Fight Aging!

Sarcopenia is the name given to later, more severe stages of the characteristic loss of muscle mass and strength that takes place with age. The loss is universal, ultimately leading to physical frailty. Since muscle is metabolically active, loss of muscle is also disruptive to overall metabolism, worsening insulin resistance and chronic inflammation. Like many aspects of degenerative aging, the underlying causes of sarcopenia form a web of interacting mechanisms. It is challenging to determine their relative importance, as well as which mechanisms are largely upstream versus largely downstream in the chain of cause and effect. As is usual, tracing a direct path from root causes of aging to proximate causes of disease is a work in progress, and very incomplete. Most research effort focuses on the proximate causes.

For sarcopenia, the most plausibly important and well studied proximate causes are (a) loss of muscle stem cell activity, reducing the supply of new muscle cells needed to replace losses, and (b) degeneration of the neuromuscular junctions that link the nervous system to muscle fibers. Without innervation, muscle lacks the signaling needed to provoke normal maintenance and growth in response to use. These proximate causes are of course far downstream of issues closer to the roots of aging, such as mitochondrial dysfunction, epigenetic change, senescent cell accumulation, and so forth.

Today's open access paper is an example of ongoing efforts to better understand how neuromuscular junctions falter in their function. The researchers focus in on a loss of postsynaptic excitability driven by reduced expression of the NaV1.4 sodium channel, and suggest inhibition of the CLC-1 chloride channel as a compensatory strategy to promote greater postsynaptic excitability without directly addressing the NAV1.4 issue. They found this approach to improve muscle function in aged mice.

Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition

Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibit NMJ transmission failure that correlates with muscle weakness severity.

Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a novel disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the post-synaptic NMJ membrane. Acute NaV1.4 inhibition in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans.

In a recent study on myasthenia gravis, inhibition of the ClC-1 channel was found to enhance NMJ transmission and improve muscle function in both animal models and patients with myasthenia gravis. Our current findings demonstrate that small molecule inhibition of ClC-1 can similarly enhance muscle contractile function and improve motor function assessments in aged, weak rats with confirmed NMJ dysfunction. The ClC-1 ion channel is specific to skeletal muscle, expressed along the entire muscle fiber membrane, including at NMJ, sarcolemma, and t-tubular system. This channel plays a critical role in modulating skeletal muscle excitability, especially during intense muscle activity, through cellular signaling systems activated during muscle activity.

The research community regularly produces quite fascinating data regarding the ways in which diet influences health. Take this paper, for example. Plant cells have mitochondria, we consume raw plants, and it turns out that some fraction of those plant mitochondria are making their way out of the gut, into the body, into cells, and interacting with our mitochondria to favorably alter mitochondrial function. Perhaps there is an approach to therapy here that looks like mitochondrial transfusion, or looks like an oral therapy but with extracted plant mitochondria. But knowing the degree to which diet impacts health and life expectancy suggests that the size of effect is not large enough to be very interesting. Therapies that cannot much improve on the benefits of a good set of lifestyle choices are not where we should be spending our time. If we want truly effective treatments for aging, interventions that add decades of healthy life, mimicking lifestyle choice is not a good strategy.

Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies. Mitochondria were isolated from several commonly consumed edible plants (P-Mit). The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system.

As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.

Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline.

Link: https://doi.org/10.1186/s40035-026-00565-1

Microglia are innate immune cells of the brain, analogous to macrophages elsewhere in the body. Both cell types are deeply involved in the intricate processes of tissue maintenance and regeneration. The central nervous system has only limited regenerative capacity, but it can regain some lost function following injury, such as that caused by a stroke. Researchers here find a way to improve the regenerative activities of microglia, and demonstrate that this intervention can improve outcomes following stroke in animal models.

After a stroke, the brain launches a coordinated repair program that involves several types of cells. Among these, microglia, the brain's resident immune cells, play a pivotal role. Immediately after an injury, microglia are activated to trigger inflammation, but thereafter, they rapidly transition into a reparative state and produce growth factors, such as insulin-like growth factor 1 (IGF1), which support remyelination, strengthen neural connections, and promote functional recovery. But this only lasts for two months, limiting the brain's capacity to repair further.

To uncover the molecular mechanism responsible for diminishing microglial reparative functions the researchers identified a specific transcription factor called ZFP384, which increases as the brain's spontaneous repair functions diminish. They discovered that ZFP384 diminished the expression of genes associated with microglial reparative functions. Mechanistically, ZFP384 disrupts the chromatin interactions mediated by the protein YY1 that are necessary for the gene expression associated with neural repair. As a result, the microglia lose their reparative properties despite the brain's ongoing recovery needs.

To investigate whether preventing this loss of reparative properties in microglia could help improve recovery, the team first genetically deleted the Zfp384 gene specifically from microglia in mouse models of stroke. Interestingly, these animals maintained their recovery-associated gene expression for a much longer period than normal mice. Sustaining the reparative state of microglia enhanced remyelination of damaged nerve fibers and promoted synaptic plasticity, resulting in significantly better long-term neurological function.

Based on these findings, the researchers developed a therapeutic antisense oligonucleotide (ASO), a short, synthetic strand of nucleic acids that specifically decreases expression of a targeted gene. ASO-Zfp384 was designed to suppress Zfp384 expression. Remarkably, the treatment sustained microglial reparative functions and remained therapeutic even when administered 1 week or 1 month after stroke onset. Rather than simply reducing inflammation, the ASO-Zfp384 helped retain the brain's own reparative program, enhancing post-stroke recovery from neurological deficits.

Link: https://www.eurekalert.org/news-releases/1135664

Mitochondrial transplantation is under development as a class of therapy to treat aging. Mitochondrial dysfunction is a feature of aging, and evidence from animal studies suggests that lasting improvements in health result from replacement of a fraction of native mitochondria with new, functional mitochondria delivered via intravenous infusion. Cells readily take up mitochondria from their surroundings if given the chance. The biggest challenge remains scaling up manufacture, being able to harvest from cell cultures the vast numbers of mitochondria needed to produce a reasonable level of replacement in a human patient. Work has progressed to a first in human demonstration conducted recently, but a few other companies are also moving towards human trials at some pace.

One of the most interesting questions is that of how vital it is that mitochondrial DNA haplotype matches nuclear DNA haplotype. Mitochondria are the evolved descendants of ancient symbiotic bacteria, and carry their own genome, the mitochondrial DNA. There are more than 20 distinct groupings of human mitochondrial DNA haplotypes. Over evolutionary time, most mitochondrial genes migrated into nuclear DNA, so some components of the molecular machinery in a mitochondrion come from mitochondrial DNA, some from nuclear DNA. What happens when mitochondria with a different DNA haplotype are introduced into an adult individual? What if researchers construct a much better synthetic mitochondrial DNA haplotype that outperforms all natural haplotype when it comes to producing adenosine triphosphate (ATP) with a low burden of oxidative stress, and increases the efficiency of mitochondrial quality control as well? Are there roadblocks to implementing this goal?

There is some evidence to suggest that mixing and matching between haplotypes, or changing mitochondrial haplotype in an adult individual, is modestly harmful. Today's open access paper provides more data on this front, looking at outcomes on the lifespan of flies resulting from mismatches between mitochondrial genes in nuclear DNA versus mitochondrial DNA. The effect size is around a 10% reduction in median life span, which is not all that large in a species like the fruit fly, where life span is very plastic in response to circumstances. Still, it seems likely that companies developing mitochondrial transplantation therapies will choose to be cautious and match haplotype to patient.

Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations

Mitochondria lie at the center of cellular metabolism and are key determinants of organismal ageing. Because the oxidative phosphorylation (OXPHOS) complexes are encoded by both nuclear and mitochondrial genomes, compatibility between these genomes is essential for efficient energy production and eukaryotic life. Disruption of this intergenomic coordination, via mismatches between mitonuclear genotypes, has been shown to impair metabolism with severe life-history consequences across diverse taxa. Yet, the role of mitonuclear compatibility in shaping ageing trajectories in natural populations remains poorly understood, with evidence largely limited to inbred laboratory lines.

Hormesis describes the process where mild stress can trigger protective adaptations against ensuing perturbations. In this context, mitohormetic interventions can represent a protective strategy to promote metabolic homeostasis and healthy ageing. Here, we leveraged natural genetic variation in wild Drosophila melanogaster populations to test how mitonuclear compatibility interacts with early-life metabolic stress to shape ageing phenotypes. Two mitochondrial haplotypes coexist in D. melanogaster populations along the Australian cline: "t" (most common in the north) and "m" (most common in the south), differing by 15 single-nucleotide polymorphism (SNPs) across protein-coding genes. We generated a panel of outbred populations carrying putatively coevolved ("tT," "mM") and mismatched ("mT," "tM") mitonuclear genomes.

We demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.

You might recall that last year researchers demonstrated an age-related decline in peroxisome number in cells. Peroxisomes carry out a range of functions related to oxidative and lipid metabolism, but are relatively poorly researched in the context of aging. The decline in number of peroxisomes modestly accelerates the pace of aging, as researchers found that forcing a normalization of the number of peroxisomes via prx-11 inhibition extended life in nematode worms. Here, the same researchers provide an update on how they think that this all works under the hood, providing evidence for peroxisome counts to affect life span via mitochondrial function.

Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity.

Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained.

We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

Link: https://doi.org/10.18632/aging.206395

That evolution does not optimize for species longevity is illustrated by the large number of small alterations in gene sequence or protein level that extend life in short-lived laboratory species such as nematode worms. Here, researchers note a trade-off between the activity of the unfolded protein response in various parts of the cell. When errors in protein manufacture and folding occur, unfolded and misfolded proteins emerge to cause harm. The unfolded protein response is triggered and acts to remove the problem proteins. Everything a cell does requires effort, and evolution has led to systems that balance that effort versus all of the other things a cell could instead accomplish. Therefore the unfolded protein response tends to operate at a level that is suboptimal for longevity in an organism. Further, it appears that assignment of that unfolded protein response effort across different parts of the cell is also suboptimal for longevity.

Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPRER) and the cytosolic unfolded protein response (UPRcyto) in C. elegans that influences lifespan.

We find that wild-type animals maintain high UPRER activity but low UPRcyto activity, a balance actively enforced by the transcription factor LET-607 (ortholog of mammalian CREBH). Consequently, LET-607 deficiency releases this trade-off, causing a seesaw-like rebalancing: UPRER activity decreases while UPRcyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPRcyto dependent manner. Mechanistically, LET-607 deficiency downregulates one-carbon cycle, which provides the methyl donor S-adenosylmethionine. This subsequently alleviates H3K9me-mediated repression at the promoters of UPRcyto genes, a process involving the regulators and readers of this histone mark, leading to UPRcyto activation.

Our study reveals a transcriptional mechanism that enforces a proteostatic trade-off and demonstrates that evolutionarily acquired UPR balance in wild-type animals is suboptimal for longevity, supporting the antagonistic pleiotropic theory of aging.

Link: https://doi.org/10.1111/acel.70620

Setting aside a few early attempts, the longevity industry started in earnest in the mid-2010s. It had the feel of a hype cycle, a land rush, in the context of a broader bull market. A lot of those companies no longer exist; there are disadvantages in being first into a space. One of those disadvantages is that the first cohort in any venture has the privilege of mapping the novel pitfalls by falling into them. That is done now, and we're into the next stage, which is, quite honestly, a lot more complex, messy, diverse, and hard to explain. We know how this story ends: at some point there will be no distinct longevity industry, because the goal of slowing or reversing the aging process by addressing the underlying causes of aging directly will merge into the ordinary, day to day cut and thrust of pharmaceutical and biotech development. It will be become unremarkable to attempt to treat aging as a medical condition.

We are not there yet! From the extremely conservative point of view of those who steer large pharmaceutical industry companies, treating aging remains a distinct, unproven proposition. That will continue to be the case until novel anti-aging drugs are approved by the FDA and EMA, used by hundreds of thousands of patients, produce undeniable results, and, most importantly, generate a large amount of revenue. The number of such approved drugs is somewhat less important than the collective revenue generated. You might look at the opinion of the powers that be on weight loss drugs and how that has shifted across the advent of GLP-1 receptor agonists as an example of how this shift in will take place for the first very successful anti-aging drugs.

But back to what the longevity industry looks like now, and how that differs from the early days. Today's open access paper offers an opinion on the topic, backed by some analysis. It is an interesting read, albeit very focused on just a few parts of the mainstream of the field, the most popular topics. For my part, I'd have to say that I think matters would be fairly different if the bull market in biotech and pharma had sustained itself across the 2020s rather than vanishing into geopolitics and doldrums. A new industry struggles to forge itself in an environment where funding is tight all round. Much of the present character is the character of an industry in which it is exceptionally challenging to raise funds for clinical development, no matter the promise of the technology in question. But this too shall change.

From lifespan extension to hallmark-informed gerotherapeutic prioritization: A bibliometric-guided, strategy-oriented review of anti-aging drug research

Aging is increasingly understood as a shared upstream biological process that increases vulnerability across cardiovascular, neurodegenerative, metabolic, musculoskeletal, renal, and neoplastic disorders. This view was crystallised by the original hallmarks framework and reinforced by its expanded update, which organise aging into interconnected molecular and cellular processes rather than isolated organ-specific events. The translational implication is substantial because interventions directed at aging biology could, in principle, delay or modify several age-related conditions rather than treating each disease independently. The interdependence of aging hallmarks also provides a rationale for evaluating secondary cross-hallmark effects.

Over the past decade, geroscience has moved from a conceptual proposition to an intervention-oriented discipline aimed at extending healthspan and disability-free survival. This shift has been driven by growing recognition that aging is biologically malleable and clinically consequential at the population level. Mechanisms such as cellular senescence, deregulated nutrient sensing, mitochondrial dysfunction, chronic inflammation, loss of proteostasis, and impaired stress adaptation are now regarded as potentially tractable pharmacological entry points. Accordingly, gerotherapeutic development increasingly requires alignment between molecular or pharmacological design, an aging-related biological vulnerability, measurable target engagement, an appropriate population, and a clinically meaningful endpoint.

The landscape of anti-aging drug research has shifted markedly from exploratory lifespan-extension studies toward a more structured, mechanism-informed, and translationally aware framework. Bibliometric analysis reveals that the field coalesces around three partially overlapping intervention logics - senescence-directed therapeutics, nutrient-sensing and metabolic modulators, and homeostasis-restoring compounds - each anchored in reproducible biological hallmarks. These axes collectively provide a coherent rationale for prioritizing interventions based not solely on historical visibility but on mechanistic plausibility, preclinical evidence, and early human translational signals.

The composition of the gut microbiome changes with age in ways that negatively impact health. There is enough variance in this process of change that correlations can be observed between specific species and metrics of overall composition on the one hand and risk or status of disease on the other. Researchers are building a growing body of knowledge regarding such correlations, and in many cases have found mechanisms indicating that a poor composition of the gut microbiome is a contributing factor in the development and progression of age-related disease. This is a matter of which metabolites are produced by the gut microbiome and in what amounts; some metabolites are necessary for health, others are harmful or provoke chronic inflammation. This work is the first step towards the development of therapies that can alter the composition of the gut microbiome in specific, tailored ways in order to improve health and slow the progression of aging.

Although commonly used tools, such as the Fried Frailty Phenotype, the Rockwood Frailty Index and the Clinical Frailty Scale, capture specific aspects of frailty, existing indices often fail to encompass its full functional, psychological, and physiological dimensions. The Charlson Comorbidity Index (CCI), while widely adopted for mortality risk stratification, is disease-centric and lacks sensitivity to the broader construct of frailty. To better capture this multidimensional nature, we developed the Frailty Mortality Index (FMI), a composite measure integrating functional and psychosocial aspects in addition to comorbidities. Specifically, the FMI is defined by anthropometrics (age and weight), physical function (walking speed and chair stand), current smoking, mental quality of life (QoL) survey, hospital stay duration, and the CCI.

The gut microbiome is increasingly recognized as a regulator of host physiology and potential contributor to frailty pathophysiology. It influences systemic inflammation, metabolism, musculoskeletal function, and immune and neuroendocrine signaling. While aging alters gut microbiota composition and function, gut microbiome profiles observed in frailty differ from those associated with healthy aging, reflecting not just chronological age but also deterioration of physiological processes.

In this work, we use metagenomic sequencing to investigate species-level features associated with frailty-related phenotypes captured by the FMI in SUPERB, a large Swedish cohort including 2,081 women aged 75-80 years. We demonstrate that the FMI is more strongly associated with frailty-related clinical outcomes, including injurious falls, hip fractures, and mortality, than the CCI. We further show that higher FMI is associated with reduced microbiota diversity, including lower gene richness and Shannon index. At the species level, FMI is associated with different species in Enterocloster, Clostridium, Dysosmobacter and Faecalibacterium in models accounting for the overall decline in microbiome gene richness associated with ageing, thereby distinguishing FMI-associated microbial features from general microbiota decline.

Link: https://doi.org/10.1038/s41467-026-75176-5

Neurogenesis is the name given to the creation of new neurons in the central nervous system, arising from neural stem cell populations, maturing, and then merging with existing neural networks. Neurogenesis is essential to memory and to the maintenance of brain tissue, the only way to replace neurons lost to damage or dysfunction. The pace of neurogenesis declines with age and in neurodegenerative conditions. Here, researchers investigate the link between inflammatory signaling and lost neurogenesis. The aged brain, like the aged body, is characterized by continual unresolved inflammatory signaling, a maladaptive reaction to forms of cell and tissue damage that changes cell behavior for the worse. It is disruptive to tissue structure and function. Any comprehensive package of rejuvenation therapies will have to include some way to address unwanted chronic inflammatory signaling without sabotaging the normal function of the immune system; so far, this has proven to be a difficult challenge.

Adult hippocampal neurogenesis is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to adult hippocampal neurogenesis impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-α) signalling as a key driver of neurogenic dysregulation via a previously unrecognised type I interferon autocrine/paracrine loop in human hippocampal progenitor cells.

Using a female-derived human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that tumour necrosis factor-alpha induces a robust type I interferon response in hippocampal progenitor cells, promoting chemokine-mediated and CXC motif chemokine receptor 3 (CXCR3)-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in hippocampal progenitor cells from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis.

These findings uncover a key inflammatory checkpoint regulating human adult hippocampal neurogenesis and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.

Link: https://doi.org/10.1038/s41467-026-74104-x

Aging clocks can be built from any sufficiently complex set of biological data measured in a sufficiently large number of people across a sufficiently large range of different ages. Machine learning techniques are used to find algorithmic combinations of data points that predict age to some sufficient threshold of accuracy. The algorithm is then applied to people who were not in the original sample populations, and most such clock algorithms do an acceptably good job of hitting the mark when considered over groups of people. Unfortunately they are not all that useful for an individual; in part the variance is a problem, but the main challenge is that it is entirely unclear in most clocks as to what the results actually mean. It is also unclear as to how we should expect any given clock to react to any given intervention used to treat aging.

The best path forward to making aging clocks useful for individuals, and for the assessment of novel therapies to treat aging, is probably to collect as much data as possible and observe the emerging patterns. Classes of therapy will have to be assessed in parallel with clocks. Different populations and different strategies for clock use will have to be assessed against actual outcomes, such as mortality rate and disease incidence years later. This won't be a fast process.

Nonetheless, interesting new findings emerge on a fairly regular basis as the use of clocks spreads. In today's open access paper, for example, research demonstrate that change over time in clock assessments is a useful piece of information, perhaps much more useful than single measures. This is particularly relevant to the use of clocks by an individual rather than in a population study, as many of the unknowns become irrelevant when one person uses the same clock repeatedly over a period of years to measure something that may be closely related to the pace of biological aging.

Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort

Over the past years, several proxy biomarkers of biological aging have been developed and validated, with the most advanced using data from DNA methylation. Broadly termed 'epigenetic clocks,' these methylation-based markers of aging have been shown to predict several adverse health outcomes, including mortality, independently of chronological age.

However, whether longitudinal changes in these phenotypes provide additional information on health outcome prediction over and beyond one single measure has not been demonstrated. Based on cross-sectional studies, we cannot definitively exclude that deviations of DNA methylation age from chronological age are determined early in life and are not modulated by behavioral, environmental exposures or changes in health status. In addition, if biological aging clocks are to be used to track the effectiveness of intervention over time, it is important to demonstrate that deviations of epigenetic clock trajectories reflect meaningful changes in health status.

In this longitudinal study of 699 adults from the InCHIANTI cohort followed for up to 24 years, we evaluated whether temporal acceleration of several epigenetic clocks-including first-, second- and third-generation epigenetic clocks-was associated with mortality. We found that faster increases in several clocks were linked robustly to higher risk of death, independent of baseline epigenetic age and other confounders. These findings suggest that dynamic changes in epigenetic aging reflect evolving health status and may serve as sensitive indicators for interventions aimed at extending healthspan and longevity.

When a cell becomes senescent, it ceases replication, grows in size, and devotes its energies to secreting a potent mix of pro-growth, pro-inflammatory signals. Cellular senescence serves useful purposes in embryonic development, wound healing, and suppression of cancer. It also marks the Hayflick limit on replication of somatic cells; a somatic cell either undergoes programmed cell death or becomes senescent on reaching the Hayflick limit. In those scenarios, the senescent cells are destroyed by the immune system shortly after serving their purpose. Unfortunately, the aging immune system becomes ever less capable of efficiently clearing senescent cells, and senescent cells begin to accumulate. Their signaling becomes harmful when sustained over the long term, disruptive to tissue structure and function. This is an important component of degenerative aging.

Senescence is a highly heterogeneous phenotype, and this heterogeneity arises from several layers of biological diversity. Different cell types may vary in their susceptibility to enter senescence and in the molecular pathways they activate upon entering this state, in addition to the core cell-cycle arrest machinery. This context-dependent variability is pronounced, such that senescent cells do not share a universal molecular signature, necessitating the use of multiple markers for their accurate identification. Microenvironmental conditions, including inflammatory cues, extracellular matrix composition, oxygen levels, and immune context, further shape the senescence response and senescence-associated secretory phenotype (SASP). Moreover, distinct senescence-inducing stimuli may engage overlapping but not identical signaling networks, leading to variation in gene-expression profiles, metabolic changes, and secretory programs. Together, these factors can create a spectrum of senescent cell phenotypes that differ in their impact on tissue physiology.

In this review, we focus on the major inducers of cellular senescence. While well-established inducers such as DNA damage and oxidative stress are central drivers of senescence in aging and disease, we also discuss physiological and context-specific triggers to provide a more comprehensive and integrative perspective on senescence induction. Starting from the first-described form of senescence, replicative senescence associated with prolonged cell culture, we provide a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarize the molecular mechanisms through which they trigger the senescence program. Integrating insights into these distinct stimuli, the signaling pathways they engage, and their functional consequences might help to clarify how distinct populations of senescent cells contribute to aging, cancer, and age-related pathologies, and assist in the development of new therapeutic strategies aimed at modulating senescence and its deleterious consequences without deteriorating its beneficial functions.

Link: https://doi.org/10.18632/aging.206391

An interesting question with regard to the growth in the age-related burden of senescent cells is the degree to which it is altered by lifestyle choice. Or, to put it another way, we know the degree to which better lifestyle choices affect pace of aging and life expectancy: how much of that effect is due to a reduced burden of senescent cells? Can the existing burden be reduced by better lifestyle choices, and by how much? Here, researchers review the evidence for dietary lifestyle choices to influence cellular senescence and find it lacking, as the existing body of clinical trial data is not large enough and consistent enough to support definitive statements. As the researchers note, the data is supportive of the hypothesis that dietary choice has more of an impact on the behavior rather than number of senescent cells. The burden remains.

Cellular senescence is a fundamental mechanism of ageing, characterised by stable cell cycle arrest and the acquisition of a pro-inflammatory secretory phenotype (SASP). Nutritional interventions are widely proposed to modulate ageing biology, but their effects on cellular senescence in humans remain unclear. We systematically synthesised evidence from interventional human studies assessing the impact of nutritional strategies on biomarkers of cellular senescence.

Twenty-nine articles (27 trials; 3,811 participants) were included. Across studies, nutritional interventions modulated multiple senescence biomarkers to varying extents, with calorie restriction producing the most recurrent reductions in circulating inflammatory and secretory factors commonly included in SASP panels as well as senescence-associated transcriptomic signatures. Classical markers of cell cycle arrest (e.g., CDKN2A/p16, CDKN1A/p21) and telomere length were largely unchanged or highly variable. Calorie restriction mimetics, particularly metformin and rapamycin, showed context-dependent effects, most evident under conditions of metabolic or physiological stress. Among dietary supplements, n-3 polyunsaturated fatty acids may modulate selected inflammatory/SASP-related circulating markers, although the evidence for dietary supplements remains limited and heterogeneous.

In humans, available evidence suggests that nutritional interventions may preferentially affect senescence-associated inflammatory and secretory biomarker profiles, particularly SASP-related mediators, rather than markers more directly related to senescent cell abundance. However, because SASP factors and circulating cytokines are heterogeneous and not specific to senescent cells, these findings should be interpreted as evidence for possible modulation of senescence-associated markers rather than definitive effects on senescence burden. These observations support the use of multi-marker and functionally relevant endpoints in future clinical studies targeting biological ageing and cellular senescence.

Link: https://doi.org/10.1016/j.arr.2026.103224

It seems a little early in the development of partial epigenetic reprogramming as a class of therapy to be thinking about which of the other approaches to aging it can best be combined with. Nonetheless, a proposal for therapeutic plasma exchange and partial epigenetic programming to go well together is the topic of today's open access paper. The argument is that these two classes of approach are addressing different layers of the dysfunction of aging, and should this do little to interfere with each other's benefits.

Until such time as someone comes up with a safe, viable small molecule reprogramming therapy, it seems likely that reprogramming will remain quite limited in scope because of the delivery challenges inherent in gene therapy. Very few delivery systems have any potential to deliver a payload well to the whole body (or even most of the body), and none of the established options are capable of this outcome. Even when delivery is good for a given tissue, the many different cell types making up that tissue likely vary widely when it comes to optimal dose and duration of reprogramming agents. It is a challenge.

On the therapeutic plasma exchange front, even the most basic, initial questions around dosing and efficacy remain to be answered. Because there is little profit in this type of therapy, no-one with deep pockets has any incentive to run the extensive trials that would be needed to provide definitive answers. As things stand, it seems likely that forms of therapeutic plasma exchange and plasma dilution will spread throughout the medical tourism space, but no firm data will emerge in the near future. This the case for numerous therapies adopted by clinics outside the US and Europe, but which do not bring in enough revenue for someone to sponsor formal clinical trials.

Systemic recalibration and epigenetic resetting as complementary strategies in ageing biology

Systemic and cellular rejuvenation strategies differ fundamentally in their therapeutic targets and in the biological level at which they intervene. Systemic interventions such as therapeutic plasma exchange or young blood administration primarily modify the extracellular and circulating environment. Through removal of pro-ageing and pro-inflammatory factors, or provision of pro-youthful factors, these approaches may improve intercellular communication and reduce adverse systemic influences such as chronic inflammation. Their principal strength lies in the breadth of action across multiple tissues. Their principal limitation is that they do not directly reverse intracellular age-associated changes. Cells with aged epigenomes, altered transcriptional programmes, and accumulated damage may therefore remain only partially responsive.

Partial reprogramming intervenes at the level of intracellular ageing mechanisms. It directly addresses loss of epigenetic information, which the Information Theory of Ageing proposes as the fundamental cause of mammalian ageing. By resetting elements of the epigenetic landscape, partial reprogramming reverses age-associated states such as mesenchymal drift and metabolic dysfunction at their source. Its principal strength lies in mechanistic depth. Its limitation is contextual dependence, because a persistently aged tissue environment may still impose inflammatory, structural, and extracellular constraints that partial reprogramming alone cannot fully resolve. The most important translational question is not which strategy is generally superior, but which biological constraint dominates in a given disease setting and whether both levels require simultaneous intervention.

The dilution hypothesis is examined together with its limitations and the unresolved complexities of systemic interventions. The challenge of cell-autonomous ageing is also considered, particularly the persistence of cell populations that remain refractory to systemic rejuvenation. A conceptual framework integrating these two axes of ageing is then presented. This framework suggests that combined systemic recalibration and targeted partial reprogramming warrant further investigation as a multimodal approach to ageing intervention. Future research priorities include mechanistic clarification of this systemic-cellular interaction and development of robust biomarkers to evaluate multimodal interventions.

Every mechanism of aging influences all of the other mechanisms of aging. Our biology is a big tangled ball of interactions. As a follow up to a recent post on the connection between mitochondrial dysfunction and senescent cell accumulation in the context of intervertebal disc degeneration, here find a different viewpoint that focuses on the connection between epigenetic aging and senescent cell accumulation. In the nucleus of the cell, epigenetic decoration of nuclear DNA and supporting molecules control its structure; these decorations include DNA methylation and modifications to the histone proteins that DNA is spooled onto. Structure in turn determines which genes are expressed, which proteins manufactured. Patterns of epigenetic control over nuclear DNA structure change with age in characteristic ways, some mix of adaptive and maladaptive reactions to other mechanisms of aging, possibly mixed in with a fundamental disruption to this system of control deriving from the repeated operation of DNA repair.

Intervertebral disc degeneration (IDD) is the leading pathological cause of low back pain, while current clinical treatments are only palliative and cannot reverse the programmed cellular senescence driven by epigenetic dysregulation. This process is characterized by progressive loss of nucleus pulposus (NP) cell identity and establishment of a self-amplifying senescence-associated microenvironment. In this review, we synthesize recent advances elucidating how heterogeneous senescent cell populations and their secretory phenotype (SASP) orchestrate a destructive vicious cycle in IDD.

We further dissect the synergistic interplay among DNA methylation, histone modifications, and non-coding RNAs that constitutes the "epigenetic aging clock" and drives premature cellular aging within the disc. Notably, we evaluate emerging therapeutic strategies aimed at clock reversal, including senolytic clearance of senescent cells, epigenetic remodeling using small-molecule inhibitors or CRISPR-Cas9 editing, and cellular reprogramming approaches ranging from induced pluripotent stem cell (iPSC) differentiation to direct lineage conversion. We propose a synergistic "clear, prime, then seed" roadmap that sequentially combines these interventions for optimal regeneration. This work provides a systematic theoretical framework for the clinical translation of epigenetic-targeted therapy for IDD, and breaks through the cognitive limitation of traditional mechanical wear theory.

Link: https://doi.org/10.3389/fragi.2026.1842955

STING is a master regulator of inflammatory signaling, triggered by a range of different sensor proteins for foreign material or forms of damage within a cell. With age, these sensors become overly active even in the absence of the usual stimuli, such as the presence of infectious agents, and the resulting inflammatory response is maladaptive, spreading harms further rather than helping the situation. Continual, unresolved inflammatory signaling is characteristic of old age, and it is disruptive to tissue structure and function. Here researchers note that inflammatory signaling in the body harms the brain via long-range communication between cells that is mediated via production and uptake of extracellular vesicles. Vesicles are small membrane-wrapped packages of molecules, carrying information from one cell to another. Their contents can change dramatically depending on the state of the originating cell, and this is one of the ways in which harms can spread, particularly in the context of chronic inflammation.

All animals age. However, aging is a heterogeneous process, and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same speed. For instance, neurodegeneration, a hallmark of aging, generally manifests later than other peripheral aging signs. The genetic determinants of aging are not completely understood.

Gain-of-function (GoF) mutations in leucine-rich repeat kinase 2 (LRRK2GoF) are major genetic risk factors for Parkinson's disease (PD). By analyzing PD patients and LRRK2GoF mice, we show that PD represents an accelerated aging disorder driven by STING-dependent inflammation. This inflammation begins peripherally, disrupts the blood-brain barrier, and causes dopaminergic neurodegeneration.

Mechanistically, aging or LRRK2GoF causes endolysosomal decline, resulting in cytosolic self-DNA accumulation and the release of DNA-containing extracellular vesicles (EVs) that activate the cGAS-STING pathway within and between cells. Our findings identify LRRK2GoF as a key driver of accelerated aging and systemic inflammaging through DNA-containing EVs, highlighting potential therapeutic targets to counteract inflammaging and neurodegeneration.

Link: https://doi.org/10.1016/j.celrep.2026.117640

Intervertebral disc degeneration is a complex dysfunction in the tissue maintenance and tissue properties of the discs between vertebrae. The discs allow flexibility of the spine, cushion impacts, and hold the spine together. Weakening of disc structures leads to tears and other failures that produce a sizable negative impact on the ability of an individual to function. A large subset of the population shows measurable degeneration of intervertebral discs even before reaching age 40, and after that point it becomes a majority. This is a universal aspect of aging, and the question is only how long it will take before something important breaks under stress.

Interestingly, intervertebral disc degeneration is strongly connected to cellular senescence. There are clear lines to be drawn between the burden of senescent cells and the mechanisms leading to loss of disc structural integrity. Senolytic therapies to selectively clear senescent cells have done well in animal models of degenerative disc disorders. Similarly, mitochondrial dysfunction is also strongly linked to intervertebral disc degeneration. Both loss of mitochondrial function and burden of senescence are correlated - the former tends to increase the pace at which the latter grows. It is interesting to note today's open access study, in which improved mitochondrial function also reduces cellular senescence in the course of restoring some lost function to an aged tissue.

Activation of Sirt3 reprograms mitochondrial function to regenerate intervertebral disc degeneration

Intervertebral disc degeneration is the principal pathological basis of low back pain. Currently, there are limited therapeutic strategies to regenerate intervertebral disc. In this study, we found the expression of SIRT3 is significantly negatively correlated with the degree of disc degeneration in humans. In mice, knockout of Sirt3 resulted in pronounced disc degeneration accompanied by increased expression of inflammatory mediators and senescence-associated factors.

Transcriptomic analyses in mice revealed that Sirt3 deficiency was closely associated with dysregulation of calcium signaling pathways and impaired adenosine triphosphate (ATP) synthesis. Bioinformatics analyses identified Ckm and Atp2a1 as hub genes linking Sirt3 deficiency to calcium homeostasis disruption and ATP metabolic dysfunction.

Importantly, the administration of Sirt3 activator 2-APQC in a D-galactose-induced aging mouse model significantly ameliorated intervertebral disc degeneration-associated pathological changes, evidenced by restored mitochondrial function, reduced inflammation and cellular senescence, and rescued expression of hub genes Ckm and Atp2a1.

Studies tend to show that even a late life adjustment of lifestyle can meaningfully improve health and reduce mortality risk. It is never too late to gain some benefit from a better diet, more physical activity, greater physical fitness, and loss of excess visceral fat tissue. As an illustration of this point, researchers here show that older people who improve their lifestyle choices exhibit a sizable reduction in the risk of cognitive impairment versus those who retain a poor set of lifestyle choices.

This study included 6,765 older adults from the Chinese Longitudinal Healthy Longevity Survey. Data on lifestyle, including dietary habits, sleep quality, physical, cognitive, and social activity were self-reported from 2008 to 2014. Cognitive function was measured using the Mini-Mental State Examination from 2014 to 2018. Over a mean follow-up period of 5.9 years, 1,659 participants (24.5%) developed cognitive impairment. Three distinct lifestyle behavior trajectory classes were identified: "Low-Declining" (n = 4,342, 64.2%), "Moderate-Improving" (n = 1,777, 26.3%), and "High-Declining" (n = 646, 9.5%).

Compared with the Low-Declining group, the Moderate-Improving group was associated with a lower risk of cognitive impairment (hazard ratio, HR = 0.368), a longer time to cognitive impairment onset (mean = 6.433 years) and a slower rate of annual cognitive decline (0.806 points per year). Similarly, the High-Declining group showed a reduced risk (HR = 0.629, delayed onset (mean = 4.969 years) and a slower decline rate (0.543 points per year) compared with the Low-Declining group. Thus an upward trajectory of moderate lifestyle engagement, as well as a high but declining class, was associated with better cognitive outcomes compared with persistently low or declining engagement.

Link: https://doi.org/10.1186/s13690-026-02007-w

How far can one go, practically speaking, and in the relatively near future, to develop therapies to treat aging based on replacement of worn parts? Some forms of replacement therapy have existed for decades, and have arrived at a fairly sophisticated level of development. These approaches include organ transplantation and replacement of damaged bone with non-biological materials. These therapeutic options have their limitations and drawbacks, the largest of which is the need for major surgery. One view of the present era in biotechnology is that it represents an effort to move from approaches requiring major surgery to approaches that regrow and replace tissues in situ without major surgery, based on either cell therapies or manipulation of native cell populations. This transition is a slow one, clearly.

Recent discoveries and therapeutic developments in longevity science have made it increasingly clear that a vast amount of age-related damage and systemic changes at the level of molecules, organelles, cells, tissues, organs, and organisms must be reversed to yield durable and multi-tissue rejuvenation as well as further extensions in healthy lifespan. Advanced biological and synthetic replacement, maintenance, and multi-targeted damage-removal strategies for cells, tissues, and organ systems represent some of the most promising longevity interventions, with the potential to reverse an unprecedented fraction of age-related changes, and to prevent, slow, or even reverse age-related diseases and dysfunction.

We define replacement-based ageing interventions as strategies that replace cells, tissues, organs, physiological systems, or cellular components (e.g., mitochondria or genes) with biological or synthetic alternatives. Biological replacements include transplantation of stem cells, organs, and bioprinted tissues (e.g., progressive brain replacement using cells and biomaterials), bioengineered cell therapies (e.g., CAR-T and synthetic cells), and therapeutic plasma exchange. Synthetic replacements include prostheses, external medical devices (e.g., dialysis machines), and brain-machine interface systems (e.g., cortical implants).

Replacement-based approaches are predicted to act synergistically with emerging regeneration and synthetic damage-removal technologies capable of targeting and exporting hundreds of molecular and organellar damage types from cells without relying solely on inherently limited and declining endogenous repair, clearance, and export processes.

Link: https://doi.org/10.1111/acel.70516

Age-related impairment of drainage of cerebrospinal fluid from the brain is a topic of increasing interest. This was pioneered by the work of Leucadia Therapeutics, specifically focused on the drainage path for the olfactory bulb leading through the cribriform plate, but most present work is focused instead on the glymphatic system drainage that parallels the vasculature supplying the brain. The two pathways decline in capacity with age, but for very different reasons, and will need different forms of therapy. Thin channels for fluid flow through the cribriform plate ossify shut with age. The glymphatic system suffers from a failure of regulation of peristaltic flow through vessels, however.

Cerebrospinal fluid drainage is a way to remove metabolic waste from the brain. Declining flow means that this waste will build up. This includes the protein aggregates associated with neurodegenerative conditions, and probably a great many other forms of metabolic waste that individually have more subtle effects, but collectively act to provoke cell dysfunction when present at high levels. One of the more important consequences is thought to be a maladaptive inflammatory reaction in glial cells in the brain, which in turn drives the onset and progression of neurodegenerative conditions.

In today's open access paper, researchers assess measures indicative of loss of cerebrospinal fluid drainage in patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD), which is a failure of the normal suppression of muscle activity during REM sleep. iRBD is now recognized as a very early symptom of synucleinopathies such as Parkinson's disease. Synucleinopathies are characterized by the aggregation and spread of misfolded α-synuclein through the central nervous system, and associated neuroinflammation. A failure of cerebrospinal fluid drainage can only make this worse, closing off one way to remove aggregated proteins, and increasing inflammation as a consequence.

CSF turnover dysfunction: a hidden early biomarker in iRBD?

Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy.

Here, we used MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.

Vaccinations can produce a lasting effect known as trained immunity, altering the behavior of the innate immune system and resulting in both a reduction in the chronic inflammation of aging and a more effective immune response to unrelated infectious agents. Arguably the largest body of research into trained immunity involves the BCG vaccine for tuberculosis, widely used outside the United States. A lesser body of work examines the trained immunity effects of a small number of other vaccines that are more commonly provided to adults rather than children. For most vaccines, there is no human data, and trained immunity itself is well documented, but not well understood in detail. Here, researchers report on a small trial to assess the effects of BCG vaccination on older people with and without Alzheimer's disease, to see whether the changes produced by trained immunity are sizable enough to justify further trials and widespread use.

Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart.

We show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.

Link: https://doi.org/10.1038/s43856-026-01691-7

Senescent cells are involved in tissue regeneration. Cells enter a senescent state following injury, and in the usual course of events assist in the intricate coordination between immune cells, stem cells, and other cell types that is required to regrow tissue. These senescent cells are then cleared by the immune system. With age, in poorly regenerative tissues, or in severe or persistent injuries, the presence of senescent cells following injury can become excessive and maladaptive. The signaling produced by senescent cells lasts too long, the cells are not cleared, and it causes further harm. As researchers here note, this is what happens following a heart attack, suggesting that there is likely some timing for the delivery of senolytic therapies to selectively destroy the cells become senescent immediately following the ischemic injury of a heart attack that could improve patient outcomes.

Currently, the primary causes of death following myocardial infarction include sudden cardiac death, malignant arrhythmias, and acute heart failure, all resulting from myocardial necrosis caused by coronary artery occlusion. Cellular senescence refers to the permanent arrest of cell proliferation in response to stress stimuli; it serves as a crucial tumor defense mechanism and is closely associated with tissue aging and chronic inflammation. The senescence-associated secretory phenotype (SASP) is one of the most characteristic features of senescent cells. Cardiac cells develop a SASP and secrete SASP factors in response to stimuli such as oxidative stress, DNA damage, and hypoxia, playing a key role in immune regulation and tissue repair following myocardial infarction.

The SASP exhibits marked spatiotemporal heterogeneity following myocardial infarction: during the acute phase, it contributes to inflammatory amplification and immune cell recruitment; during the subacute phase, it is involved in inflammation resolution, matrix remodeling, and scar formation; and during the chronic phase, it promotes chronic inflammation, paracrine senescence, pathological fibrosis, and cardiac dysfunction. Spatially, the SASP influences scar stabilization in the infarct zone, inflammation-electrophysiological coupling in the border zone, and compensatory remodeling in the distal region. The sustained expression of the SASP is a major driver of adverse ventricular remodeling and excessive fibrosis following myocardial infarction.

Therefore, targeting senescent cells and persistent, pathological SASP represents a highly promising therapeutic strategy in the field of cardiovascular regenerative medicine. This review will discuss senescence in different cell types following myocardial infarction, the spatiotemporal heterogeneity of the immune response mediated by the SASP after myocardial infarction, and the immune cells regulated by the SASP.

Link: https://doi.org/10.3389/fimmu.2026.1850084

There is a large body of evidence in animal studies to show that treatment with dasatinib and quercetin clears a fraction of the lingering senescent cells present in tissues throughout the body to restore more youthful function to many different organs and systems. Today's open access paper, focused on kidney rejuvenation via removal of senescent cells, is yet another to add to the scores of existing studies. Dasatinib is a generic chemotherapeutic drug, while quercetin is a plant flavonol; both cost little. Dasatinib can be readily obtained these days via anti-aging clinical practices, offshore pharmacies, and the other usual approaches to access low cost prescription drugs. Quercetin can be found in any supplement store.

Sadly, exactly because dasatinib and quercetin are cheap compounds, there is very little incentive for anyone to fund the sizable expense of running large clinical trials to first establish optimal dosing, and secondly confirm that this treatment is as good for aged humans as it is for aged mice. Those trials that have taken place were funded by academic institutions, were small, exploratory, and the results were promising. Only larger trials can move from promising to "yes, this works," however. Meanwhile, any older person willing to put in the effort can run their own study of one, and see how a range of biomarkers look before and after treatment. The human trials suggest that side-effects for a short course of treatment are minimal compared to potential benefits.

Multi-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapy

Cellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D + Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D + Q in naturally aged mice using multi-omics approaches. Beginning at 12 months of age, mice assigned to the treatment arm received biweekly oral gavage of the D + Q cocktail for a total duration of 8 months.

We show that D + Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D + Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D + Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D + Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D + Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling.

Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.

Animal studies suggest that the composition of the gut microbiome is at least as important as diet and exercise when it comes to influencing the pace and progression of aging. Both diet and exercise influence the gut microbiome as well - nothing in the body acts in isolation. The composition of the gut microbiome changes with age, and in animal studies approaches that restore a more youthful balance of microbial populations to aged animals improve health and extend life span. Here, researchers review what is known of the links between the metabolites produced by the gut microbiome and the health of aged tissues in the body, with a particular focus on muscle and the brain.

Cognitive frailty, characterized by the coexistence of physical frailty and cognitive impairment, has emerged as a major challenge in aging populations and is closely linked to sarcopenia, neurodegeneration, and chronic inflammation. Increasing evidence suggests that the gut microbiota acts as a central regulator of neuromuscular and neurocognitive aging through the integrated gut-brain-muscle axis.

This review highlights how microbial dysbiosis, reduced short-chain fatty acid (SCFA) production, systemic endotoxemia, and altered microbial metabolites contribute to mitochondrial dysfunction, neuroinflammation, anabolic resistance, and impaired neuroplasticity. Key signaling mediators, including SCFAs, bile acids, tryptophan-derived metabolites, cytokines, and myokines such as irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B, orchestrate bidirectional communication among the gut, skeletal muscle, and brain.

We further discuss the role of exercise-induced microbiota remodeling and muscle endocrine signaling in promoting mitochondrial biogenesis and cognitive resilience. In addition, emerging translational strategies including probiotics, prebiotics, postbiotics, polyphenol-rich functional foods, marine bioactives, and precision nutrition are explored as potential interventions targeting this axis. Collectively, the gut-brain-muscle axis provides a novel systems biology framework for understanding cognitive frailty and developing integrated therapeutic strategies for healthy longevity.

Link: https://doi.org/10.3390/microorganisms14061366

Researchers here describe an approach to encouraging regrowth of small vessels in heart tissue, involving transplantation of organoids composed of the various cell types needed to form new vessels. Like other cell therapy strategies for an injured or aged heart, delivery involves making a patch of pseudo-tissue that is layered onto the surface of the heart. The patch mimics enough of the function of a natural extracellular matrix to increase survival of transplanted cells. More generally, we might consider whether this sort of strategy would work for other tissues; loss of capillary density is a feature of aging throughout the body, and ways to restore a more youthful extent of capillary networks could be meaningfully beneficial.

Ischemic heart disease (IHD), also known as coronary artery disease, is a leading cause of death and morbidity. IHD arises when blood vessels of the heart become clogged, blunting oxygen and nutrient supply to heart muscle cells, which eventually die off, leading to heart attack or heart failure. Although larger blood vessels can be replaced surgically to restore blood flow, there is currently no treatment targeting smaller blood vessels, so-called microvessels, which are essential for the uniform blood circulation within the heart muscle.

Researchers made vascular organoids, which are small aggregates of cells capable of forming new blood vessels, from endothelial progenitor cells (EPCs) isolated from human blood and mesenchymal stem cell-derived smooth muscle cells (SMCs) from human bone marrow. The team then placed patches of vascular organoids onto the outer heart surface of pigs with IHD and followed them for four weeks. Encouragingly, heart function in pigs receiving organoid patches was improved compared to untreated animals, and progression of IHD towards heart failure was mitigated. The organoid patches survived for several weeks and individual cells from the surface patches were found in deeper layers of the pig hearts suggesting they are migrating into the heart.

Link: https://www.eurekalert.org/news-releases/1133607

The point of studying the biochemistry of very long-lived humans is to try to better understand which of the many underlying mechanisms of damage and dysfunction that drive degenerative aging are the most important and thus should be prioritized for the development of therapies. One can look at the differences in the sequences of proteins, expression of proteins, and the operation of metabolism and try to infer why those differences tend to exist more often in long-lived individuals, try to make a link to a known form of damage. The point is not to to try to emulate the specific biochemistry of long-lived individuals: all that will happen as a result of that is a modest decrease in pace of aging, while one will still wind up frail, greatly impacted by degeneration, and with a very high mortality rate. It is a small gain. We would like to engineer larger gains.

In today's open access paper, researchers find that SIRT6 variants that are more common in centenarians are protective because they reduce the burden of senescent cells in aged tissues. The response to that finding should be to ramp up development of more and better senotherapeutic research programs with the goal of selectively removing senescent cells from the aging body on an ongoing basis, or at the very least halting the harmful signaling that is the primary mechanism by which lingering senescent cells are disruptive to structure and function in surrounding tissues. The response should not be to deliver better versions of SIRT6 into patients via gene therapy, as this will be far less beneficial.

Centenarian SIRT6 variants elevate SIRT6 protein and enhance cellular senescence resistance

Centenarians represent a natural model of delayed human aging, offering a unique opportunity to uncover genetic mechanisms that promote longevity. However, the functional consequences of the genetics variants carried by these long-lived individuals remain poorly characterized in physiologically relevant systems. Here, we introduced two linked missense variants in SIRT6 enriched in Ashkenazi Jewish centenarians into the endogenous SIRT6 locus of human embryonic stem cells and differentiated them into somatic lineages to define their effects in a native genomic context.

We revealed that centenarian variants elevated endogenous SIRT6 protein abundance through weakened interaction with vimentin, and altered endogenous SIRT6 enzymatic activities, including enhanced mono-ADP-ribosyltransferase activity and reduced deacetylase activity. Functionally, these variants delayed replicative senescence and conferred resistance to progerin-induced stress, accompanied by preservation of DNA repair gene expression programs and suppression of transposable element derepression. Guided by these findings, we evaluated the translational potential of both genetic and pharmacological interventions, demonstrating that adeno-associated virus (AAV)-mediated delivery of centenarian SIRT6 or pharmacological activation of SIRT6 using fucoidan from Fucus vesiculosus (Fucoidan-FV) partially attenuated aging-associated molecular defects, including genome instability and LINE1 derepression, in progeria fibroblasts.

Together, these findings demonstrate that centenarian variants exert multifaceted effects on SIRT6 function to enhance cellular stress resistance, and providing a framework for translating genetic discoveries from long-lived individuals into mechanistic insight and potential gerotherapeutic strategies for healthy aging.

The more severe later stages of Alzheimer's disease are characterized by altered forms of tau protein aggregating inside neurons to cause dysfunction, inflammation, and cell death. Researchers here show that tau can spread between neurons via extracellular vesicles, and identify the protein arc as necessary to this process. Once a mechanism involved in the spread of pathological proteins is developed, it is potentially a target for future therapies that might slow the progression of disease.

Neurodegenerative diseases are characterized by protein aggregation in specific brain regions that spread across the brain as the disease progresses. A major histopathological hallmark of Alzheimer's disease (AD) and tauopathies, such as frontotemporal dementia (FTD) and chronic traumatic encephalopathy, is intracellular neurofibrillary tangles that consist of misfolded tau protein. During aging, tau becomes hyperphosphorylated, resulting in misfolding and a decreased affinity for microtubules. Tau pathology is transmitted cell to cell, and the spread and levels of pathological tau strongly correlate with the degree of cognitive decline in AD patients.

We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain extracellular vesicles (EVs) purified from transgenic rTg4510 mutant tau mice (rTgWT) crossed with Arc knockout mice (rTgArc KO) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTgArc KO mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.

Link: https://doi.org/10.1016/j.cell.2026.06.008

The gut microbiome generates a vast range of metabolites, some beneficial or even necessary to health, and some actively harmful, provoking chronic inflammation or other dysfunction. With age the balance of microbial populations making up the gut microbiome changes for the worse. Researchers have observed declines in the generation of some beneficial metabolites and increases in the generation of some harmful metabolites. Among the harmful metabolites, the neurotoxic imidazole propionate has been shown to accelerate atherosclerosis, and evidence suggests a contribution to a range of other age-related conditions. Here, researchers report on evidence in mice and humans for imidazole propionate to accelerate the pace of neurodegeneration leading to Alzheimer's disease.

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology.

In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD.

In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.

Link: https://doi.org/10.1038/s41467-026-74744-z

The retina is considered a part of the central nervous system. As is the case for the brain, a barrier of specialized cells surrounding the blood vessels supplying retinal tissue controls the passage of molecules between blood and tissues. This barrier becomes dysfunctional with age and age-related conditions, and leaks inappropriate molecules into retinal tissue to cause further damage and dysfunction. Again, this is very analogous to barrier dysfunction in the brain, and is thought to be a major contributing factor in age-related neurodegeneration and consequent degenerative conditions.

One of the approaches under development for the treatment of damaged retinal tissue, such as in the context of macular degeneration or diabetic retinopathy, is to produce new cells that can replace dead or dysfunctional cells, or otherwise help to improve function via a health profile of secretions. In today's open access paper, researchers report on generation of endothelial cells of the retinal barrier from induced pluripotent stem cells. When introduced into a damaged mouse retina, these cells help to repair tissue and restore a functional vasculature.

Derivation of functional retinal endothelial cells from human pluripotent stem cells for therapeutics and modelling

Retinal tissue has the highest energy and oxygen usage in the body due to the retina's intense and continuous neuronal activity. This demand leads to a crucial reliance on the inner blood-retina barrier (iBRB) to maintain ocular homeostasis. The iBRB is a specialized anatomical unit composing the vasculature located within the internal retinal layers of the central nervous system. Retinal endothelial cells (RECs) in the iBRB are continuous endothelial cells (ECs) that form tight junctions to regulate the diffusion of small molecules, such as ions and water, across their cell-cell interface.

Dysfunction and vascular leakage of the iBRB have been identified as a hallmark of numerous retinal microvascular diseases, including diabetic retinopathy (DR), the leading cause of blindness and a common pathology found in patients with diabetes mellitus. The breakdown of the iBRB occurs due to prolonged hyperglycaemia exposure, leading to increased permeability of the endothelial barrier and reduced oxygen delivery to the retina, causing ischaemia. As DR progresses, it can eventually lead to bleeding, retinal detachment and irreversible blindness.

In this study we harnessed Wnt-β-catenin signalling to derive RECs from human induced pluripotent stem cells (iRECs) that can generate a continuous endothelial barrier with a characteristic retinal phenotype and genotype as well as iBRB functionality. We established the therapeutic potential of the iRECs for the ischaemic eye using an oxygen-induced retinopathy (OIR) mouse model. When injected into oxygen-induced retinopathy mice, iRECs integrated into the host vascular network and revascularized the ischaemic eye, rescuing the tissue.

The growth in number of senescent cells with age is an important mechanism of degenerative aging. Many studies in mice have demonstrated rapid rejuvenation and reversal of many different aspects of aging and age-related conditions via selective destruction of senescent cells in aged tissues. Here, researchers review what is known of the way in which the age-related expansion of the senescent state in cell populations impedes stem cell function in older individuals. Stem cells support tissues by generating a supply of daughter somatic cells to replace losses, as well as via signaling that is important to regenerative capacity. As stem cell activity declines so too does tissue function and health.

Several cellular settings have been identified where senescence induction seems to exclude stem cell activity, thereby suggesting a functional competition between the two processes. One such example are mesenchymal stem cells (MSCs) used in therapy. Many of the potentially beneficial MSC properties are attributed to their ability to grow as high-density monolayers known as MSC sheets, which however can rapidly acquire senescence features under sustained high-density conditions. Another case of functional competition between senescence and stemness relates to bone marrow mesenchymal stem cells (BMSCs) which constitute a lifelong reservoir for somatic cell generation, and are shown to be significantly useful in bone regenerative medicine. It has, however, been observed that BMSC osteogenic differentiation is inhibited by senescence, thereby limiting the BMSC regenerative potential.

A considerable body of evidence where documented antagonism between senescence and stemness is pivotal for physiological homeostasis refers to muscle tissue. Muscle tissue regeneration relies heavily on satellite cells, a quiescent adult stem cell population whose regenerative capacity declines upon aging. Stellite cells from geriatric populations fail to retain their quiescent state under normal conditions, which extensively impacts their self-renewal and regenerative properties. Resting satellite cells in geriatric mice switch to a pre-senescence state thereby losing quiescence, a process driven by p16INK4A derepression. Thus maintenance of quiescence in adults, in fact, relies on repression of senescence.

Given that senescence is intrinsically characterized by proliferation arrest, while stemness refers to an inherent self-renewal capacity and production of differentiated progeny, the two cellular states are often perceived as mutually exclusive. Indeed, in this review we present an accumulation of evidence where the establishment of senescence may impose a barrier to stemness during natural processes such as aging, and upon reversing this functional competition (e.g. via genetic or pharmacological interventions) cell fate may change, as shown in multiple cell types and tissues such as MSCs, muscle satellite cells, dental pulp stem cells, or pancreatic β-cells.

Interestingly extensive functional synergy between the two states is widely observed in cancer, because the "dark side of senescence" may promote tumorigenic traits through senescent cell paracrine activity or even escape from the senescent state itself. Such activity was found to occur at least in B-cell lymphomas, liver, colon, and lung cancer.

Link: https://doi.org/10.18632/aging.206387

Accelerated aging conditions are not really accelerated aging conditions; each is a dysfunction in which one specific mechanism runs amok, generating damage and dysfunction that superficially resembles the damage and dysfunction of aging. Most of the known accelerated aging conditions are strongly connected to malfunctions in DNA repair, and dysfunction arises at least in part due to an accumulation of mutational damage in critical cell populations. Here, researchers describe an accelerated aging condition in which the underlying dysfunction is an increase in DNA methylation, distorting the epigenetic regulation of nuclear DNA structure and gene expression, again in ways that are superficially similar to the epigenetic changes of aging. Just as DNA repair disorders provide some insight into normal aging, with caveats, so too we might expect an epigenetic disorder to shed some light. The fine details still matter, however. Dysfunction is not equivalent to accelerated aging, even if it has the appearance of accelerated aging.

Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies.

Here we describe an epigenetically driven accelerated aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we implicate DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.

Link: https://doi.org/10.1038/s41588-026-02633-8

In recent years, researchers have noted that one variant of the BPIFB4 gene is associated with human longevity. This was discovered in the usual way, by noting that older populations tend to have a higher proportion of individuals carrying the variant than is the case for younger populations. In other words, individuals without the protective variant have an incrementally higher mortality rate. The longevity-associated variant of BPIFB4 appears to reduce cardiovascular dysfunction and mortality, and also reduces the chronic inflammatory signaling characteristic of aging. That slowed cardiovascular aging may or may not be entirely a consequence of the reduced inflammation; that remains to be determined.

Studies in mice have shown similar outcomes, and, interestingly, the BPIFB4 protein is robust enough to deliver orally and still produce benefits. Meanwhile, investigations of the underlying biochemistry of BPIFB4 and its role in the body continues, seeking a better understanding of how exactly it works.

Today's open access paper reports on new findings regarding the way in which BPIFB4 interacts with the immune system, which appears to be mediated via the activities of platelets. Platelets are cell fragments manufactured by megakaryocyte cells; they might be thought of as mini-cells that exhibit the surface features and some of the contents of their megakaryocyte progenitors. The primary purpose of platelets is to produce clotting when needed, but even when that is not happening, platelets are active participants in the complex dance of interactions between cells. Researchers suggest that effects hinge on the degree to which CD47 appears on platelet surface membranes, which offers a possible path to developing a drug to mimic BPIFB4 benefits.

The LAV-BPIFB4-Platelet-CD47 Axis: A Novel Mechanism Associated With Immune Resilience in Longevity

Long-living individuals (LLIs) possess remarkable genetic resilience, characterized by protective variants that confer immune robustness and resistance to age-related diseases. The longevity-associated variant of BPIFB4 (LAV-BPIFB4), enriched in centenarians, demonstrated pleiotropic benefits including reduced inflammation, cardiovascular protection, and immune system rejuvenation. However, the molecular mechanisms underlying these protective effects remain incompletely understood.

Here, we revealed that LAV-BPIFB4 fundamentally reshaped the immune features of platelets to establish enhanced immunomodulatory capacity through CD47 upregulation. Of note, centenarians displayed an elevated percentage of circulating CD47+ reticulated platelets (RPs), a condition mimicked by LAV-BPIFB4 carriers which exhibited significantly elevated CD47 levels both on RPs and mature platelets' surface. In agreement with an early acquirement of CD47 overexpression, MEG-01 megakaryoblastic cells overexpressing LAV-BPIFB4 produced CD47-high platelet-sized particles.

Functionally, platelets from LAV carriers suppressed monocyte activation and inflammatory cytokine production through CD47-dependent mechanisms, selectively reducing p38 MAPK activation while leaving NF-κB signaling largely unaffected in response to lipopolysaccharide. Recombinant LAV-BPIFB4 administration in vivo increased CD47 on murine platelets and reduced, ex vivo, LPS-induced monocyte activation, validating cross-species therapeutic potential. Critically, recombinant LAV-BPIFB4 protein phenocopies genetic effects, rapidly increasing CD47 expression on wild-type platelets through cytoskeleton-dependent trafficking mechanisms and conferring enhanced anti-inflammatory capacity. This might represent a translatable strategy to replicate some of the biological features associated with a longevity-associated variant beyond genetic carriers.

The nature of medical regulation makes it extremely expensive to develop a new drug, and considerably less expensive to find a new use for an existing approved drug. Thus repurposing drugs receives more attention than it perhaps should, and the typical outcome is a new marginal use rather than something impressive. This will happen for treatments for aging as well, no doubt. People will find that many existing approved drugs have some small effect on aging and life span in animal studies, and some of those will be marketed and used, and none of that will make any great difference to the world. What are the odds of discovering that an existing drug has an effect size similar to that of rapamycin? Which is to say ~20% life extension in mice and maybe a few years in humans, though that remains to be seen. That is an interesting question; it may be possible for effects on the order of a few additional years of life expectancy to hide in the existing human data because no-one looked that hard. Much more than that seems unlikely, though.

Despite the thousands of genes implicated in age-related phenotypes, effective interventions for aging remain elusive, due to the multifactorial nature of longevity and the interconnectedness of molecular components involved. Here we introduce a network medicine framework to map 2,358 longevity-associated genes onto the human interactome to identify drug-repurposing candidates capable of modulating specific hallmarks of aging. We find that genes associated with each hallmark form a connected subgraph, or hallmark module, allowing us to measure the network proximity of 6,442 compounds to each hallmark.

We then introduce a transcription-based metric, pAGE, which evaluates whether drug-induced expression shifts reinforce or counteract known age-related expression changes within each hallmark module. By integrating network proximity and pAGE, we identify drug-repurposing candidates targeting specific hallmarks and provide a falsifiable framework to leverage genomic discoveries for accelerating drug repurposing in longevity. Our findings are interpretable, revealing molecular mechanisms through which drugs modulate hallmarks.

Link: https://doi.org/10.1038/s43587-026-01161-8

Aging clocks cannot be trusted to produce useful data for any novel intervention in aging. They are produced via machine learning approaches applied to biological data from a large study population, and there is very little understanding of how underlying mechanisms of aging connect to the data used to build the clock. Thus effects on aging produced by way to change mitochondrial function or clear senescent cells may or may not be accurately reflected by any given clock - the only way to find out is to run a lengthy, expensive life span study, which defeats the point of having a quick and simple measure. The only practical way forward to make clocks more trustworthy in the near term, or at least to understand which clocks are most consistent, is to gather as much data as possible on their responses to interventions known to at least modestly impact aspects of aging, and that is exactly what is happening.

Aging-related chronic diseases are driven by multiple mechanisms, motivating efforts to develop feasible interventions that can attenuate biological aging. DNA methylation-based epigenetic clocks, particularly measures of the pace of aging such as DunedinPACE, are sensitive to relatively short-term changes in aging processes. However, evidence from randomized controlled trials remains limited. We conducted a randomized controlled trial to test a 12-week multimodal lifestyle intervention comprising exercise and dietary guidance involving daily consumption of yogurt containing Bifidobacterium longum BB536 on DNA methylation-based aging measures in overweight men aged ≥50 years.

The intervention group exhibited a significant deceleration in DunedinPACE, corresponding to an estimated 2.2% slower pace of aging, whereas no meaningful change was observed in the control group. Exploratory analyses further identified a significant reduction in DNAmCystatinC, a renal-related GrimAge surrogate marker, while no clock within the biological age remained significant after false discovery rate correction. These findings suggest that a feasible, multimodal lifestyle intervention-including exercise and dietary guidance with daily consumption of yogurt containing Bifidobacterium longum BB536-may be associated with short-term changes in selected DNA methylation-based aging measures. Larger and longer-term studies are warranted to confirm the durability and clinical relevance.

Link: https://doi.org/10.18632/aging.206386

Ethicists seem a little stuck on the idea that treatments to slow and potentially reverse aspects of aging are only available to the wealthy, or will only be available to the wealthy. Today's open access complaint about making the world a better place at least manages to also touch on what I think is the more pertinent issue, which is knowledge. One can't try interventions that seem plausibly likely to produce benefits in the matter of degenerative aging without knowing that the option is there. One can't make an assessment of the odds of benefit versus harm without knowing a fair amount about biology, mechanisms of action, and the state of the field. One can't accumulate that knowledge without understanding which of the many sources of information are lying through their teeth in order to make money. One can't substitute wealth for knowledge and pay middlemen to point in the right direction without knowing which of those middlemen are corrupt and selling a bill of goods. It's a knowledge problem all the way down.

The most plausible, well-studied initial approaches to treat aging are also readily available at generic drug prices. Rapamycin. Senolytic compounds like the dasatinib and quercetin combination. Or they are free if we're also counting exercise and calorie restriction. The next step up, exosome therapies and stem cell therapies, can be obtained for a few thousand dollars per treatment given a lot of legwork and cost comparison on the part of the patient. The futuristic approaches like partial epigenetic reprogramming? At some point there will be versions that cost little. Just wait.

I suspect that ethicists and journalists and others who like to grind axes on the activities of the wealthy are deceiving themselves. They look at a few exceptional and vocal wealthy people who are spending a great deal on personal health as a hobby and see that as broader reality, rather than a tiny minority engaged in doing unusual things with their time and funding. The reality is that most wealthy people do little that is out of the ordinary when it comes to their health, and have little to no knowledge regarding potential advances in the treatment of aging. Meanwhile, a relatively small number of interested non-wealthy people quietly put in the time to learn the bounds of the possible and undertake self-experiments by trying rapamyin or senolytics, or saving up for exosome treatments. The mainstream pays very little attention to that contingent, and perhaps justifiably so - as for the vocal wealthy self-experimenters, they are a tiny minority of the population.

Meanwhile, most people have no idea. Medicine and biology are not in their wheelhouse, why would they have any idea as to what is in process and speculative and potentially useful? The knowledge problem is the hard problem here, not the finance. Given something that may be useful, and costs little, how does one cut through the background noise of nonsense and self-interest to produce and present clinical proof and induce widespread use? It is a collective action puzzle, and our species does not have a good track record when it comes to solving those.

The Ethics of Extending Life: Longevity Medicine and Health Inequity

In one survey, nearly 80% of 1000 US respondents said they'd like to live to be 120 years old, but only if they remained mentally and physically healthy. Without that hypothetical guarantee, far fewer people wished to live such a long life. We not only want to live longer, we want to live longer and better. From stem cell therapy to biomarker tracking, from genomics to AI algorithms that support early disease detection, medicine has entered a new era in which some view aging as a condition that can be managed and mitigated, provided the right tools are used.

Due to limited accessibility and high costs, those in economically and socially privileged positions have been the first to benefit from these advancements. As life-lengthening medical interventions continue to develop, health span extension may become stratified along socioeconomic lines, concentrating its benefits among the already privileged. Without intentional policy and ethical frameworks, these innovations may deepen population health inequities.

There is another, more subtle accessibility challenge facing longevity medicine: "Even if you made every longevity medicine intervention free, you still need to interpret all that information." That requires the consumer to possess a high degree of health literacy, which is typically higher in well-educated, high-income individuals. "Wealthy patients walking into longevity clinics aren't just buying the intervention, they're buying someone to do that cognitive work and navigation for them, to be the quarterback of their health, or the CEO of their health, which is a service that's almost completely absent from primary care for most other people." Without someone to provide context and guidance, the large amount of data that longevity medicine testing reveals may simply be disregarded, or worse, widen disparities.

Longevity medicine offers fantastic potential for increasing health span - a hope that many of us dream of - but the future of longevity medicine will be defined by not just how long we can live, but by who gets the opportunity to do so.

Pulmonary fibrosis is an age-related condition. Good evidence connects it to the burden of senescent cells in the aging lung, but its causes are otherwise relatively poorly understood. Therapeutic options remain poor, and the prognosis for patients is quite ugly. Fibrosis is nanoscale scarring, an inappropriate buildup of excess extracellular matrix that is disruptive to tissue function. Researchers here explore a loss of the capacity of fibroblast cells to degrade extracellular matrix structures in aged tissue, and identify a regulatory gene that can be overexpressed to produce a greater defense against fibrosis in aged mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease whose incidence and severity increase markedly with age, indicating that aging is a primary risk factor for IPF. A study in murine models demonstrated that while bleomycin-induced pulmonary fibrosis (PF) can resolve spontaneously in young mice, this reparative capacity is significantly impaired in older animals, potentially causing persistent fibrosis.

A key mechanism underlying extracellular matrix (ECM) degradation involves the phagocytosis of collagen fibrils by fibroblasts and macrophages and their subsequent lysosomal degradation. Aging has been shown to impair the capacity of lung fibroblasts to degrade collagen independently of matrix metalloproteinase activity. Therefore, we hypothesized that an age-associated decline in collagen phagocytosis by fibroblasts is linked to lysosomal dysfunction. However, the upstream regulators governing this process remain poorly defined.

In vivo, aged mice showed impaired fibrosis resolution and reduced lung fPRDM16 levels. Fibroblasts from aged mice exhibited reduced collagen I phagocytosis, elevated lysosomal pH, and increased mitochondrial reactive oxygen species (mitoROS). Enhancing lysosomal function with rapamycin or scavenging mitoROS with mitoquinone restored phagocytosis. fPRDM16 expression was downregulated with age and upon transforming growth factor-β (TGF-β) stimulation. Its overexpression rescued phagocytic defects, improved lysosomal acidification, and reduced mitoROS, thereby disrupting a pathogenic mitochondria-lysosome feedback loop.

We conclude that fPRDM16 downregulation in aging impairs fibroblast-mediated collagen clearance via a mitochondria-lysosome dysfunction loop. Targeting fPRDM16 may represent a novel therapeutic strategy to promote fibrosis resolution.

Link: https://doi.org/10.1016/j.cmp.2026.02.002

If used sensibly, models of aging can offer some insight into the bounds of the possible with regard to which classes of biological mechanism are more or less important in determining pace of aging, onset of disease, and life span. Researchers here use a specific type of model, the saturating removal model of damage accumulation, and tinker with the parameters to see which of the processes represented by those parameters best predict the observed range of life spans across species. Perhaps the most interesting outcome is that mice and humans end up in different broad buckets in terms of categorizing how mechanisms of aging interact; this is far from the only study to suggest that this is the case.

The saturating removal (SR) model was defined and calibrated based on longitudinal damage measurements in mice (senescent cells) and Escherichia coli (membrane damage). The model is based on the simplifying hypothesis that the damage that causes aging can be summarized by a scalar x and that life cannot persist above a certain level of x. The biochemical nature of x can be different in each species. The SR model describes the dynamics of damage by a stochastic differential equation that includes production, removal, and noise. Production rises linearly with age, whereas removal saturates at high damage. Death occurs when damage exceeds a threshold. The SR model explains many quantitative patterns of aging including Gompertz and Weibull hazard curves, distributions of human frailty index, disease incidence curves, and heritability of lifespan.

Different species age in similar ways but their lifespans differ by orders of magnitude. It is not clear how these similarities and differences arise from the accumulation of damage that underlies aging. Does long lifespan arise from reduced damage production, increased removal, or enhanced robustness to damage? Here we apply the saturating removal model and fit it to survival data from well-studied species. Several parameters have near-universal values including ratios of removal rate, noise amplitude, and death threshold. The model parameter that best predicts lifespan is the damage production rate, which spans seven orders of magnitude.

We identify two distinct aging regimes: ballistic aging where damage production outpaces removal, characterizing yeast, nematodes, flies, and mice, and quasi-steady-state aging, where damage tracks a moving set point of balanced production and removal, characterizing humans, dogs, guinea pigs, and cats. These results provide a mechanistic model-based basis of comparative aging that awaits experimental validation.

Link: https://doi.org/10.1038/s43587-026-01138-7

Intermittent mild hypoxia has been shown to slow aging and improve health in animal studies, and is used in medicine in some contexts. It is a form of stress and encourages a hormetic response from cells that on balance improves health. Long term hypoxia or severe hypoxia tips over into outright harm, overwhelming any beneficial mechanisms that attempt to compensate. Human data suggests that high altitude living, at the point where mild hypoxia is induced by the lower oxygen content of the air, results in accelerated aging. For example, researchers have shown that these populations exhibit accelerated immune aging. These populations are not yet large enough or well studied enough to go much beyond this sort of investigation of a few aspects of their physiology. Epidemiology for more solid evidence of accelerated aging is lacking, for example, and much of the existing data on mortality and age-related disease could be explained by comparative poverty rather than any sort of comprehensive acceleration of aging.

Recall that epigenetic age is usually assessed from a blood sample, and the only cells in a blood sample with nuclei and nuclear DNA are immune cells. Thus epigenetic age assays are really a measure of immune aging rather than systemic aging. To the degree that those two correlate, this is fine. But they are not the same thing, and the immune system is subject to pressures and mechanisms not relevant to other cell types in other tissues. Thus epigenetic age in those other cell types and tissues is more interesting in a research context.

Today's open access paper provides more evidence for intermittent hypoxia to accelerate epigenetic age, though the question remains as to whether aging is a good description for is actually occurring inside cells, meaning a shift in nuclear DNA structure in response to low oxygen levels. In mice, the researchers looked at a few different tissues, and found that epigenetic age acceleration only occurred in old mice, and went away when hypoxia treatment was halted. The researchers also note human data from the AltitudeOmics study, which involved blood samples rather than tissue samples, and so measured immune aging rather than tissue aging.

Intermittent hypoxia induces reversible epigenetic age acceleration in old mice

Epigenetic mechanisms are considered adaptive regulators of gene expression, yet mechanisms driving aging-associated DNA methylation remain unclear. Prior work hinted that epigenetic aging might reflect a response to oxygen availability, with age-differential methylation in immune cells enriched near binding sites for hypoxia-responsive factors ARNT and REST. To test this hypothesis, we exposed adult (11 months) and old (23 months) mice to 1 month of intermittent hypoxia (IH) followed by normoxic recovery.

IH induced epigenetic age acceleration in lungs, spleen, and heart in old mice only. This acceleration reversed upon return to normoxia. Reversible shifts were enriched at bivalent domains and PRC2 targets, indicating oxygen-sensitive chromatin remodeling.

Human translational validation from the AltitudeOmics project in which 19 young adults underwent baseline testing near sea level then again after rapid ascent to 5260m confirmed rapid, conserved epigenetic aging. Our findings establish oxygen availability as a primary, conserved modulator of epigenetic aging across tissues and species, showing that oxygen fluctuations are a potent, reversible driver of epigenetic aging.

Sadly, we live in an age in which the media likes to generate conflict, and in which the role of personal responsibility in most aspects of life (and certainly in the matter of medicine) is denigrated. It is a culture that rejects risks, costs, and benefits that cannot be quantified easily, and demands a centralized, legalistic approach as to who is and is not permitted to take those risks. On the other side of the fence, those taking the risk of trying new therapies that are not fully understood are in all too many cases doing it without sufficient forethought and planning. Too many people take wishful thinking and popularist rhetoric as fact. They don't want to understand the details, and look for quick, certain answers where quick, certain answers doesn't exist. This is not a great environment in which to try to promote a responsible attitude to medical self-experimentation and risk, such that self-experimentation is encouraged as a way to make progress towards a better world in which people are healthier than would otherwise be the case. But what is the alternative? Age to death on the normal schedule and not rock the boat? Sometimes the boat needs to be rocked.

Bryan Johnson often tinkers with his daily regimen of drugs, peptides in the form of both supplements and injections and other medical interventions in pursuit of a longer life. He's part of a growing crowd of tech entrepreneurs who are seeking extra years by hacking their own bodies - and sharing their exploits widely through social media and other channels. Wealthy longevity evangelists are often seen as translators of early-stage science to the public, who turn preliminary or anecdotal findings into so-called stacks that combine supplements, other compounds, protocols and therapies, long before FDA approval.

But there is a danger to this growing phenomenon: researchers who study ageing and longevity warn that these biohacks have not been clinically tested, meaning that it's unclear whether they work or might harm people. There is no medical intervention that is proven to extend human life by targeting ageing itself, says Andrew Steele: "There probably are things on our radars that might work, but nothing has ever been tried in humans." Nir Barzilai is torn about the impacts that the biohackers have. Take Johnson's tinkering with various supplements and drugs, which is usually based on some kind of evidence: "If you're asking, 'Is he taking something that doesn't make sense?' I would say, no, these things are based on biology but not on clinical evidence."

Neither Steele nor Barzilai are cynics. Both say that some of the protocols being tested and touted by Silicon Valley elites could have a meaningful impact on lifespan and healthspan - the time during which people are not affected by chronic disease and disabilities related to ageing. But the evidence isn't there yet. Matt Kaeberlein calls it "a signal-to-noise problem". In the limited available data about these interventions, he says, "there's signal there, but there's a whole lot of noise". That makes it hard for the public to separate the two.

Link: https://www.scientificamerican.com/article/silicon-valleys-longevity-biohackers-are-engaged-in-a-dangerous-experiment/

Hematopoietic cell populations reside in the bone marrow. A tree of ever more specialized progenitor cell populations descends from the root hematopoietic stem cell population, responsible for ultimately producing red blood cells and white blood cells. Hematopoietic stem cell populations are known to become damaged and dysfunction with age, and this is one of the contributions to immune system dysfunction in later life. It also produces effects such as platelets that are more prone to causing inappropriate clotting and thrombosis. Here, researchers provide evidence to suggest that the intermediate hematopoietic progenitor cell populations are much less impacted by aging than is the case for hematopoietic stem cells, and might be buffering the loss of stem cell function to allow for maintained hematopoietic function. It is a little early to understand what this might mean for approaches to therapy, and what the implications are for the importance of hematopoietic stem cell function in aging. It is certainly interesting, however.

Aging of the hematopoietic system has profound consequences for organismal health and longevity, attributed to the well-characterized functional aging of hematopoietic stem cells (HSCs). Here, we tested whether progenitor cells may demonstrate age resistance to enable hematopoietic homeostasis throughout life despite the functional decline of upstream HSCs. Strikingly, our results revealed unwavering reconstitution capacity by young and old progenitors, demonstrating that intermediate progenitors are functionally unaffected by aging and placing Flk2+ multipotent progenitors (MPPFs) as a potential source of age resilience.

This unique finding was emphasized by unchanged transcriptomic, proliferation, and mitochondrial capacity of young and old MPPFs, revealing remarkable similarities upon aging. Considering that HSCs functionally decline with age, yet intermediate progenitors remain unperturbed and "age resilient", we posit that MPPFs may play an essential role in protecting downstream progenitors from inheriting age-related properties from HSCs. We propose three potential mechanisms for how MPPFs maintain hematopoietic integrity and homeostasis with age.

Link: https://doi.org/10.1016/j.stemcr.2026.102965

Genes produce proteins at a pace determined by epigenetic control over nuclear DNA structure. That epigenetic control changes with age for reasons that are incompletely understood. A promising possibility is that repeated activation of DNA repair processes depletes specific factors needed for maintenance of DNA structure, but that needs further confirmation. The pace of protein production changes in a characteristic way with age for countless different proteins. Of that large number, some are known to cause harm, and are associated with aspects of degenerative aging. These are potential targets for gene therapies; I listed a large number of them some years ago, and that set has only grown since then.

Gene therapy technology has existed for decades, but is not yet very broadly used. A narrow subset of such therapies are becoming increasingly used in the medical tourism industry as potential treatments for aging. Why aren't we swimming in dozens of commercially available gene therapy implementations to dial up expression of gene X or dial down expression of gene Y to improve late life health? The short answer is that gene therapy has a delivery problem. It is somewhere between very hard and impossible to deliver gene therapies safely and effectively to most tissues in the body, given the tools presently available. The therapeutic applications being explored most aggressively these days largely fall into a small set of categories, where local delivery of a relatively small amount of a well-explored gene therapy vector (such as plasmids or AAV) does the job. For example, to turn a small number of fat cells into factories to produce a beneficial signaling protein that will circulate throughout the body - such as klotho, follistatin, and so forth. Or where a delivery mode can hit desired tissues with high specificity, such as intranasal delivery of AAV to reach parts of the brain.

Gene therapies that can reliably and selectively produce expression in a small inner organ require direct injection, which developers largely reject as an option outside the context of severe disease. Intravenous injection of gene therapy vectors that produce sufficient expression in a target inner organ without overloading the liver or bearing an unacceptably high risk of an immune reaction is an unsolved problem for near all target organs. Further, systemic injection of high dose gene therapy vectors has caused deaths in recent years, and is thus not in favor for anything but the most severe disease conditions. Being able to change gene expression in cells throughout the body with a single intravenous treatment (again without overloading the liver or provoking the immune system) also remains a pipe dream; while a few programs offer hope for progress on this front, no established gene therapy vectors are capable of doing this.

Partial epigenetic reprogramming is thought to offer the potential to bypass targeting of individual genes by rejuvenating the control over DNA structure and gene expression. But this approach still suffers from all of the delivery issues of gene therapy, alongside the likely need for different dosage and duration in different tissues. At the end of the day, yes, the technological capability exists to change the behavior of aging cells for the better. It is trivial to do so in a cell in a dish. The delivery challenges are what prevents the research and development communities from bringing this capability into patients in the near term. For now the field is focused on only a few genes, approaches, and tissues that are a good fit for the limited delivery capabilities that exist.

Gene therapy for aging and longevity

Over 2000 genes have been linked to increased longevity in a variety of models, but the translation of these findings into clinical applications remains challenging. Gene therapy is a potential strategy for extending healthspan by targeting genes associated with longevity or age-related diseases. This approach involves transferring genetic material directly into target tissue using viral or nonviral vectors, thereby enabling the augmentation, suppression, or precise editing of genes. This review examines multiple gene therapy strategies and their respective technical challenges, with a particular focus on identifying the most promising genetic targets for future interventions.

Many different gene delivery vectors have been engineered in recent decades. They can broadly be divided into physical, chemical, and virus-based methods. All gene delivery vehicles must overcome the same set of issues: efficient delivery to target locations, evasion of host immune responses, sufficient packaging size, controlled expression levels, reversibility and stability, redosability, and cost-effectiveness. In other words, each vector represents a multidimensional optimization problem in which certain existing properties determine whether a vector is more suitable for some applications over others. In the context of longevity therapies, additional requirements include a broad distribution profile, very-long-acting and stable expression, and high safety standards, as such interventions must remain effective over extended periods and are also intended for use in individuals without overt disease.

The main obstacle longevity gene therapies need to overcome is the ability to deliver the genes of interest to many or all tissues in the body. Most of the genes known to extend longevity are expressed intracellularly and across numerous tissues in the body. In this review, we identified multiple gene candidates from animal and human studies as potential targets for longevity gene therapies. Based on its advantages in gene delivery, AAV-mediated gene therapy is currently the most suitable platform for longevity gene therapy, but technical challenges remain, such as whole-body delivery and biomechanical limitations.

To accelerate the longevity gene therapy field, several key technical advancements are desirable. These include new AAV serotypes or vehicles for broader delivery across the body; better systems for controlled expression in individual organs, compact, reversible, or controllable expression systems; improved immunosuppressors to prevent anti-vector or anti-transgene immunity; compact molecular tools for safe and controlled integration; and new (possibly automated) production and quality control pipelines to reduce manufacturing costs.

In mammals the male reproductive system outlasts the female reproductive system over the course of aging, but mechanisms of damage and dysfunction still eventually lead to a loss of fertility. The epididymis, where sperm cells mature, is a critical portion of the testes. As researchers here note, while observations of degeneration are readily available, there is relatively little understanding of the aging of the epididymis at the detailed level of cellular biochemistry. After better characterizing epididymal cells in young and aged non-human primates, the researchers found a proximate cause of problems: loss of FOXO1 expression drives cellular senescence, and senescent cells then disrupt structure and function in the surrounding tissue via their inflammatory secretions.

Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcriptionally perturbed epithelial cell type. Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age.

Functional studies in human epididymal epithelial cells demonstrated that FOXO1 deficiency drives cellular senescence. Mechanistically, FOXO1 transcriptionally activates LHX1, and this axis is essential for counteracting senescence. Furthermore, intervention with senescence-resistant mesenchymal progenitor cells or their exosomes mitigated epididymal aging phenotypes and restored FOXO1 expression in vivo and in vitro. Our study establishes the FOXO1-LHX1 axis as a key protective pathway against primate epididymal aging, providing mechanistic insights and potential therapeutic targets for preserving male reproductive health.

Link: https://doi.org/10.1093/procel/pwag020

Senile lentigo, an age spot, is a form of photoaging in response to UV exposure featuring a darkening of the skin. An increased burden of cellular senescence is thought to play an important role in photoaging more generally, and here researchers show that age spots contain an increased number of senescent cells. It is likely that these senescent cells are an important driver of the altered structure of skin and altered behavior of skin cells in an age spot. It is also likely that intermittent use of senolytic drugs will slow skin aging and even improve function in already aged skin, based on research conducted to date, but there is surprisingly little published human data on this front despite a number of companies offering plausibly senolytic skin products, and the growing off-label use of senolytic drugs such as dasatinib and quercetin.

In the dermal and epidermal layers of the skin, various manifestations of aging have been associated with an accumulation of senescent cells, namely fibroblasts, keratinocytes, and melanocytes. We and others have previously reported an accumulation of senescent cells in chronologically aged epidermis upon exposure to chronic low-dose UV radiation and in the epidermis of precancerous actinic keratosis, age-associated lesions that frequently occur in sun-damaged skin. Since the prevalence of photoaging in Asian populations commonly results in skin hyperpigmentation, we here extended our investigation to senile lentigo (SL), a common age-associated hyperpigmentation disorder caused by chronic UV exposure.

Facial skin biopsy samples from 9 donors of Korean ethnicity, classified under type III or IV on the Fitzpatrick scale, were collected from both perilesional and lesional sites. Expectedly, we observed a higher degree of pigmentation and more melanocytes. To determine whether SL lesions are associated with an accumulation of senescent cells, we stained sections for well-characterized hallmarks of senescence: p16INK4A, lamin B1, and increased nuclear size.

Using these markers we found an accumulation of senescent cells in SL epidermis. This is of particular interest because we and others have previously observed an accumulation of senescent keratinocytes in actinic keratosis lesions and in chronically UV-exposed skin. Moreover, it is noteworthy that patients with Hutchinson-Gilford progeria, a premature aging syndrome caused by an altered form of lamin A that triggers cellular senescence, exhibit widespread hyper- as well as hypopigmentation. However, the extent to which different cell types within the skin contribute to this phenotype remains unclear. Importantly, while the senescence-associated secretory phenotype in senescent human fibroblasts is well characterized, very little is known about the senescence-associated secretory phenotype in keratinocytes.

Link: https://doi.org/10.1016/j.jid.2026.04.024