Fight Aging!

As for all tissues, bone derives its structural properties from the composition and structure of its extracellular matrix. This matrix constantly undergoes dynamic modification: osteoclast cells break down the matrix, while osteoblast cells build it up. Throughout much of adult life, a sufficient balance exists between these processes of creation and destruction to ensure that bones remain structurally sound. With old age, however, the balance shifts slowly to favor osteoclasts. The result is a loss of bone mineral density over time, leading eventually to osteoporosis, brittle bones, and fracture or breakage in an already frail elderly individual.

The aging of the immune system is one of the contributing factors to this erosion of bone tissue maintenance. Chronic inflammation on the part of the immune system is a feature of aging, driven by maladaptive reactions to damage and dysfunction, and this is disruptive to the balance between osteoblasts and osteoclasts. There are other issues besides this. For example, innate immune cells are deeply involved in tissue maintenance, but too many of these cells relinquish these necessary tasks to adopt other, less helpful behaviors in aged tissues. Today's open access paper reviews the aging of the immune system through the lens of bone tissue, the links between what is known of immune aging and what is known of the declining maintenance of bones.

Immune cell senescence and chronic bone diseases: osteoimmune mechanisms and therapeutic perspectives

Immune cell senescence is an important intermediary linking organismal ageing, chronic low-grade inflammation, and disordered bone metabolism. With advancing age, immune cells undergo systemic functional remodeling and exhibit a series of characteristic alterations, including reduced proliferative capacity, skewed differentiation, abnormal migration and homing, impaired phagocytic and clearance functions, and changes in their secretory profile. These changes persistently disrupt the osteoimmune microenvironment and ultimately promote enhanced bone resorption, suppressed bone formation, and deterioration of bone quality.

This review centers on the immunological basis of bone homeostasis and systematically summarizes the major biological features of immune cell senescence, with a particular focus on the key cellular mechanisms through which it drives chronic bone disease. It further analyses its pathological manifestations and disease-specific differences in osteoporosis, osteoarthritis, rheumatoid arthritis, and diabetes-related bone disease. Current evidence indicates that the contribution of immune cell senescence varies across different diseases: its pathogenic association appears to be relatively more direct in osteoporosis and rheumatoid arthritis, whereas in osteoarthritis and diabetes-related bone disease it more often acts as a contributor to inflammatory amplification and microenvironmental deterioration.

At present, intervention strategies targeting immune cell senescence mainly focus on modulation of macrophage polarization, immune-mediated clearance of senescent cells, restoration of adaptive immune homeostasis, and mesenchymal stem cell (MSC)-related improvement of the local microenvironment, but overall these approaches remain at the preclinical or early translational stage. Future studies should integrate single-cell sequencing, spatial transcriptomics, and multi-omics approaches to define local immune cell senescence landscapes and establish robust biomarker systems, thereby promoting the transition from mechanistic research to precision intervention in chronic bone diseases.

Twenty years ago or so, researchers were investigating the possibility of building therapies based on upregulation of TFAM expression to improve mitochondrial function in aged tissues. While some initial results were promising, as it turned out the mitochondrial biochemistry of TFAM is complicated and too much is as bad as too little. This makes it a poor target for gene therapy, and a challenging target for small molecules. The field moved on to easier possibilities, as often happens. Still, nothing ever really stops entirely in the life sciences. Here find a review of the present state of knowledge regarding TFAM, and some speculation as to what future therapies might look like.

Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology.

However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts.

In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.

Link: https://doi.org/10.3389/fragi.2026.1830839

Like many age-related conditions, Parkinson's disease is associated with uncommon mutations and genetic variants that increase its likelihood, severity, and pace of progression. PINK1 is a protein involved in identifying damaged mitochondria to be broken down by the quality control mechanisms of autophagy. Loss of effective PINK1 function clearly accelerates mitochondrial dysfunction and increases cell death in neurons placed under the stress induced by the aggregation of misfolded α-synuclein that is characteristic of Parkinson's disease. PINK1 in Parkinson's disease is also an example of the way in which identifying genetic contributions to an age-related condition may not actually help all that much. The interactions between disease mechanisms and mitophagy are sufficiently complex for knowledge of the role of PINK1 mutations to illuminate relatively little about the rest of the problem, and for interventions targeting PINK1 to fail.

Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited.

Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network.

This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.

Link: https://doi.org/10.3389/fnagi.2026.1865383

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