochromatin mediated silencing in Drosophila Melanogaster eyes and we use PEV to examine the association between heterochromatin state changes and aging.

Pericentric inserts causing PEV showed suppressed variegation phenotypes in old age compared to young age and were confirmed to be associated with progressively increasing transcription, indicating loss of heterochromatin mediated silencing. Within a single population, animals with enhanced PEV phenotypes live longer than those with more suppressed PEV phenotypes, suggesting that small differences in environmental or genetic factors within this population could be responsible for differences in heterochromatin and lifespan.

Environmental factors could enhance heterochromatin, reduced nutrient diet and lower temperature coincided with enhanced heterochromatin and longer life. Furthermore, genetic variants associated with long life, including chico mutants, lead to increased heterochromatin and enhanced PEV phenotypes. Therefore, aging can be linked to heterochromatin loss and developmental increases in heterochromatin are associated with longevity. Thus, PEV reporters act as aging clocks demonstrating loss of heterochromatin that progresses with age and epigenetic alterations that can promote longevity.

The addition and removal of methyl groups from specific locations on the genome is one of the epigenetic mechanisms used to control the structure of DNA in the cell nucleus, such as which sequences are hidden via compaction into heterochromatin and which remain accessible to allow the expression of genes. That the pattern of DNA methylation changes with age in characteristic ways is what allows the existence of epigenetic clocks, the use of DNA methylation status to assess biological age. That epigenetic control over gene expression changes with age also makes it a potential target for the development of therapies to treat aging, particularly now that partial reprogramming studies have amply demonstrated that reversing age-related epigenetic changes is possible in principle.

As individuals age, the precise regulation of DNA methylation gradually deteriorates, leading to widespread epigenetic drift. This loss of control results in both global hypomethylation and site-specific hypermethylation, disrupting normal gene expression patterns. Global hypomethylation can lead to genomic instability, activation of transposable elements, and oncogene expression, while localized hypermethylation may silence tumor suppressor genes or genes critical for immune regulation and metabolic function. These changes are increasingly recognized as contributors to the development of chronic diseases. For example, aberrant DNA methylation patterns have been implicated in cancer, cardiovascular disease, type 2 diabetes, and neurodegenerative disorders such as Alzheimer's disease.

One of the most promising trends is the integration of DNA methylation data with other layers of biological information, such as transcriptomics, proteomics, metabolomics, and microbiomics. This multi-omics approach offers a holistic view of aging by capturing complex molecular interactions/network that DNA methylation alone cannot fully explain. Combining these datasets can refine biological age estimates, identify novel aging biomarkers, and uncover mechanisms driving age-related functional decline.

Parallel to these analytical advances, there is growing interest in interventions targeting epigenetic aging. Lifestyle modifications, including diet, exercise, and stress management, have demonstrated potential to modulate DNA methylation patterns and slow epigenetic age acceleration. Pharmacological approaches, such as senolytics, epigenetic modulators, and novel small molecules, are under investigation for their ability to reverse or delay methylation-based biological aging. Clinical trials integrating methylation clocks as endpoints are beginning to evaluate the efficacy of these interventions, potentially enabling real-time monitoring of biological age and intervention impact.

Link: https://doi.org/10.3389/fmolb.2025.1734464

Rapamycin is the most well studied of the mTOR inhibitors. It produces immunosuppression at high doses, and has been used in this context in the clinic for more than twenty years. At lower doses it mimics aspects of the beneficial metabolic response to calorie restriction, om particular an increased operation of the cellular maintenance processes of autophagy. In animal studies this has been demonstrated to slow aging and extend healthy life. Human clinical trial data for this lower dose anti-aging usage remains relatively sparse, unfortunately, but the results that do exist are interesting.

Rapamycin is one of the most intensively studied compounds with potential effects on longevity. Available experimental data indicate that inhibition of the mTOR pathway and activation of autophagy lead to improved cellular homeostasis, reduced oxidative stress, and a slowing of aging processes across multiple model organisms.

Current clinical studies in humans, although limited in number and involving small populations, suggest that low doses of rapamycin may enhance immune function, reduce visible signs of skin aging, and positively influence well-being and metabolic parameters.

Despite these promising findings, knowledge regarding the long-term safety, efficacy, and optimal dosing regimens of rapamycin remains limited. Further, multicenter, randomized clinical trials are needed to determine whether modulation of the mTOR pathway can represent an effective and safe strategy to support healthy human aging.

Link: https://doi.org/10.7759/cureus.98514

Rapamycin and other mTOR inhibitors mimic some of the mechanisms making up the response to calorie restriction. Their most interesting effect is to increase the operation of autophagy in cells. Autophagy is a collection of processes responsible for recycling damaged or unwanted proteins and structures in the cell. A large proportion of the approaches shown to modestly slow aging in yeast, worms, flies, and mice are characterized by increased or more efficient autophagy; it is a universal response to stress of any sort placed upon a cell. Too much autophagy can be a bad thing, but a modest increase improves health in the context of the dysfunctional, damaged environment of aged tissues.

Another feature of mTOR inhibitors, and the age-slowing interventions that are characterized by upregulated autophagy, is that the burden of harmful, inflammatory senescent cells that linger in aged tissues is reduced. The present thinking on this topic is that this reduction does not occur because senescent cells are destroyed by the intervention, but rather that the pace at which cells become senescent is reduced. This seems sensible: more autophagy allows cells to better maintain function and resist damage, and thus fewer cells will be tipped over the line into senescence in response to damage.

Here, however, researchers argue that, at least in immune cells, the effects of mTOR inhibition on cellular senescence do not emerge from autophagy. Instead, there is a direct effect on the burden of DNA damage in these cells, and it is that reduced DNA damage that leads to a reduced number of cells becoming senescent. Further work will have to be conducted in order to fully understand how exactly mTOR inhibition produces this outcome.

Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability.

In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition.

To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

Structures of the endoplasmic reticulum are where the folding of newly synthesized proteins takes place in the cell. The endoplasmic reticulum is also involved in a range of other activities relevant to the manufacture of proteins and other molecules, such as quality control and recycling of misfolded proteins. Researchers here describe how the endoplasmic reticulum changes in structure with age, and link this to changes in the recycling of endoplasmic reticulum structures via autophagy. They suggest that these changes are compensatory, but become maladaptive in later life.

The morphological dynamics of the endoplasmic reticulum (ER) have received little attention in the context of ageing. Here we established tools in C. elegans for high-resolution live imaging of ER networks in ageing metazoans, which revealed profound shifts in ER network morphology that are driven by autophagy of ER components (ER-phagy). Across a variety of tissues, we consistently found a decrease in ER protein levels and cellular ER volume, and a structural shift from densely packed sheets to diffuse tubular networks. The ER content also declined in yeast and mammalian systems, and proteomic atlases of the ageing process in worms and mammals showed that age-onset collapse in ER proteostasis function is a broadly conserved aspect of the ageing process

We found that Atg8-dependent ER-phagy is the key mechanism driving turnover and remodelling of the ER network during ageing. A targeted screen for mediators in C. elegans revealed that the physiological triggers of ER-phagy in an ageing metazoan model are cell-type specific. Tissue-specific roles of ER-phagy receptors may help to explain why the ubiquitous macroautophagy machinery seems to be a universal requirement for longevity assurance in metazoan genetic studies, whereas the importance of selective ER-phagy mediators has been slower to emerge. Subsequently, we demonstrate that the two pathways capable of blocking age-associated ER-phagy, TMEM-131 and IRE-1-XBP-1, are required for mTOR-dependent lifespan extension in C. elegans.

Importantly, not all changes that occur during ageing reflect pathogenesis. The earliest remodelling events are likely to be adaptive responses to the cessation of developmental programmes and rising metabolic and cellular damage. We propose a model where age-dependent ER remodelling serves as an adaptive step in the ageing process associated with reprogramming of the proteostasis network. However, although data indicate that the net effect of ER-phagy on lifespan is positive, we speculate that early pronounced remodelling of ER structures is likely to trigger pleiotropic trade-offs later, especially in longer-lived cells and animals.

Link: https://doi.org/10.1038/s41556-025-01860-1

In recent years, researchers have established that a great many proteins can aggregate to some degree in cells of the aging brain, and that this likely contributes to loss of function. This issue is distinct from the few well-known proteins such as amyloid-β that aggregate to a very large degree in the context of neurodegenerative conditions. Here, researchers provide evidence for this generalized aggregation across more than a thousand proteins to contribute to impaired maintenance of synapses in the aging brain.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing. Here we engineered tools that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age.

The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1038/s41586-025-09987-9

Cryonics refers to the low-temperature storage of the body (or at least the brain) at death to offer the chance that a more technologically capable future can restore that individual to life. It is an unknown chance, possibly a small and unknown chance, but cryonics is certainly a better option that the other end of life alternatives facing someone who is going to age to death before rejuvenation biotechnology and the medical control of aging becomes a reality. Cryonics remains a very good idea that should be far more widely used, significantly supported, and undergoing aggressive technological development to improve capabilities. But it is very far from being widely used and suffers from the same situation that afflicted the aging research community thirty years ago: a minority field with too little financial and popular support to generate the desired degree of progress.

Newfound enthusiasm for the development of means to treat aging has led to a vast (if very unevenly distributed) investment in the field, hundreds of companies working on all sorts of approaches. A tiny fraction of that enthusiasm for doing something to address age-related disease and mortality has spilled over into support for cryonics. Even that tiny fraction is proving to be transformative. I pick on Alcor as the example because I am signed up with Alcor, and therefore do pay more attention to what is going on there, but the field as a whole is showing progress. Europe has its own modern cryopreservation organization these days, Tomorrow.bio, their focus on customer service raising the bar for the community. Meanwhile Until Labs is working on making reversible vitrification of organs a commercial possibility, a best foot forward to generate further capital and legitimacy for cryonics.

After years of little visible progress and too little funding to improve on that situation, Alcor has of late acquired what is for a non-profit a sizable influx of capital. Enough to not just establish new research programs with new equipment, but to address look and feel and customer service priorities, such as a modernization of the website and creating a portal and modern relationship management system for their customers - and no doubt more under the hood than that. Alcor comes to the table with the DNA of decades of year to year struggle as a small non-profit serving a small community. Shedding some of those historical habits and culture will be necessary in order for a commercial industry of cryopreservation to emerge.

In a better world, this could have happened decades ago, driven by a broad popularist realization that cryopreservation to travel into a potentially far better future is the best of all options, turning an end into a hiatus. But it didn't. At least the first increments of such a sea change are happening now. A few excepts from a recent Alcor newsletter follow, for those who don't keep tabs on how this industry is modernizing.

Fundraising & Endowment: 2025 closed out as one of the stronger fundraising years in Alcor's history, including a major gift from the Rothblatt family - one of the largest individual donations Alcor has ever received. About 75% of donations came from people who hadn't given at that level before. The goal is to build an operational endowment similar to what exists for the Patient Care Trust, which is very healthy. The operations and administrative side, however, has historically struggled to keep pace. A comparable endowment would allow Alcor to focus on growth rather than making ends meet. Expect a significant fundraising initiative announcement in the near future.

First-Ever In-House Whole Body CT Scan: The team performed Alcor's first-ever in-house whole body CT scan. The scan itself went smoothly: they used the new ceiling trolley and hoist to transfer the patient from the perfusion table directly onto a radiotranslucent scanning tray, completed the scan in just a few minutes, transferred the patient back, and proceeded directly to cooldown. That patient is now in long-term storage. After everything it took to get here, it was well worth the wait. Being able to validate cryoprotectant distribution in-house and in real time opens up a lot of doors for quality assessment and research.

CT Scanning for Vitrification Assessment: we are putting the CT scanner to good use and have already started producing valuable data. Pre- and post-cooling scans show clear differences between frozen kidneys and vitrified kidneys. The next step: quantifying exactly how much ice forms in different regions using a newly purchased differential scanning calorimeter. This will let the team precisely correlate CT images with ice content - a tool that could become standard for assessing cryopreservation quality in organs and patients alike

Organ Cryopreservation: The team continues refining porcine kidney cryopreservation protocols. About 40% of kidneys show excellent vitrification with minimal ice formation. The other 60% show small ice crystals in the inner medulla - the part of the kidney that's hardest to perfuse.

Brain Slice Cultures: we are developing long-term brain slice cultures that can survive 2-3 weeks in a CO2 incubator. Using assays to measure metabolic activity, they've established a baseline comparing fresh tissue versus straight-frozen tissue. The goal: cryopreserve brain slices, rewarm them, and show maintained viability and functionality over time. This would be a significant contribution to the literature - evidence that brain tissue can remain alive and functional after proper cryopreservation. Additional human brain tissue experiments are also in the works, with a neurosurgery partnership nearly finalized.

New Project: Antifreeze Protein Gene Integration: A particularly exciting update is that we are developing a project to integrate antifreeze protein genes directly into cells via gene therapy. The idea is that if cells can produce their own antifreeze proteins internally, they might survive freezing and thawing better without needing external cryoprotectants. This is early-stage - they're still screening candidate proteins from fish, beetles, and other organisms. Potential applications include improving CAR-T cell therapy, which could be relevant for both cryonics and mainstream medicine.

The protein BDNF is known to encourage neuroplasticity in the brain and otherwise assist in protecting the health and function of neurons. Numerous studies have demonstrated upregulation of BDNF to improve cognitive function in the context of aging and neurodegenerative conditions. Much of this work focuses on very indirect paths to the upregulation of BDNF, such as manipulation of the gut microbiome, but here researchers take the direct approach of a viral gene therapy introduced into brain tissue via stereotactic injection. They show that this can improve cognitive function in mouse models of Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS).

We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3xTg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3xTg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps).

Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.

Link: https://doi.org/10.1016/j.gendis.2025.101649

Cancer diagnosis and treatment tends to involve the removal of lymph nodes, leading to impaired flow in the lymphatic system and either transient or permanent lymphedema. In aging, lymph nodes become fibrotic and structural disorganized, impairing the ability of immune cells to use the lymphatic system to coordinate a response to infection. One possible approach to these problems is the generation of artificial lymph nodes, or at least suitable arrangements of cells that will form themselves into a functional lymph node and connect to the lymphatic system once implanted into the body. A number of different groups have made progress towards this goal, to the point of demonstrating the creation of partially functional lymph nodes in animal studies; the research program noted here is the most recent.

The increase in cancer incidence has accelerated the need for secondary lymphedema treatments after lymphadenectomy because lymph nodes cannot be regenerated. Recently, many attempts have been made to treat secondary lymphedema by forming lymphatic vessels using three-dimensional cellular structures. Of these, three-dimensional cellular structures composed of lymphatic endothelial cells (LECs) and fibroblasts fabricated using a cell stacking technique by coating functional proteins on the cell surface were reported to form a lymphatic network inside the structures, demonstrating the formation of a lymphatic lumen structure after transplantation in mice. Unfortunately this cellular structure has not been effective for the treatment of secondary lymphedema. Therefore, lymph node regeneration or reconstruction using therapeutic cells has not been achieved, and the development of a better therapeutic method is desired.

This study aims to develop a bioengineered three-dimensional tissue composed of LECs and mesenchymal stem/stromal cells (MSCs), which has immunomodulatory functions and can prolong the survival of transplants for lymph node reconstruction. To fabricate the bioengineered tissue simply, we establish a centrifugal cell stacking technique with no additives. This bioengineered tissue, termed "centrifuge-based bioengineered lymphatic tissue" (CeLyT), forms a lymphatic network inside the tissue during culture for several days. CeLyTs induce the formation of lymph node-like structures, with characteristics similar to lymph nodes, after transplantation into mice, and the formation of this lymph node-like structure suppress edema following lymphadenectomy in mice. Therefore, CeLyTs composed of LECs and MSCs might be a cell-based therapeutic strategy for secondary lymphedema.

Link: https://doi.org/10.1038/s41467-025-65121-3

Transposable elements, or transposons, are DNA sequences capable of directing the protein machinery surrounding nuclear DNA to haphazardly insert copies of the transposon elsewhere in the genome, potentially breaking other necessary sequences. Transposons are thought to be the remnants of ancient viral infections, but given that transposon activities are most likely an important mechanism of evolution, driving functional changes that can then be selected, that may not be universally true.

Transposons are suppressed in youth, the structure of DNA managed by epigenetic mechanisms to package away transposon sequences into heterochromatin structures and thus hide them from transcription machinery in the cell nucleus. With advancing age the epigenetic control of DNA structure changes in a variety of ways, altering the expression of many genes to contribute to loss of function, but also unleashing transposons to an ever greater degree.

Beyond mutational damage, transposon activity generates molecules that the cell has evolved to recognize as foreign and react to with inflammatory signaling. The activity resembles a viral infection, in essence. It may be that the greatest harm done by transposon activation is not in fact the mutational damage to DNA, but rather the contribution to a state of systemic sterile inflammation that is characteristic of aging, disruptive to tissue structure and function.

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications, and the reactivation of transposable elements (TEs).

TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation, and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Most of the approaches demonstrated to alter metabolism in ways that modestly slow aging and extend life involve an increased efficiency of autophagy. This includes mild stresses resulting from exercise, calorie restriction, heat, cold, and low levels of toxin exposure. The processes of autophagy act to recycle damaged or otherwise unwanted cellular components into amino acids that can be used for further protein synthesis, improving cell function. Thus there is interest in the scientific community in finding drugs that can induce increased autophagy. The best known, most readily available, and most advanced in the clinic are varieties of mTOR inhibitor, rapamycin being the canonical example. But many other classes of small molecule may prove to be interesting enough to develop into drugs.

Macroautophagy, henceforth referred to as autophagy, is a cellular process that, in part, can act to break down damaged, dysfunctional, or otherwise unwanted components. Autophagy is crucial for maintaining proteostasis and is a necessary system for cellular survival under stressful conditions. Autophagic efficiency declines during aging, leading to the buildup of damaged proteins and organelles, as well as other nonviable cellular debris.

The amino acid response (AAR) pathway is a highly conserved mechanism that reacts to low levels of amino acids with the increased translation of Gcn4 (in yeast), ATF-4 (in worms), and ATF4 (in mammals). We have previously shown that activation of this pathway through the chemical inhibition of tRNA synthetases (tRS) can activate autophagy and extend lifespan in both worms (C. elegans) and yeast (S. cerevisiae).

In this study, we identify four additional tRNA synthetase inhibitors, REP8839, REP3123, LysRS-In-2, and halofuginone, that extend both healthspan and lifespan in C. elegans. These compounds also trigger a significant upregulation of autophagy, specifically at their lifespan-extending doses. These phenotypes partially depend on the conserved transcription factor ATF-4. Our findings further establish tRNA synthetase inhibition as a conserved mechanism for promoting increased lifespan and now healthspan, with potential implications for therapeutic interventions targeting age-related decline in humans.

Link: https://doi.org/10.3390/biom16010073

Cell therapies seem the least likely of approaches to make it into the clinic as a treatment to selectively destroy the senescent cells that linger to cause harm in aged tissues. While it is a very plausible goal to take a CAR T cell therapy and target it to senescent cells, or use adoptive transfer of other immune cell types known to attack senescent cells, as these are just variations on strategies already well demonstrated to work in other contexts, the cost and logistical effort is enormous in comparison to other approaches to the selective destruction of senescence cells. It is far more likely that therapies to adjust the operation of native immune cells, such as the approach under development by Deciduous Therapeutics, or forms of senolytic vaccine, will emerge from this line of thinking.

One of the most significant risk factors for diseases is aging. Interestingly, some organisms, such as naked mole-rats and most turtles, do not exhibit typical aging-like symptoms or increased mortality as they become older. These aspects indicate that aging is not necessarily an essential event for animal life and are avoidable. Overcoming aging would free humans from age-associated diseases (AADs) and prolong lifespans.

Recent studies have demonstrated that one of the causes of age-related organ dysfunction is excessive chronic inflammation caused by the accumulation of senescent cells (SNCs) and their senescence-associated secretory phenotypes (SASPs). Therefore, the development of drugs and medication to remove SNCs is ongoing.

Natural killer (NK) cells are integral components of the innate immune system that are critical for clearing SNCs. Beyond this direct function, NK cells also orchestrate innate and adaptive immunity responses to survey and eradicate these compromised cells. Consequently, preserving NK cell function throughout the aging process is paramount for mitigating AADs and promoting robust health in later life.

Simultaneously, NK cell-based senotherapy presents compelling avenues for addressing the multifaceted challenges associated with SNC accumulation and aging. Recent investigations into adoptive NK cell-based senotherapy have demonstrated considerable promise in rejuvenating immunosenescence, facilitating SNC elimination. The accumulating evidence provides a promising proof-of-concept for adoptive NK cell-based senotherapy, indicating its potential as a development in longevity therapeutics.

Link: https://doi.org/10.3389/fimmu.2025.1737572

The degree to which human longevity is inherited is one of a large number of interesting research topics that, while being related to aging, has little to no relevance to the question of how to treat aging as a medical condition. In developing means to repair or resist the cell and tissue damage that causes degenerative aging, the focus must be on the damage, not the differences from individual to individual. How it is that aging progresses somewhat differently from individual to individual will become increasingly irrelevant as therapies to slow and reverse aging emerge.

That said, today's open access paper on the heritability of longevity is quite interesting. The argument put forward by the authors is that previous efforts to quantify the degree to which individual variance in longevity is determined by one's immediate ancestry have produced underestimates because they failed to properly compensate for the effects of premature death resulting from accidents, infectious disease, and the like. If the strategy for assessment used in the paper is employed instead, then human heritability of longevity is higher than past results, and also more in line with the heritability of other physical traits.

At the same time, the big picture on the genetics of aging that has emerged in recent years, with the advent of very large population databases such as the UK Biobank, is that genetics plays only a small role in determining life expectancy. It is far outweighed by lifestyle choice in the vast majority of people. A high heritability but low contribution of genetic variance suggests that heritability largely exists as a result of the cultural transmission of lifestyle choices; parents that take better care of their health tend to have children who take better care of their health, and vice versa.

Heritability of intrinsic human life span is about 50% when confounding factors are addressed

Understanding the heritability of human life span is fundamental to aging research. However, quantifying the genetic contribution to human life span remains challenging. Although specific life span-related alleles have been identified, environmental factors appear to exert a strong effect on life span. Clarifying the heritability of life span could direct research efforts on the genetic determinants of life span and their mechanisms of action.

Previous studies have estimated the heritability of life span in various populations with results ranging from 15 to 33%, with a typical range of 20 to 25%. Recently, studies on large pedigree datasets estimated it at 6 to 16%. These studies contributed to growing skepticism about the role of genetics in aging, casting doubt on the feasibility of identifying genetic determinants of longevity. Current estimates for the heritability of human life span are thus lower than the heritability of life span in crossbred wild mice in laboratory conditions, estimated at 38 to 55%. They are also lower than the heritability of most other human physiological traits, which show a mean heritability of 49%.

Most life-span studies used cohorts born in the 18th and 19th centuries, with appreciable rates of extrinsic mortality. Extrinsic mortality refers to deaths caused by factors originating outside the body, such as accidents, homicides, infectious diseases, and environmental hazards. Another factor that varies between studies is the minimum age at which individuals must be alive to be included, referred to as the cutoff age. To our knowledge, these two factors - extrinsic mortality and cutoff age - have not been systematically investigated for their effect on heritability estimates of life span.

Here, we explored the effects of extrinsic mortality and cutoff age on twin study estimates of heritability. We used model-independent mathematical analysis and simulations of two human mortality models to partition mortality into intrinsic and extrinsic components. We tested our conclusions on data from three different twin studies, including the SATSA (Swedish Adoption/Twin Study of Aging) study, containing data from twins raised apart that have not been previously analyzed for life-span heritability. To test generalizability to non-Scandinavian cohorts, we also analyzed siblings of US centenarians. We found that extrinsic mortality causes systematic underestimates of the heritability of life span and that cutoff age has a mild nonlinear effect on these estimates. When extrinsic mortality is accounted for, estimates of heritability of life span due to intrinsic mortality rise to about 55%, more than doubling previous estimates.

This is an example of the very earliest stages of research leading to drug discovery, the identification of a potential target protein, here CUL5, that can be manipulated to change cell metabolism in a specific way, here meaning a reduction in the amount of tau protein in the cell. Aggregation of altered tau is a feature of late stage Alzheimer's disease, a cause of cell dysfunction and death in the brain. Reducing tau levels is one possible approach to the problem, though given that tau has a normal and necessary function in the brain, it may not be the best possible approach. At this stage, researchers do not know how CUL5 functions to affect tau levels, and thus a good deal of further work stands between the present discovery and the emergence of any practical outcome.

Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPR interference screen in induced pluripotent stem cell (iPSC)-derived neurons.

In comparison to other tau screens previously reported in the literature, our data have broadly similar patterns of hit genes. A previous genome-wide screen for modifiers of tau levels performed in SHY5Y cells has several shared classes of genetic modifiers. Surprisingly, this screen identified CUL5 as a negative modifier of tau levels. Since CUL5 regulates hundreds of substrates, it is not surprising that CUL5 knockdown has different phenotypes in different contexts.

We find CUL5 expression to be correlated with resilience in tauopathies along with genes encoding CUL5 interactors, including ARIH2 and SOCS4. However, the molecular mechanisms by which CUL5 affects neuronal vulnerability in AD remains to be identified. A broad distribution of CUL5 expression is seen in different neuronal subtypes in the Seattle Alzheimer's Disease Brain Cell Atlas suggesting that CUL5 may modulate disease vulnerability via multiple mechanisms. For instance, it is possible that CUL5 expression affects vulnerability via tau ubiquitination. But, considering CUL5's known role in immune signaling, another possibility is that CUL5 expression affects vulnerability via the neuro-immune axis.

Link: https://doi.org/10.1016/j.cell.2025.12.038

Parkinson's disease is driven by the spread of misfolded α-synuclein through the brain. The most evident symptoms result from the death and dysfunction of motor neurons, caused by the presence of misfolded α-synuclein. Once α-synuclein misfolds, it is capable of inducing other molecules of α-synuclein to misfold in the same way, and this dysfunction can slowly spread from cell to cell. In recent years, researchers have shown that in a sizable fraction of Parkinson's disease cases misfolded α-synuclein first emerges in the intestines and then spreads to the brain. Here, researchers uncover more of the mechanisms by which this transmission takes place, with an eye to finding ways to intervene in the earliest stages of the condition in order to prevent later consequences.

Emerging evidence suggests that Parkinson's disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut-brain axis remain elusive.

Here we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction and modulate the expansion of T cells that travel from the ENS to the brain through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, prevents T cell expansion and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut-brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.

Link: https://doi.org/10.1038/s41586-025-09984-y

Aging research is not a field marked by its unity. At the high level there is some degree of consensus on the need to treat aging as a medical condition, and that this is a plausible goal given time and effort. But ask questions about any particular detail regarding the mechanisms of aging, how to progress towards therapies, the bounds of the possible, and the state of the field, and you will usually find almost as many opinions as there are researchers to hold them. This is characteristic of a field of study in which far more remains to be discovered than has been mapped to date. The research community cannot be said to fully understand the cell, let alone how an organism made up countless cells of many diverse types changes over time.

Still, enough is known to make inroads. We can target senescent cells for selective destruction. We can replace mitochondria. We can reprogram epigenetic patterns. And so forth. We can have opinions on how well any specific class of therapy will perform, but only by earnestly trying a given approach - building the therapies, conducting the clinical trials, and bringing drug into widespread use - will we actually find out how well that approach works.

As recent history demonstrates, the creation of novel therapies is a slow process in the present environment of medical regulation. Ten years is a rapid pace for the move from idea to first clinical trial. Another decade might pass between that first trial and commercial availability of the resulting drug for the average patient. Success for any given line of research is not inevitable. Viable therapies can be completely ignored because the drugs involved are generic, or the approach otherwise cannot be effectively patented and monopolized. A long road lies ahead, given the way in which medical research and development is presently conducted.

Past, present and future perspectives on the science of aging

Juan Carlos Izpisua Belmonte: In the next decade, I expect aging research to move from describing decline to restoring function. High-resolution human datasets, from single-cell and spatial maps to longitudinal studies, will provide a clearer picture of how aging progresses across tissues. At the same time, systemic biology will become even more important, with interorgan communication and circulating signals serving as key therapeutic entry points. Clinically, biological age measures will help to personalize prevention and allow earlier intervention. In the long term, I am hopeful that these developments will reshape medicine.

Steve Horvath: Over the next 10 years, I expect the field to shift decisively from measuring aging to modulating it in humans. I hope that epigenetic clocks will continue to mature into tools for evaluating interventions in individuals and even at population scale. My hope is that the aging field will identify safe, well-tolerated interventions that are capable of rejuvenating multiple human organ systems.

Bérénice A. Benayoun: In the next decade, I think the future of our field will be precision geroscience - understanding what shapes aging trajectories and which levers can be potentially acted upon to promote long-term health, not only based on private unique genetic variation but also other important factors that we are just beginning to appreciate/

Steve N. Austad: I see a takeover by massive omics. I am not suggesting this is a bad thing. It will certainly lead to a personalization of health and medical treatments, but I don't think it will lead to the kind of breakthrough that something like antibiotics represented. I think there will be more interventions on the market over that time (mostly supplements) - some might even be effective, although I doubt they will outdo what the best lifestyle choices do now. Real breakthroughs, if they come, will be further out than 5-10 years.

Terrie E. Moffitt: Over the next 5-10 years, I envision aging research evolving into an era of close integration between basic and clinical sciences, much like what has been achieved in hypertension, diabetes and cancer research. As our understanding of the molecular mechanisms that regulate aging deepens, we will see the identification of diverse therapeutic targets and an acceleration in the development of drugs, vaccines and other interventional strategies.

Guang-Hui Liu: The coming decade will probably see a shift towards precision geroscience. Multidimensional aging clocks may become clinically useful tools for quantifying biological age and intervention effects. We anticipate early human trials targeting newly recognized aging drivers, and advances in gene and cell-based regenerative strategies. Critically, the field is moving towards a unified medical paradigm: targeting the root causes of aging to prevent multiple chronic conditions together, rather than individually.

Vadim N. Gladyshev: I expect to see organ- and systems-resolved aging maps and clinically qualified aging biomarkers; routine real-time biological age monitoring (omics, digital, wearables, and imaging); embryo-inspired rejuvenation cues; advances in replacement; insights from long-lived species on complex interventions that slow down aging; and advances in the theoretical understanding of aging.

Vera Gorbunova: I expect the first antiaging interventions to be approved and introduced to clinical practice. I see aging biomarkers to become a routine part of a health check-up linked to individualized recommendations on improving healthspan. I also expect the development of safe interventions focused on restoring a more youthful epigenome, and preventative strategies to enhance genome stability and improve DNA repair to become available.

David A. Sinclair: I expect the emergence of interventions that treat common diseases by resetting cellular age and allowing the body to heal itself. This will include Yamanaka factor mediated epigenetic reprogramming, due to be tested in humans in 2026, followed by epigenetic editing, small-molecule reprogramming drugs and AI-guided therapies. Within 10 years, I foresee whole-body rejuvenation.

George A. Kuchel: I firmly believe that the future of geroscience, and also its most important impact, will be in the prevention of multiple chronic conditions, which are among the most prevalent and typical features of aging in humans.

John W. Rowe: First, there will be a dramatic increase in the number of clinical trials focused on senescence and age-related disorders with interventions arising from geroscience. Second, we are lagging behind in care of older persons and geriatric medicine continues to suffer severe workforce inadequacies, especially for those with low or middle income. Societies must recognize the need and develop incentives, including financial, to bolster all facets of the eldercare workforce including public health, acute care and long-term care. Third, we have largely viewed aging as an accumulation of deficits and have systematically neglected the valuable capabilities that older people bring to society.

Oskar Hansson: In the space of neurodegenerative diseases, I think we are now moving into the therapeutic era, and I hope that the research community will develop several effective and safe interventions for these devastating brain diseases. Personally, I have especially high hopes for different genetic medicine approaches.

Anne Brunet: The field is moving forward very rapidly, and it is amazing to be part of it! I think there will be several translational breakthroughs in the next 5 to 10 years, notably for devastating age-related diseases such as Alzheimer's disease. Research-wise, it will be very cool to see what happens because so much more is feasible at the organismal level, and it will be an era of quantitative physiology that can be done at scale.

Ming Xu: In the next 5 to 10 years, I expect that the field of aging research will make incredible progress in these three directions. (1) I expect to see a significant rise in large-scale, human clinical trials for geroscience interventions. (2) Single-cell and spatial omics technologies will allow us to reveal the cellular and tissue-specific heterogeneity of aging. 3) AI will become an indispensable tool for aging research. AI and machine-learning models will be used to understand the complexity of multiomics data, identify novel aging targets and design personalized therapies.

Eiji Hara: Cellular senescence research is currently attracting considerable attention, with growing evidence that senescent cells are deeply involved in aging and various age-related diseases. Many studies suggest that targeting senescent cells could help to prevent or treat age-related conditions. Over the next 5-10 years, I expect we will gain a clearer understanding of several critical questions: which types of senescent cells drive specific pathologies, what are the optimal strategies for selective elimination versus functional modulation of these cells, and what are the potential risks of senolytic interventions.

Jing-Dong J. Han: I envision the next decade as the era when aging research becomes a predictive science. Big data will provide the 'language' of aging - a comprehensive, high-resolution dictionary of biological changes. AI models will be the 'translator', enabling us to read this language to forecast health trajectories, identify vulnerabilities and design personalized interventions long before clinical symptoms appear. The goal will be to move from treating age-related diseases to preemptively managing the aging process itself.

Felipe Sierra: As with all other areas of human activity, the field will be dominated by AI and other computer-based approaches to translate the biology of aging into interventions. In addition, I believe the field will succeed within the next 5 years at identifying predictive and clinically useful biomarkers that will take us into a more quantitative stage of research. I fear that, combined, AI and biomarkers will 'suck up the oxygen' from more basic mechanistic research, and this in turn will lead to progressively diminishing returns from AI and biomarkers.

Matt Kaeberlein: I am optimistic that the importance of geroscience will continue to gain recognition, and lead to greater investment from both public and private sectors. I expect substantial engagement from major pharmaceutical companies and anticipate the first FDA approval for a drug that slows aging, probably in companion animals. That milestone would mark a turning point for translational geroscience. Clinically, the landscape will remain frothy for a while. Some longevity clinics already practice evidence-based medicine, whereas others promote unproven or even unsafe interventions. Over time, I expect consolidation around data-driven, ethical standards.

The development of atherosclerosis is very different in males versus females. In the commonly used mouse models that develop atherosclerotic plaque in response to a high fat diet this is very evident. Interestingly, ovariectomized female mice develop plaque in a very similar way to male mice, indicating the importance of hormones to the mechanisms of atherosclerosis. In humans, atherosclerosis is broadly a male condition up to the age of menopause, at which point women start to catch up to the male extent of atherosclerotic plaque and subsequent cardiovascular disease and mortality.

Cardiovascular disease (CVD) is the leading cause of death for both men and women in the United States, though the age of onset differs by sex. Historical estimates suggest men experience earlier onset of coronary heart disease (CHD) by about 10 years as compared with women. Sex-specific differences in CVD are attributed to multiple different pathways, including hormonal influences, differences in cardiovascular health behaviors and factors, and exposure to adverse social determinants of health. Historically, men had higher rates of smoking, diabetes, and hypertension. However, population shifts in cardiometabolic risk phenotypes have resulted in similar or higher rates of obesity, diabetes, and hypertension in women than men. Additionally, the overall prevalence of smoking has decreased and is similar among men and women.

This study analysed data from the CARDIA (Coronary Artery Risk Development in Young Adults) study, a prospective multicenter cohort study. US adults aged 18 to 30 years enrolled in 1985 to 1986 and were followed through August 2020. Sex differences in the cumulative incidence functions of premature CVD (onset earlier than 65 years), were compared overall and for each subtype (CHD, heart failure, stroke).

Among 5,112 participants with a mean age of 24.8 ± 3.7 years at enrollment and a median follow-up of 34.1 years, men had a significantly higher cumulative incidence of CVD, CHD, and heart failure, with no difference in stroke. Men reached 5% incidence of CVD 7.0 years earlier than women (50.5 versus 57.5 years). CHD was the most frequent CVD subtype, and men reached 2% incidence 10.1 years earlier than women. Men and women reached 2% stroke and 1% heart failure incidence at similar ages. Sex differences in CVD risk emerged at age 35, persisted through midlife, and were not attenuated by accounting for cardiovascular health.

Link: https://doi.org/10.1161/JAHA.125.044922

A recent human trial of α-ketoglutarate supplementation failed to show benefits, but researchers continue to show interest in α-ketoglutarate based on results in cells and animal studies. In this example, researchers link α-ketoglutarate availability to the regulation of cellular senescence via TET. It may be that this interaction is not as important to cellular senescence in humans as it is in mice, or that middle aged people (40 to 60) don't have a large enough burden of senescent cells to make effect sizes resulting from α-ketoglutarate supplementation easily visible, or that the optimal dose is higher than the trial dose. Regardless, it seems a poor substitute for senolytics if the goal is to influence the burden of senescence in older people.

Cellular senescence, a state of stable cell-cycle arrest associated with aging, is characterized by a distinct pro-inflammatory secretome. This study systematically interrogates the critical role of the α-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating senescence in human somatic cells. Downregulating TET expression and activity, either genetically (siRNA) or pharmacologically (via C35), or limiting AKG bioavailability through a targeting peptide, trigger widespread epigenetic reprogramming, amplify pro-inflammatory signaling, and enhance the senescence-associated secretory phenotype (SASP), ultimately driving cells toward replicative senescence.

Conversely, augmenting AKG bioavailability or TET expression and activity significantly enhances cellular resilience to stress, effectively preventing and reversing senescent phenotypes. These findings not only position the AKG-TET axis as a critical regulatory nexus of cellular senescence but also challenge the traditional view of senescence as a fixed endpoint, revealing its dynamic and plastic nature susceptible to therapeutic intervention.

Link: https://doi.org/10.1016/j.isci.2025.114298

Amyloid is a category, referring to proteins that clump together and precipitate from solution to form solid fibrils or other structures. At least hundreds of different proteins are capable of forming amyloids given suitable alterations to their structure or surrounding conditions, but most of the research attention given to this activity is directed towards toxic, pathological amyloids that form in great excess in the context of neurodegenerative conditions (such as amyloid-β, α-synuclein, and tau), followed by the few amyloids outside the brain that do the same to contribute to severe cardiovascular and other conditions (such as transthyretin or medin).

In today's research materials, researchers provide evidence for a specific type of amyloid formation to be involved in the creation and maintenance of long-term memory. This is very different from the basis for pathological amyloidosis, and involves different proteins, but given the research community focus on that amyloidosis, there has perhaps been a tendency to write off all forms of amyloid as harmful byproducts of cellular metabolism. A brief glance at the history of our understanding of biochemistry suggests that this sort of viewpoint is usually mistaken; if a process exists, evolution will eventually lead to its incorporation into some necessary aspect of cell function.

How Brain May Deliberately Form Amyloids to Turn Experiences Into Memories

The prevailing model of memory hypothesizes that a change in synaptic strength is one of the mechanisms through which information is encoded in neuronal circuits. While changes in synaptic strength require alterations in the synaptic proteome, the mechanisms that initiate and maintain these changes in synaptic proteins remain unclear. Molecular chaperones play a critical role in proteome function, and act as an interface between the environment and the proteome. Chaperones guide proteins to attain the correct folded state. It has long been thought that in the nervous system, chaperones help proteins to either fold correctly or prevent proteins from harmful misfolding and clumping.

A new study found that in Drosophila, one of a family of J-domain protein chaperones, CG10375, which they named "Funes", does something unexpected - it allows proteins to change their shape and form functional amyloids that house long-term memory. "This expands the idea of a protein's capacity to do meaningful things, and suggests there is an unknown universe of chaperone biology that we've long been missing." Thus amyloids are not always harmful unregulated byproducts as previously thought. Amyloids can be carefully controlled - serving as tools the brain uses to store information. Ultimately, the research reveals for the first time a critical step in the process of how long-lasting memories endure.

In fruit flies, a prion-like protein called Orb2 (and its relative protein CPEB in mammals) must undergo self-assembly at the synapses, the gap between two neurons, to maintain a memory. Orb2 belongs to a class of nonpathological amyloids, where amyloid formation enables a protein to acquire a new function. Over time, the researchers began to hypothesize that the difference between a harmful and a helpful amyloid may depend on whether Orb2's assembly process is tightly regulated by other proteins.

The researchers discovered Funes by manipulating the concentrations of 30 different chaperones in the fly's memory centers. Flies with increased levels of Funes showed a remarkable ability to remember an odor-reward link after 24 hours - a standard proxy for long-term memory. But the most surprising discovery came at the molecular level. Researchers engineered Funes variants that could bind Orb2 but could not trigger its transition into amyloid and found the flies' long-term memory failed. This indicated that Funes is an essential component for long-term memory formation.

Diseases of the eye are often the indication of choice for new, advanced forms of medicine, particularly gene therapies. Delivery to the eye is straightforward and proven, effective doses can be very low, and the structures of the interior of the eye are relatively isolated from the rest of the body. All told, the risk to patients is much lower than would be the case for targeting, say, the liver, which makes it a great deal easier to convince investors and regulators to support such a program. Thus we shouldn't be all that surprised to see that the first clinical trial of partial reprogramming to rejuvenate epigenetic control over nuclear DNA structure and gene expression will focus on regeneration of the damaged retina.

The FDA has given the go-ahead for the first ever human trial of a partial epigenetic reprogramming therapy. The FDA's decision clears an investigational new drug application for Life Bioscience's ER-100, a gene therapy designed to rejuvenate damaged retinal cells in people with serious, age-related eye diseases. The biotech is now preparing to commence a Phase 1 first-in-human study to show its therapy can be delivered safely in patients with open-angle glaucoma and non-arteritic anterior ischemic optic neuropathy (NAION).

As a first-in-human trial, Life Bioscience's study is primarily focused on safety and tolerability. Instead of using all four Yamanaka factors, ER-100 employs three of the factors (Oct4, Sox2, and Klf4) delivered transiently to reset age-associated epigenetic markers while keeping cells committed to their original function. By excluding c-Myc, a factor associated with uncontrolled growth, the strategy is intended to lower the risk of tumors that has historically concerned regulators and clinicians. From a safety perspective, the company's preclinical studies in non-human primates demonstrated that ER-100 was well tolerated in NHPs, with no systemic toxicities.

"The therapy uses a doxycycline-inducible system, giving us precise control over when the genes are active and allowing treatment to be paused or stopped if needed. In addition, ER-100 is delivered locally to the eye, limiting systemic exposure. Multiple preclinical animal models have demonstrated controlled gene expression, favorable biodistribution, restoration of epigenetic markers, and improvements in visual function which has collectively provided the foundation for FDA clearance."

Link: https://longevity.technology/news/fda-clears-first-human-trial-of-epigenetic-reprogramming-therapy/

Ferroptosis is a form of programmed cell death associated with iron metabolism. A body of evidence supports a role for excessive ferroptosis in the progression of Alzheimer's disease and other age-related conditions, a maladaptive reaction to forms of age-related damage present in the brain, such as mitochondrial dysfunction, an increased burden of senescent cells, chronic inflammatory signaling, and so forth. Researchers are starting to consider suppression of ferropotosis as an approach to treating neurodegenerative conditions, which leads to papers such as this one, a discussion of the mechanisms by which exercise acts to reduce ferroptosis. That is a step along the road to identifying potential targets for drug development. Attempting to mimic specific outcomes of exercise, calorie restriction, or other environmental effects on metabolism is a widely employed strategy, though it seems unlikely to be capable of more than modestly slowing disease progression or modestly reducing severity.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical link between cellular senescence and Alzheimer's disease (AD). Senescent cells disrupt iron metabolism, promote peroxidation-prone lipid remodeling, and suppress antioxidant defenses, creating a pro-ferroptotic environment that accelerates neuronal degeneration. This review integrates recent mechanistic evidence demonstrating that these senescence-induced changes heighten ferroptotic susceptibility and drive AD pathology through pathways involving protein aggregation, autophagic failure, and inflammatory synaptic loss.

Importantly, physical exercise has emerged as a pleiotropic intervention that counteracts these ferroptotic mechanisms at multiple levels. Exercise restores iron homeostasis, reprograms lipid metabolism to reduce peroxidation risk, reactivates antioxidant systems such as GPX4, enhances mitochondrial and autophagic function, and suppresses chronic neuroinflammation. Moreover, systemic adaptations through muscle, liver, and gut axes coordinate peripheral support for brain health. By targeting ferroptosis driven by cellular senescence, exercise not only halts downstream neurodegenerative cascades but also interrupts key upstream drivers of AD progression.

These findings position ferroptosis as a therapeutic checkpoint linking aging biology to neurodegeneration and establish exercise as a mechanistically grounded strategy for AD prevention and intervention.

Link: https://doi.org/10.3389/fcell.2025.1742209

Autophagy is the name given to a complex collection of processes responsible for identifying and recycling damaged or otherwise unwanted structures in the cell. Typically, a structure flagged for recycling is engulfed by an autophagosome, which is transported to and fuses with a lysosome, and the structure is broken down inside the lysosome by enzymes. An optimal level of autophagy for the maintenance of cell function only occurs in response to stress, including heat, cold, lack of nutrients, toxins, oxidative damage to important molecules, and so forth. Thus mild stresses that inflict relatively little damage to a cell can improve the function of cells, tissues, and organs, leading to a greater resistance to the damage and dysfunction of aging. Most of the well studied interventions shown to modestly slow aging and extend life in animals involve an increased operation of autophagy.

Researchers and the longevity industry continue to work towards the development of drugs capable of upregulating autophagy to produce health benefits in older people. These efforts include examples in the well studied category of mTOR inhibitors, drugs that can mimic some of the beneficial metabolic response to exercise and calorie restriction, as well as a good number of unrelated programs at various stages of preclinical and clinical development. Meanwhile, there is a continued effort to better understand and measure autophagy. One of the challenges is that autophagy consists of many different steps, an assay can only obtain insight into one step, and increased activity in any given step can be a sign of increased function, but it can also be a sign that autophagy is dysfunctional and backed up.

Links between autophagy and healthy aging

Several if not all manifestations of aging can be postponed by a healthy lifestyle involving a balanced diet coupled with regular exercise and sufficient sleep. Similarly, various genetic and pharmacological longevity interventions can exert beneficial effects across species in a conserved manner, extending both lifespan and healthspan. While all these interventions-ranging from genetic perturbations to pharmacological supplementation to lifestyle changes-affect diverse biological processes, a common candidate mechanism underpinning at least some of their benefits is autophagy, a cellular recycling process essential for maintaining cellular homeostasis.

In this review, we summarize how autophagy is affected by various pharmacological and lifestyle factors, with a focus on studies in which autophagy has been shown to play a causal role in promoting healthy aging. Specifically, we review the molecular mechanisms through which pharmacological agents, dietary restriction, exercise, sleep adjustments, as well as temperature modulation affect autophagy to extend lifespan and often also healthspan in model organisms and humans.

Still, major gaps remain in human research due to limited assays to monitor autophagy and the scarcity of longitudinal studies linking autophagy dynamics to health outcomes. Closing this gap is a key challenge in converting discoveries from model organisms into interventions that consistently enhance healthy aging in humans. By summarizing current findings and highlighting remaining uncertainties, this review aims to provide a roadmap for translating insights on autophagy from model organisms into strategies to promote healthy aging in humans.

The best thing that researchers can do with the presently established aging clocks, such as Phenotypic Age, is to gather as much data as possible on the relationship between the clock output and meaningful outcomes such as disease risk and mortality. Hence the existence of studies such as the one reported here. Even now, going on twenty years into the use of aging clocks, it remains unclear as to whether any of the existing, relative well-used clocks will produce a reasonable assessment of the effects of any novel potentially age-slowing or age-reversing therapy. An understanding of the links between what is measured in the clocks and the underlying processes of aging have not been established and will be very challenging to establish, and thus it is impossible to predict whether a clock will overestimate, underestimate, or just fail when it comes to assessing the quality of any given intervention in aging. This is the case even for clocks such as Phenotypic Age that use clinical chemistry rather than omics measures. In this environment, gathering more data is probably the best path forward.

Accelerated biological aging serves as a risk factor for age-related diseases, its role in the prognosis of Parkinson's disease (PD) remains ambiguous. This study investigates the association between biological aging and the mortality in PD patients. Data were sourced from the UK Biobank. Independent prognostic factors for mortality in PD patients were assessed by Cox regression model, and a nomogram was developed to predict the survival of PD patients. A total of 569 PD patients were enrolled in this study.

Phenotypic age (PhenoAge) and PhenoAge acceleration (PhenoAgeAccel) were found to affect the survival in PD patients. Independent risk factors for PD mortality included age, male gender, smoking, underweight, depressive mood, low-density lipoprotein, and higher genetic susceptibility. The nomogram constructed based on PhenoAge showed robust prediction performance for mortality in PD patients. PhenoAge emerges as a pivotal PD mortality predictor, enabling the identification of individuals experiencing accelerated biological aging and implementing targeted interventions.

Link: https://doi.org/10.1038/s41531-026-01268-0

Adult life expectancy has exhibited a slow upward trend over the course of past decades, perhaps a year of increased life expectancy every decade, but the pace varies from year to year, region to region, and between socioeconomic groups. The trend exists as a result of improvements in medicine that impact the pace of aging as a side-effect, as therapies that deliberately target the mechanisms of aging have yet to reach widespread use. The contribution of medical advances is then layered with the effects of lifestyle differences, particularly the prevalence of obesity, public health programs such as efforts to reduce smoking, and other line items that can differ between populations and regions. Researchers here use European data to illustrate this point, and also note differences over time in the life expectancy trend.

This study makes several potential contributions to the ongoing debate on life expectancy trends in high-income countries. Our study examines these trends using data at the level of subnational regions: in total, we cover 450 regions in 13 Western European countries. We believe that addressing life expectancy at a fine geographical level is paramount in understanding the potential to further improve human longevity, as national aggregates mask large differences within countries. For example, in France, there are stark contrasts between laggard regions in the north and vanguard regions in the south and east. The disparities between eastern and western Germany, and northern and southern Belgium are equally pronounced. Together, they tell a compelling story of uneven regional progress.

Our study identified two distinct phases in the evolution of life expectancy gains over the past three decades. The first phase, from 1992 to 2005, was characterized by stable and substantial life expectancy gains in Western Europe (about 2.5 months per year for females and 3.5 months per year for males). Over this period, the pace of gains across regions quickly converged. In contrast, the second phase, from 2005 to 2019, marked a period of declining life expectancy gains. By 2018-2019, annual gains had decreased to about one month per year for females and two months for males.

During the earlier 'golden era', it was laggard regions that made the greatest gains in life expectancy. By contrast, the period 2005-2019 was much less favourable, as laggard regions saw shrinking gains in life expectancy. The driving forces behind this impressive reversal of fortunes can be better understood through the convergence-divergence framework, which explains the mechanisms leading mortality levels across populations to either converge or diverge. According to this theory, major innovations (e.g., drugs that reduce blood pressure) may initially trigger divergence, as some countries or groups are better positioned to benefit from them. Once access broadens, convergence tends to follow.

Link: https://doi.org/10.1038/s41467-026-68828-z

In today's open access paper, researchers review the evidence for exercise to slow the aging of muscle tissue in part because it improves DNA repair mechanisms. How exactly damage to nuclear DNA contributes to aging beyond creating a raised risk of cancer remains a debated topic, despite recent conceptual advances. Nuclear DNA damage occurs constantly, near all of which is repaired. Yet the remaining damage largely occurs in genes that are not used or that are not all that important, and in cells with few replications remaining. Thus the ability to cause harmful alterations to cellular metabolism throughout a tissue was thought to be limited.

The first way in which nuclear DNA damage could meaningfully impact aging is via somatic mosaicism. When mutations occur in stem cells, those mutations spread slowly throughout a tissue over time via the descendants of the somatic daughter cells created by the mutated stem cells. A mosaic of combinations of mutations is established over years and decades, and there is at least some reasonably convincing evidence for this to increase the risk of a few age-related conditions.

More recently, researchers have provided evidence for the repeated repair of DNA double strand breaks, whether successful or not, and wherever the break occurred in the genome, to cause epigenetic changes characteristic of aging. These epigenetic changes alter the structure of nuclear DNA and thus the expression of genes. If support for this mechanism continues to accumulate, it provides a way for random molecular damage to DNA to produce the consistent outcome of harmful age-related epigenetic changes that is observed to occur in all cells.

In this second viewpoint, interventions such as exercise that are thought to slow aging in part by improving the operation of DNA repair mechanisms may not in fact be working as hypothesized. They may indeed be changing the operation of DNA repair, but the primary outcome of interest is to reduce the negative effects of double strand repair on the epigenetic control of nuclear DNA structure and gene expression, rather than improving the efficiency of DNA repair more generally.

Impact of exercise-induced DNA damage repair on age-related muscle weakness and sarcopenia

Sarcopenia, the progressive and generalized loss of skeletal muscle mass, strength, and function with aging, poses a significant public health challenge. A key contributor to sarcopenia is the accumulation of DNA damage, both nuclear and mitochondrial, coupled with a decline in DNA repair efficiency. This genomic instability, exacerbated by chronic oxidative stress and inflammation, impairs critical cellular processes including protein synthesis, mitochondrial function, and satellite cell regenerative capacity, ultimately leading to myofiber atrophy and weakness. Intriguingly, regular physical exercise, while acutely inducing transient DNA damage, concurrently activates and enhances DNA damage repair pathways, serving as a powerful physiological modulator of genomic integrity.

This review comprehensively explores the intricate interplay between exercise, DNA damage, and DNA repair in the context of age-related muscle decline. We delve into the molecular hallmarks of DNA damage (e.g., 8-OHdG, single and double strand breaks) and the major repair mechanisms (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, non-homologous end joining), detailing how acute exercise modalities (e.g., high-intensity interval training, resistance training) induce specific damage types primarily via reactive oxygen species. Crucially, we synthesize emerging evidence suggesting that chronic exercise training may upregulate the efficiency and capacity of DNA repair enzymes, particularly OGG1 in base excision repair, thereby mitigating the accumulation of deleterious genomic lesions. This exercise-induced enhancement of DNA repair directly contributes to maintaining mitochondrial health, preserving muscle stem cell function, and combating cellular senescence and inflammation, ultimately delaying or ameliorating sarcopenia and improving muscle functional outcomes in older adults.

Researchers have been publishing more data of late from the CALERIE trial of human calorie restriction that took place over the course of a few years. The participants aimed at a 25% reduction in calorie intake, and ended up achieving something more like 12-15%. The trial started nearly 20 years ago at this point. It is often the case that tissue samples and data remain intact and potentially useful long after the study is complete, awaiting greater funding and interest, as well as the existence of more advanced analysis technologies.

Small non-coding RNAs (smRNAs), approximately 20-35 nucleotides in length, represent a diverse class of regulatory molecules that include microRNAs (miRs) and piwi-interacting RNAs (piRs). These nanoscale molecules are key regulators of gene expression, orchestrating complex networks to maintain genome stability and contribute to post-transcriptional gene regulation and cellular homeostasis.

Caloric restriction (CR) extends lifespan and enhances healthspan across species. In humans, the CALERIE Phase 2 trial demonstrated that CR improves inflammation, cardiometabolic health, and molecular aging. To explore underlying mechanisms, we examined CR-induced changes vs. ad libitum (AL) in smRNAs across plasma, muscle, and adipose tissue. Using smRNA sequencing, we analyzed miRs and piRs over 12 and 24 months, comparing CR levels (%CR) and group assignments (CR vs. AL).

We identified 16 smRNAs associated with %CR and 41 with CR vs. AL. Although tissue-specific expression varied, shared pathways emerged, including insulin signaling, circadian rhythm, cell cycle regulation, and stress response. Cross-species analysis revealed 17 miRs altered by CR in both humans and rhesus monkeys. These findings suggest smRNAs are key molecular mediators of CR's effects on aging and longevity, offering insight into biological mechanisms of CR and potential targets for age-related interventions.

Link: https://doi.org/10.1016/j.isci.2025.114514

The immune system is made up of many specialized populations of cells. Even within well recognized categories such as T cells of the adaptive immune system, there are numerous subcategories, defined by surface markers, that exhibit meaningfully different behaviors. The example for today is γδ T cells, known to be involved in the clearance of senescent cells. Unlike other T cells, γδ T cells behave more like innate immune cells, able to attack pathogens and potentially harmful cells without the need for other components of the adaptive immune system to process antigens for recognition. The γδ T cell population is relatively poorly understood, but like the rest of the immune system, it changes with age in ways that are likely in part dysfunctional, in part compensatory.

The transcription factors of the forkhead box O (Foxo) family, particularly Foxo1, play a pivotal role in regulating α/β T-cell key cellular processes. Interestingly, we recently found that the age-related decline in Foxo1 expression in mouse α/β T cells may drive the disruption of their peripheral homeostasis and contribute to the aging of this T-cell compartment. γ/δ T cells form a distinct subset of lymphocytes, differing from NK cells, B cells, and α/β T cells by combining adaptive properties with rapid, innate-like responses. Findings related to Foxo1 in α/β T cells prompted us to investigate how the functional capacities of γ/δ T cells are affected by aging, as well as whether Foxo1 expression could be modulated in this T-cell compartment with age.

In this study, we demonstrate that, as observed for α/β T cells, the homeostasis of the peripheral γ/δ T-cell compartment is markedly altered with age. Indeed, a comparison of the γ/δ T-cell compartment within the secondary lymphoid organs of old (18-month-old) and young (3-month-old) adult mice reveals that aging promotes the expansion of innate-like γ/δ T cells and enhances their capacity to produce IL-17. Notably, we found that these age-related changes were associated with the loss of Foxo1 expression within this T-cell compartment.

Finally, as observed in α/β T cells, our results indicate that the age-related decline in Foxo1 expression in γ/δ T cells is likely driven by a similar T cell-extrinsic factor. In this context, we identify type I IFNs as a key regulator that down-regulates Foxo1 in IL-17-producing γ/δ T cells with age and enhances the capacity of Ly-6C- CD44hi γ/δ T lymphocytes to mount a rapid in vivo response during aging.

Link: https://doi.org/10.1111/acel.70389