Fight Aging!

Circulating oxytocin levels are known to decline with age, and a number of research groups have focused on upregulation of oxytocin as an approach to treating aging. A couple of papers published a few months ago are indicative of the animal studies presently taking place, the first focused on increased longevity in mice achieved via the combined reduction of TGF-β and increase in oxytocin, and the second evaluating intranasal delivery of oxytoxin as a route to improve function in the aging brain.

Today's paper reports on another example of oxytocin delivery in aged mice. These researchers are also focused on the brain, but in this case the oxytocin is delivered via intraperitoneal injection. As with most peptide or protein therapies, the effects are limited in scope as the delivered molecules have a short half-life. Repeated treatments are required, often daily, as is the case here. Given further progress towards the clinic, however, we might expect that the community of developers presently assessing gene therapies to safely transform a small number of cells into long-lasting factories that produce a desired circulating molecule (such as klotho or follistatin) will add oxytocin to their list.

Oxytocin enhances neurogenesis and synaptic plasticity to attenuate age-related cognitive decline in aged mice

Brain aging is characterized by progressive structural and functional deterioration, leading to cognitive decline and impaired social functioning. A key factor in this process is the age-related decline in adult neurogenesis, particularly in the hippocampal dentate gyrus, which is linked to deficits in learning, memory, and increased social anxiety. Oxytocin, a neuropeptide synthesized in the hypothalamus, regulates social behavior, cognition, and emotion by acting on brain regions including the hippocampus. Importantly, oxytocin levels decrease with age, potentially contributing to cognitive impairment.

Here, we examined whether chronic intraperitoneal oxytocin administration could attenuate cognitive decline in aged mice. Twelve-month-old mice received oxytocin injections (0.5 mg/kg) five times weekly for 13 weeks. Behavioral testing at 12 weeks of treatment using the object-place recognition task showed enhanced spatial learning and recognition memory in oxytocin-treated mice compared with saline controls. Immunohistochemistry revealed significantly increased doublecortin (DCX)-positive cells in the hippocampus, indicating enhanced neurogenesis. Furthermore, oxytocin treatment upregulated the expression of glutamate receptor 1 (GluR1) and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B), which are markers of synaptic plasticity.

These findings suggest that chronic oxytocin treatment is associated with enhanced neurogenesis and synaptic plasticity, which may contribute to improved cognition in aged mice. Our results support oxytocin as a potential therapeutic agent for age-related cognitive decline.

Epigenetic clocks have existed for long enough for numerous large study databases to include data on their use. Thus meta-analysis papers are emerging to assess this body of data as a whole. This is a necessary part of the process of gaining confidence in the ability of epigenetic clocks, and indeed aging clocks in general, to rapidly assess the potential of any novel form of intervention intended to slow or reverse aspects of aging. This is a much needed capability. In many ways, efforts to treat aging as a medical condition proceed blindly, given just how much time and funding is required in order to understand whether one approach is better or worse than another. If there was a way to quickly assess the quality of an anti-aging therapy immediately after its application, then the field could adjust quickly to pursue the best paths forward. The hope is that aging clocks can be that tool - but we are clearly not there yet.

Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.

24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28,325 participants (14,757 female; median of mean age 65.2 years). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11,162; standardised β coefficient 0.06), PhenoAge EAA (eight studies; n=10,371; standardised β coefficient 0.07), GrimAge EAA (eight studies; n=10,371; standardised β coefficient 0.11), and pace of ageing (five studies; n=7,895; standardised β coefficient 0.10) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6,143; standardised β coefficient 0.02) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.

In conclusion, higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.

Link: https://doi.org/10.1016/j.lanhl.2025.100773

TDP-43 is one of a small number of proteins in the brain that can misfold or otherwise become altered in ways that allow toxic aggregates to form, or even encourage other molecules of the same protein to become dysfunctional in the same way. TDP-43 aggregation in later life is a relatively recent discovery, and has a neurodegenerative condition newly named for it, limbic-predominant age-related TDP-43 encephalopathy (LATE). It has also been found that TDP-43 is likely important in amyotrophic lateral sclerosis (ALS), and thus progress on that front seems likely to help with other forms of TDP-43 pathology. Here, researchers report a promising discovery in the biochemistry of TDP-43 aggregation in the context of ALS.

Amyotrophic lateral sclerosis (ALS) is a lethal adult-onset motor neuron disease, characterized by disruption of neuromuscular junctions (NMJs), axonal degeneration and neuronal death. Most ALS cases are linked to TDP-43 pathology, characterized by its mislocalization from the nucleus to the cytoplasm and the formation of phosphorylated aggregates. TDP-43 is a multifunctional DNA-binding/RNA-binding protein with roles in transcriptional and splicing regulation, RNA processing and RNA transport/subcellular localization.

Recently, we showed that TDP-43 co-localizes with the core stress granule component G3BP1 in axonal condensates of patients with ALS and mice. These TDP-43-G3BP1 condensates sequester RNA and inhibit local protein synthesis, resulting in mitochondrial malfunction and NMJ disruption with subsequent axonal degeneration. Furthermore, recent studies revealed aggregation of TDP-43 in peripheral motor axons of patients with ALS during initial diagnosis. Thus, axonal TDP-43 condensates exert pathological regulation over essential local synthesis events.

Here, we studied the localized accumulation of TDP-43 in axons and NMJs. Our findings highlight the presence of distal TDP-43 pathology in patients with SOD1 ALS and mouse models. We found that TDP-43 accumulates at NMJs due to aberrant local synthesis triggered by a reduction in miR-126a-5p within muscle extracellular vesicles. This chain of events ultimately initiates neurodegeneration. Notably, delivery of miR-126 is neuroprotective in neuromuscular co-cultures, delays TDP-43 accumulation at NMJs, and postpones the onset of motor symptoms in the SOD1G93A mouse model of ALS.

Link: https://doi.org/10.1038/s41593-025-02062-6

The human gut microbiome is made up of a few thousand distinct microbial species. The relative sizes of these populations shift in response to day to day circumstances, such as variations in diet, but one would expect consistency from one year to the next. Over longer spans of time, the gut microbiome ages. Populations producing beneficial metabolites are reduced in number, while populations that provoke the immune system into chronic inflammatory behavior grow in number. This data is derived from both animal and human studies. One can control what happens to a mouse over the course of its life, but for human data the detailed history of any particular individual is largely a mystery.

Antibiotics and a range of other pharmaceuticals produce dramatic short-term effects on the composition of the gut microbiome. To a large degree, the gut microbiome restores itself once the pharmaceutical is no longer present. That said, we might well ask how much of the observed human data on gut microbiome aging is produced by, say, antibiotic use. Researchers have observed gut microbiome changes in population studies taking place as early as the mid-30s, and it is hard to envisage any form of meaningful degeneration taking place at that age. But exposure to antibiotics and other pharmaceuticals? That is very prevalent. In later life, given the presence of chronic diseases of aging, there is a great deal more chronic pharmaceutical use, as well as the employment of pharmaceuticals with meaningful side effects. We might again ask how much of the observed aging of the human gut microbiome at the population level results from the use of these treatments versus mechanisms of aging.

Drug-mediated disruption of the aging gut microbiota and mucosal immune system

The dynamic relationship of gut microbiota, mucosal immunity, aging, and pharmaceutics interventions has a significant impact on overall physiological functions and disease susceptibility. Aging is associated with changes in the gut microbiome including decreased microbial diversity, reduced short-chain fatty acid (SCFA) production, and elevated pathobiont proportions. These changes are associated with impaired mucosal immunity, increased intestinal permeability, and heightened systemic inflammation in the host, which can exacerbate age-related disorders.

Medications such as proton pump inhibitors (PPIs), metformin, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antibacterials also influence gut microbiota function. PPIs may alter microbial colonies and induce overgrowth of pathogenic bacteria, which compromises the mucosal defenses and in severe cases, the resulting infections may cause ulcers. Metformin, through its metabolic benefits, causes Akkermansia muciniphila to increase in relative abundance, which is associated with improved gut barrier composition. NSAIDs, because of their strong anti-inflammatory properties, disturb gut homeostasis by increasing intestinal permeability, reducing prostaglandin synthesis, and inducing dysbiosis in the host. Corticosteroids, through their immunosuppressive mechanisms, reduce microbial diversity and secretory immunoglobulin A levels, impairing mucosal immunity and enhancing the host's susceptibility to infections. Antibacterials are a major disruptor of the gut microbiota, causing a decline in beneficial bacteria and an increased risk for opportunistic infections such as Clostridium difficile.

To address drug-induced dysbiosis, probiotics and prebiotics products may be helpful to restore microbial balance, enhance SCFA production, and reinforce mucosal defenses. Individualized gut microbiota profiling may enable safer medication usage by identifying patients that are at an increased risk for dysbiosis-related complications. Additionally, development of microbiota-sparing medications and targeted therapies may help to enhance gut health outcomes in aging populations. Future research should address the long-term effects of pharmacological agents on gut microbiota and mucosal immunity in aging populations, as well as identification of connections between microbiota, immune function, and the effects of medications. Integrating microbiome-conscious approaches into clinical practice could allow healthcare providers to optimize patient care

Muscle mass and strength decline with age, a long-term consequence of accumulating molecular damage and its effects on muscle stem cell populations and neuromuscular junctions, among other mechanisms. Once past an arbitrary line in the sand, this loss is defined as an age-related disease and called sarcopenia, a part of age-related frailty. Here, researchers show that the state of sarcopenia correlates with the presence of age-related cardiovascular and respiratory conditions. This is not surprising: all of these conditions arise from the same underlying forms of damage to cells and tissues that accumulate with age.

Sarcopenia, the progressive loss of muscle mass and function, is a common condition in older adults and has been linked to both cardiovascular disease (CVD) and chronic respiratory diseases (CRD). However, the association between long-term changes of sarcopenia and cardiorespiratory multimorbidity remains underexplored. This study aims to investigate how changes in sarcopenia burden over time relate to cardiorespiratory multimorbidity. Data from the China Health and Retirement Longitudinal Study (CHARLS) were used, including 5,186 participants with mean age of 58.2 ± 8.4 years. Sarcopenia was assessed using criteria for muscle mass, strength, and physical performance.

A total of 301 (5.8%) participants experienced cardiorespiratory multimorbidity. Four distinct sarcopenia trajectory groups were identified: persistently low, moderate-to-low, low-to-high, and persistently high burden. Compared to the reference (persistently low group), the low-to-high trajectory of sarcopenia burden had the strongest association with cardiorespiratory multimorbidity (odds ratio, OR: 2.64), followed by the persistently high group (OR: 2.05) and moderate-to-low group (OR: 1.90). Thus Changes in sarcopenia burden are significantly associated with cardiorespiratory multimorbidity, with a rapid increase in sarcopenia burden (low-to-high trajectory) being particularly detrimental.

Link: https://doi.org/10.1016/j.jnha.2025.100670

The composition of the gut microbiome changes with age. Microbial populations that produce beneficial metabolites needed for optimal tissue function decline in number, while microbial populations that provoke the immune system into chronic inflammatory signaling increase in number. In recent years, researchers have demonstrated a range of specific consequences of gut microbiome aging, relationships with age-related loss of function and disease. This body of literature adds weight to the development of more precise means to produce lasting rejuvenation of the composition of the gut microbiome, an outcome that can be achieved via fecal microbiota transplantation or flagellin immunization, but with relatively little control over the exact outcome.

The gut microbiota is essential for immune function, nutrient absorption, digestion, and pathophysiological processes. However, aging influences alterations in the composition and diversity of gut microbiota. This age-related imbalance in the gut microbial community, characterized by reduced microbial diversity, loss of beneficial bacteria such as butyrate producers, and an increase in pathogenic species, results in gut dysbiosis. Dysbiosis is associated with impaired intestinal barrier integrity, weakened immune function, and elevated systemic inflammation, creating a vicious cycle that accelerates cellular senescence, tissue aging, and age-related kidney diseases.

Renal dysfunction further exacerbates this process by reducing toxin clearance and promoting the accumulation of uremic metabolites, which disrupt gut microbial balance. In turn, gut dysbiosis impairs kidney function, creating a self-perpetuating cycle of microbial imbalance and renal damage. Hence, breaking this vicious cycle of dysbiosis and kidney damage is important. This review sheds light on the bidirectional relationship between gut microbiota and kidney aging. It also highlights the potential of microbiota-targeted interventions to restore microbial balance and delay the onset of age-related issues.

Link: https://doi.org/10.1186/s12986-025-01032-w

The distinctive biochemistry of senescent cells has enabled researchers to produce proof of concept demonstrations for a range of ways to destroy senescent cells while having relatively little effect on non-senescent cells. The most established approach to date is to target well explored mechanisms that function to hold back senescent cells from programmed cell death. Senescent cells are primed to undertake programmed cell death, unlike normal cells. Thus sabotaging those mechanisms in normal cells has little effect, and delivering a sabotaging small molecule to a mix of normal and senescent cells will only kill large numbers of the senescent cells.

A more recent approach that is now progressing towards the clinic involves the use of prodrugs. A cytotoxic molecule, such as a chemotherapeutic drug, is modified to become a prodrug molecule with some added structure that interferes in its normal cell-killing function, making it safe. The trick lies in ensuring that this modification can be reversed only in the target cells that the prodrug is intended to affect. For example, senescent cells express high levels of β-galactosidase, which removes galactose where that decoration is added to another molecule. When the β-galactosidase inside a senescent cells interacts with a prodrug created by conjugating a chemotherapeutic with galactose, the toxic chemotherapeutic is unmasked. In normal cells, the prodrug remains intact and produces no harm.

Selective clearance of senescent cells has shown promise for the treatment of the degenerative joint disease of osteoarthritis, in which inflammation drives loss of cartilage and joint dysfunction. Senescent cells are responsible for generating much of that inflammation, in addition to disrupting tissue structure and maintenance in other ways. Unfortunately, early trials by UNITY Biotechnologies employed a local administration strategy and class of senolytic drug that were likely suboptimal. The results in human patients were poor in comparison to the results in animal models, and will probably discourage further clinical work on osteoarthritis until such time as senolytic drugs are approved by regulators for other uses.

β-galactosidase-targeted senolytic prodrug ameliorates preclinical models of post-traumatic osteoarthritis

Cellular senescence plays an important role in the pathogenesis of osteoarthritis (OA). Elimination of senescent chondrocytes by senolytic small molecule compounds show therapeutic effects in OA mice. However, results from a recent phase II clinical trial in the treatment of patients with painful knee OA were not optimistic. Hence, the development of new senolytics with different mechanisms for OA anti-ageing therapy is appealing. SSK1, a prodrug that consists of gemcitabine modified with an acetyl galactose moiety, could target senescence-associated β-galactosidase and eliminate senescent fibroblasts. SSK1 improves physical function and lifespan in aged mice and demonstrates good anti-inflammatory effect in non-human primates. The therapeutic action of SSK1 in OA disease deserves comprehensive investigation.

An oxidative stress-induced cellular senescence model was established to evaluate cell viability, replication, and genotoxicity after SSK1 treatment. Human OA chondrocytes and explants were collected to evaluate the therapeutic effect of prodrug SSK1 in vitro. In vivo evaluation was performed in young and aged male murine models. SSK1 (intra-articular injection every 3 days) was administrated 2 weeks after anterior cruciate ligament transection (ACLT) surgery. Animals were sacrificed 8 weeks after surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology, and pain-related behaviour tests.

SSK1 showed precise, efficient, and broad-spectrum elimination of senescent chondrocytes. When co-cultured with human osteoarthritic chondrocytes and cartilage explants, the senolytic SSK1 prevented the generation of senescence-associated secretory phenotype factors, enhanced production of extracellular matrix (ECM) molecules, and promoted a regenerative chondral environment. Intra-articular administration of SSK1 showed improved pain response, enhanced retention of ECM, and remodelled subchondral bone homeostasis in both young and aged ACLT-induced OA murine model. Thus SSK1 is an effective candidate for senolytics in alleviating OA. The anti-ageing therapeutic effect of SSK1 lies in restoring a regenerative phenotype by improving the proliferation microenvironment, and reducing the accumulation of apoptotic signals in the joint microenvironment.

Researchers here assess the effects of supplementation with the L-BAIBA metabolite combined with exercise in older mice. It modestly improves both muscle and bone, adding it to the long list of approaches that can help in some small way to resist the age-related declines in muscle mass, muscle strength, and bone mineral density. As often noted here, something better than this is required if we want to control aging rather than merely gently slow it down. Tinkering with metabolism can and does have small positive effects, which unfortunately combine in unpredictable ways, but if we want bigger and better outcomes, then we have to focus instead on repair of the cell and tissue damage that causes aging. You can't fix a malfunctioning engine by changing the oil mix, and you can't meaningfully rejuvenate a human (or a mouse) by altering metabolite intake.

Contracting skeletal muscles secrete the metabolite L-β-aminoisobutyric acid (L-BAIBA), which when supplemented in the diet can mitigate disuse-induced musculoskeletal dysfunction. However, the effects of L-BAIBA supplementation alone and combined with exercise on cardiac and musculoskeletal properties are currently unknown. We hypothesized that exercise with L-BAIBA supplementation would promote greater cardiac and musculoskeletal benefits than exercise alone. To investigate this hypothesis, we subjected 12-month-old (as a model of middle-age) male C57BL6 mice to voluntary wheel running (VWR) with L-BAIBA (100mg/kg/day) (VWR+L-BAIBA), VWR alone, L-BAIBA alone, or none (CTRL) for three months.

Soleus muscles from VWR+L-BAIBA, but not VWR, were larger, contracted more forcefully, and contained more slow-oxidative type I myofibers compared to CTRL. In extensor digitorum longus (EDL) muscle, VWR but not VWR+L-BAIBA improved fatigue resistance and caffeine-induced recovery. In bone, VWR+L-BAIBA but not VWR showed lower bone marrow adiposity, higher trabecular thickness, and connectivity, smaller bone diameter and Moment of Inertia, but higher Modulus of Elasticity than CTRL, suggesting L-BAIBA delays aging-induced periosteal expansion due to better bone material qualities.

These findings suggest a physiological interaction between exercise and L-BAIBA supplementation to improve soleus muscle and bone properties and reduce bone marrow adiposity.

Link: https://doi.org/10.18632/aging.206325

The well understood pathways by which cerebrospinal fluid drains from the brain are the glymphatic system and cribriform plate. These paths become less functional with age, for different reasons, and the consequently reduced drainage of cerebrospinal fluid allows metabolic waste to build up in the brain. This includes the misfolded and normally folded but excess amyloid-β that is associated with the development of Alzheimer's disease. Researchers here show that clearing amyloid-β from the brain via immunotherapy does not improve glymphatic fluid flow over the course of the first few months following treatment, reinforcing a view of Alzheimer's and other neurodegenerative conditions in which glymphatic dysfunction is a contributing factor to the development of the disease rather than a consequence of the disease.

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β peptides in the brain parenchyma, and impairment of interstitial waste clearance via the glymphatic system is suggested as one contributing factor. Recently approved disease-modifying monoclonal antibodies, such as lecanemab, are expected to slow cognitive decline by improving amyloid-β clearance. Diffusion tensor imaging along the perivascular space (DTIALPS) index has emerged as a noninvasive surrogate marker suggested to be associated with glymphatic activity. This index declines with normal aging and is significantly lower in patients with AD than in cognitively normal individuals.

The 13 participants included in this study were: (i) diagnosed with AD by neurologists; (ii) underwent brain magnetic resonance imaging (MRI) and subsequently initiated lecanemab therapy. Only participants who provided written informed consent were included. Mean DTI-ALPS index was 1.515 ± 0.152 at baseline and 1.513 ± 0.161 at 3 months, no significant difference.

The absence of early DTI-ALPS index improvement suggests that even though lecanemab treatment reduces plaque burden, the diffusion properties of perivascular spaces measured by DTI-ALPS do not change in the short term. DMT can reduce plaque burden and slow further cognitive worsening but does not restore lost function, likely reflecting the fact that neuronal damage and clearance system deficits have already been well established. Such observations, therefore, may reflect a multifactorial disease process that is not rapidly reversible during symptomatic stages, resulting in an unchanged early DTI-ALPS index.

Link: https://doi.org/10.1002/jmri.70118

Gene expression is the complex process of producing proteins from a specific gene sequence encoded in DNA. The DNA in the nucleus of a cell is constantly surrounded by the machinery of gene expression. That machinery will attempt to start the process of transcription, the first step of gene expression, for any sequence it bumps into. Recall that every part of a cell is a chemical soup of molecules moving at incredible speeds, interacting with everything that they can possibly interact with, as fast as possible, countless times every second. Control over which genes are expressed at any given time is a matter of the structure of DNA, which sequences are exposed and which are spooled around histone molecules so that they are hidden from transcriptional machinery. DNA structure is shaped by epigenetic processes, which include the addition and removal of decorations such as methyl groups to specific locations on DNA that alter its shape, modifications to the histone molecules that DNA wraps itself around, and so forth.

DNA becomes damaged constantly - again, the cell nucleus is a soup of fast-moving molecules with countless collisions and reactions taking place in every moment. DNA is protected by highly efficient repair machinery, and near every incident is fixed, even dramatic damage such as complete breakage of both strands of the double helix of DNA. A new and potentially important area of research is focused on the potential for DNA double strand break repair to produce lasting changes to DNA structure and epigenetic regulation of gene expression. This may allow researchers to explain why similar detrimental epigenetic changes occur across all cells with advancing age, driven by stochastic DNA damage that is different in every cell and largely fails to harm any sequence that is actually used by a damaged cell. Importantly, given a sufficient understanding of exactly why long-term effects result from DNA double strand break repair, researchers can focus on developing therapies to prevent this outcome.

One obvious form of therapy already known to fix these issues is partial reprogramming, exposing cells to Yamanaka factors for a period of time. But perhaps there are other approaches that do not present the same challenges that partial reprogramming presents when it comes to fixing an entire body's worth of cells. Delivery is hard, and different cell types need different degrees of Yamanaka factor exposure. If it turns out that depletion of just a few factors involved in DNA repair is the cause of epigenetic change resulting from DNA double strand break repair, perhaps restoring those targets to youthful levels will be an easier goal to achieve. But these are early days yet, and a great deal more time and funding is needed for a deeper investigation of DNA double strand breaks and their potential contribution to degenerative aging.

Repair of DNA double-strand breaks leaves heritable impairment to genome function

Eukaryotic genomes are subjected to hierarchical folding that is required to accommodate DNA wrapped around the histone scaffold (collectively called chromatin) within the three-dimensional (3D) nuclear space. Evolution harnessed the 3D arrangement of nuclear chromatin to facilitate interactions among genomic segments such as promoters and enhancers, whose proximity influences gene expression and who thus have an important role in cell fate decisions such as orderly execution of developmental programs, adaptation to a new environment, or transmission of cell identity across successive generations of dividing cells. Although beneficial in these and other physiological contexts, the 3D arrangement of the nuclear genome also enables a distinct vulnerability to environmental or metabolic assaults that can modify chromatin folding and thus derail cellular functions.

A prominent example of such stress assaults is the DNA double-strand break (DSB). Besides disrupting DNA integrity, DSBs are intrinsically coupled to massive chromatin alterations that include changes in 3D arrangement and gene silencing across megabase distances from the primary DNA lesions. Although the DSB-induced chromatin response is initially beneficial to attract genome caretakers and generate structural scaffolds for timely and efficient DNA repair, its fate after restoring the integrity of DNA sequence is unknown. This seems to be a formidable gap in understanding genome maintenance that poses important questions: Do cells restore DSB-induced chromatin folding and the associated gene expression after completion of DNA repair? If yes, is the restoration of postrepair chromatin complete and back to the predamage level? If not, do the lingering chromatin alterations cause physiological impairments that can be inherited by successive cell generations?

To answer these questions, we directed Cas9-induced DSBs to genomic loci harboring topologically sensitive protein-coding genes, as well as regulatory RNA species, to interrogate long-term consequences of DNA breakage on chromatin topology and gene activity. By combining quantitative imaging of large cell populations, DNA and RNA fluorescence in situ hybridization (FISH), and Region Capture Micro-C as readouts, we found that DSB-induced chromatin alterations do not recover to predamage level but persist as lasting changes in 3D arrangement and impaired gene expression throughout large chromatin neighborhoods that encounter, and subsequently repair, a single DSB. We show that such impairments persist through several rounds of successive cell divisions and can trigger concrete pathophysiological consequences. We term this phenomenon as chromatin fatigue and propose that it represents a hitherto unknown dimension of heritable responses to DNA breakage, with a potential to permanently alter physiology of cells that encounter DSBs through environmental or metabolic stress - but also lineages engineered for various experimental or therapeutic purposes by nuclease-based genome editing.

Finding molecules or nanoparticles that selectively target mitochondria and induce improved function is the most developed of the various strategies that might be employed to at least partially reverse the age-related loss of mitochondrial capacity thought to be important in age-related disease and dysfunction. Most of the small molecules developed to date appear to work by improving mitophagy, the processes of quality control that recycle worn and dysfunctional mitochondria, but the precise details of the mechanisms involved are incompletely understood. Mitophagy itself is incompletely understood. Continuing this trend, researchers here present a nanoparticle that is observed to improve mitochondrial function and thus cell function via improved mitophagy.

Mitophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain both mitochondrial and cellular homeostasis. Here, we report a fluoroalkylated polypyridinium that specifically targets mitochondria and exhibits high activity in mitophagy induction. The polymer effectively restores mitochondrial function and alleviates the inflammatory response in foam cells by activating mitophagy, and displays inherent red fluorescence under physiological conditions, allowing for direct tracing of its biodistribution in cells and in vivo.

Besides, the polymer nanoparticle shows high serum stability due to the antifouling properties of fluoroalkyl tags. After intravenous administration, the nanoparticle reduces oxidative stress, promotes mitophagy, and decreases cellular senescence in atherosclerotic plaques, contributing to high therapeutic efficacy. This study presents an innovative and effective strategy for the treatment of atherosclerosis and other mitochondrial dysfunction-related inflammatory conditions.

Link: https://doi.org/10.1038/s41467-025-64813-0

Researchers here present a list of open problems in aging research, mined from the literature and outreach to the scientific community. This is certainly a topic on which opinions differ as to which of these areas of research are more or less important than others. An assessment of literature and community will tend to capture these differences of opinion, and ongoing debates over the best course ahead. In large part the diversity of opinions reflects the lack of a consensus measure of aging that can accurately assess the outcome of a potentially age-slowing or rejuvenating intervention. If such a measure existed, there will likely be little debate over the best path forward.

Despite advancements, the field of longevity science is at a crucial point as it continues to face numerous open problems that hinder further progress. Recent works have highlighted fundamental knowledge gaps and strong disagreements amongst scientist studying ageing. Addressing these challenges is critical for unlocking new insights and developing effective interventions to extend both lifespan and healthspan.

We now present a new list of 100 open problems in ageing science, identified and curated through a combination of community engagement and text-mining approaches. These problems span a wide range of topics, from molecular biology and comparative approaches to translational efforts and clinical applications. By outlining these 100 problems, we aim to guide and provide goals for future research and map the key areas where knowledge gaps exist.

These open problems are presented on our website (https://longevityknowledge.app), where users can interact with and find more information on each selected problem.

Link: https://doi.org/10.1007/s11357-025-01964-4

A number of approaches to inducing muscle growth or improving muscle strength have been demonstrated in laboratory animals, in early human clinical trials, and in recent years employed in medical tourism clinics. These approaches are compensatory in the context of aging, they do not address any of the underlying issues that lead to loss of muscle mass and strength per se. An adjustment of the regulation of muscle growth to favor more growth will produce larger, stronger muscles at any age, which may help to generate greater attention and use of such therapies as they are developed.

These varied approaches directly interfere in cell signaling in some way, as it is easier to adjust the levels of circulating proteins and other molecules, or their ability to interact with cell surface receptors, then it is to adjust mechanisms that operate inside cells. Inhibition of myostatin signaling and upregulation of follistatin signaling are the presently dominant approaches. The use of antibodies targeting myostatin has been assessed, but more effort is now put toward upregulation of circulating follistatin via forms of gene therapy.

In today's open access paper, researchers discuss upregulation of a different signaling protein, FGF19. This does appear to have the effect of reducing myostatin levels, but that it only increases muscle strength rather than muscle mass suggests that other mechanisms are driving the outcome. Some indication has been given in recent years that these various strategies to grow muscle or improve muscle strength may also have a positive impact on bone mineral density. Unfortunately that doesn't seem to the be the case for FGF19.

Therapeutic potential of FGF19 in combatting osteosarcopenia: effects on muscle strength and bone health in aged male mice

Osteosarcopenia, characterized by the coexistence of osteopenia/osteoporosis and sarcopenia, represents a significant health concern in geriatrics, with an increased risk of falls and fractures. The enterokine fibroblast growth factor 19 (FGF19) was recently shown to prevent muscle weakness in preclinical models. This study investigated the therapeutic potential of FGF19 in mitigating bone and muscle deterioration in aged male mice. Twenty-one-month-old C57BL/6 male mice received daily injections of human recombinant FGF19 (0.1 mg/kg) for 21 days.

Histological and functional analyses revealed a shift toward larger muscle fibers in FGF19-treated mice as well as an increased muscle strength, without affecting muscle mass. In parallel, X-ray microtomography showed that FGF19 had no overt negative impact on bone, with a range of modest, site-specific, and opposing effects. In the distal femur metaphysis FGF19, it reduced cortical thickness, but significantly increased bone cross-sectional area, with an overall increased polar moment of inertia, a geometrical parameter linked to favorable mechanical properties. It also elevated cortical bone porosity in the same region. There were no significant effects on trabecular bone or cortical bone parameters in the proximal femur side. In the L2 vertebra, cortical porosity decreased. Histomorphometry of trabecular bone and analysis of transcriptional output of selected genes in femurs revealed only minor changes in bone cellular activities and gene expression after three weeks of treatment.

In conclusion, FGF19 treatment increased muscle strength in aged male mice, without negatively impacting aging bone.

The raised blood pressure of hypertension is damaging to sensitive tissues throughout the body, but particularly the brain. Alongside many other issues in the health and function of the vascular system, hypertension increases the pace of rupture of tiny blood vessels in the brain, each such event destroying a small volume of brain tissue. Over time this adds up to degrade cognitive function and contribute to the development of outright dementia. Thus high blood pressure is harmful, and the longer the period of time in which blood pressure is elevated, the more harm is done. Here, researchers assess cumulative blood pressure over time and find a correlation between high, sustained blood pressure and a large increase in the risk of dementia.

Cumulative blood pressure (BP), which takes into account both the magnitude and duration of BP exposure, is linked to cognitive impairment. The Chinese Longitudinal Healthy Longevity Survey (CLHLS) over 16 years was divided into two consecutive sub-cohorts, namely the 2002 sub-cohort from 2002 to 2011 and the 2008 sub-cohort from 2008 to 2018. Cumulative BP exposures were calculated as the area under the curve derived from two consequence BP measurements and their corresponding time intervals.

A total of 2,142 and 1,920 cognitively healthy older adults participants from the two sub-cohorts were included in the analysis, respectively. Over a median follow-up of 6.2 years and 7.0 years, 542 and 347 older adults experienced cognitive impairment in the two sub-cohorts, respectively. Higher cumulative systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were significantly associated with a higher risk of cognitive impairment. Compared to the lowest quartile in the two sub-cohorts, the hazard ratios for cognitive impairment risk in the highest quartile were 1.85 and 2.64 for cumulative SBP, 2.00 and 2.20 for cumulative DBP, and 1.59 and 2.10 for cumulative PP, respectively.

Link: https://doi.org/10.1186/s12877-025-06465-9

Provoking regrowth of tooth enamel by mimicking some of its structure appears to be a going concern in dental research, if judging from this paper and another similar approach using keratin. At the high level, the idea is to coat damaged enamel with material that encourages the chemical mineralization process that takes place during enamel formation. Interestingly, the specific molecular structures demonstrated here allow this process to take place even when applied to exposed dentin. We can hope that cavities and fillings will soon enough be a thing of the past.

Tooth enamel is characterised by an intricate hierarchical organization of apatite nanocrystals that bestows high stiffness, hardness, and fracture toughness. However, enamel does not possess the ability to regenerate, and achieving the artificial restoration of its microstructure and mechanical properties in clinical settings has proven challenging.

To tackle this issue, we engineer a tuneable and resilient supramolecular matrix based on elastin-like recombinamers (ELRs) that imitates the structure and function of the enamel-developing matrix. When applied as a coating on the surface of teeth exhibiting different levels of erosion, the matrix is stable and can trigger epitaxial growth of apatite nanocrystals, recreating the microarchitecture of the different anatomical regions of enamel and restoring the mechanical properties.

The study demonstrates the translational potential of our mineralising technology for treating loss of enamel in clinical settings such as the treatment of enamel erosion and dental hypersensitivity.

Link: https://doi.org/10.1038/s41467-025-64982-y