Fight Aging!

Randomly occurring mutations to nuclear DNA accumulate with age. While DNA repair machinery in the cell nucleus has evolved to be highly efficient, nonetheless some fraction of the damage accumulated via radiation and molecular interactions slips through. There is considerable debate over the degree to which the accumulation of mutations contributes to degenerative aging, and which effects are important. Clearly mutation burden increases risk of cancer, that conclusion is solid and well supported: the more mutations, the more likely it is that a cancerous combination of mutations will occur. Going beyond this, matters become less clear, however.

The current consensus on this subject is that mutations occurring in stem cell populations is important, as these mutations can spread throughout a tissue via the daughter cells created by mutated stem cells. One sees patchy waves of mutational combinations arising with age in tissues throughout the body, a phenomenon called somatic mosaicism. There is at least some correlational evidence to link somatic mosaicism with a few age-related conditions, but it is by no means a foregone conclusion that it does provide an important contribution to general metabolic dysfunction.

Many varieties of malfunction in DNA repair produce both an accelerated accumulation of mutations and the appearance of accelerated aging. It is important to note that one can argue over whether this is in fact accelerated aging, versus just an excessive accumulation of a form of damage that plays a lesser role (or even possibly insignificant role, yet to be robustly determined either way) in normal aging. It is possible that researchers will ultimately learn little of importance from DNA repair deficiencies, for all that the research community makes a great deal of use of this phenomenon in animal models in order to obtain support for theories of aging relating to DNA damage.

One final thought on DNA damage is the more recent work suggesting that the damage is important insofar as it produces double strand breaks, as repeated repair of these breaks acts to alter epigenetic marks and the structure of DNA regardless of the location of this damage in the genome. This model dispenses of the idea that random breakage in gene sequences, largely only important where it is spread though somatic mosaicism, is collectively causing metabolic dysfunction. Instead, the repeated act of repair causes the epigenetic changes to gene expression that are characteristic of aging in all cells throughout the body. This also is work in need of confirmation and further exploration.

Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength

Aging is linked to reduced tissue function and regeneration, with genomic instability, marked by accumulating somatic mutation, being a key hallmark. These mutations, arising from replication errors or DNA repair defects, are not inherited but lead to tissue mosaicism. Although genome instability and DNA damage have been characterized in aging, the functional role of somatic mutation accumulation in age-related tissue decline and age-related diseases beyond cancer remains less explored.

Whole-genome sequencing (WGS) studies have shown that somatic mutations accumulate with age in human skeletal muscle progenitor cells and other tissues, with similar observations in most tumor types. Differentiated cells often carry even higher mutation loads, highlighting the underestimated extent of age-related somatic mutagenesis. Although we previously showed that high mutation burden impairs satellite cell (SC) function in vitro, in vivo evidence for the role of somatic mutations in muscle tissue function remains limited.

Aged human cells, including SCs, show structural genetic variations such as chromosomal aberrations, single-nucleotide variants (SNVs), and short insertions/deletions (InDels). To model this, we generated muscle somatic mutator (MSM) mice by deleting the DNA repair genes Msh2 and Blm specifically in SCs. This allowed us to assess how elevated DNA damage and somatic mutations affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain, and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle.

A good deal of research interest is now focused on the composition of the gut microbiome as either (a) a contributing factor in degenerative aging, due to changes that take place with age or (b) a factor in determining natural variations in human life span. For example, a number of research groups have mapped the composition of gut microbiomes in very long-lived individuals. The study here goes a little beyond a map of species and relative population sizes to identify a metabolite produced by microbes that appears to be protective in older individuals, based on results in mice.

The gut microbiota of centenarians plays a vital role in promoting healthy longevity. We performed a cross-sectional study of 224 people from Jiaoling, China, which is globally recognised for the longevity of its residents. Compared with younger people, centenarians showed significantly increased alpha-diversity//en.wikipedia.org/wiki/Alpha_diversity">alpha-diversity, enrichment of the beneficial bacteria Lactobacillus, Akkermansia, and Christensenella, and increased redox capacity in the gut microbiota. Serum metabolomics of centenarians showed significant enrichment of antioxidant metabolites, including L-ascorbic acid 2-sulphate and lipoic acid.

Finally, we isolated and screened a strain of Lactobacillus plantarum 124 (LP124) with a good antioxidant effect on the gut microbiota of centenarians. Animal experiments further verified that mesaconic acid from LP124 regulates the gut microbiota, is anti-inflammatory, relieves oxidative stress, maintains the intestinal barrier. LP124 derived from the gut microbiota of centenarians and its metabolite mesaconic acid, have a significant positive effect on health and longevity.

Link: https://doi.org/10.1038/s41522-025-00812-9

Increased CISD2 expression has been shown to slow aging in mice, and is one of the few longevity-inducing genes robustly identified to date. Increased expression improves liver function, reduces senescent cell inflammatory signaling in skin, and generates a range of other beneficial effects along the way. CISD2 produces numerous changes in aspects of metabolism, including mitochondrial function and calcium transport. Understanding which of these effects are more versus less important, and how exactly they induce improved long-term health, remains a work in progress. Expect to see many more papers akin to the one noted here, a deep dive into the effects of CISD2 expression in one specific tissue.

Age-associated atrial myopathy results in structural remodeling and a disturbance of atrial conductance. Atrial myopathy often precedes atrial fibrillation (AF) and can facilitate AF progression. However, the molecular mechanism linking aging to atrial deterioration remains elusive. CDGSH iron-sulfur domain-containing protein 2 (CISD2) is a mammalian pro-longevity gene. We used Cisd2 knockout (Cisd2KO) and Cisd2 transgenic (Cisd2TG) mice to investigate pathophysiological mechanisms underlying age-related atrial myopathy.

Four findings are pinpointed. Firstly, in both humans and mice, the level of atrial CISD2 declines during natural aging; this correlates with age-associated damage, namely degeneration of intercalated discs, mitochondriaps://en.wikipedia.org/wiki/Mitochondrion">mitochondria, sarcoplasmic reticulum (SR) and myofibrils. Secondly, in Cisd2KO and naturally aged wild-type mice, Cisd2 deficiency causes atrial electrical dysfunction and structural deterioration; conversely, sustained Cisd2 levels protect Cisd2TG mice against age-related atrial myopathy. Thirdly, Cisd2 plays a vital role in maintaining Ca2+ homeostasis in atrial cardiomyocytes. Cisd2 deficiency disrupts Ca2+ regulation, leading to elevated cytosolic Ca2+, reduced SR Ca2+, impaired store-operated calcium entry, and mitochondrial Ca2+ overload; these compromise mitochondrial function and attenuate antioxidant capability. Finally, transcriptomic analysis reveals that Cisd2 protects the atrium from metabolic reprogramming and preserves into old age a transcriptomic profile resembling a youthful pattern, thereby safeguarding the atrium from age-related injury.

This study highlights Cisd2's crucial role in preventing atrial aging and underscores the therapeutic potential of targeting Cisd2 when combating age-associated atrial dysfunction, which may lead to the development of strategies for improving cardiac health in aging populations.

Link: https://doi.org/10.1186/s12964-025-02377-8

Inflammaging is the age-related tendency of the immune system to slip into chronic inflammation in the absence of any external provocation such as injury or infection. Research into this phenomenon has produced a list of many different contributing mechanisms: the growing burden of senescent cells that produce pro-inflammatory signaling; excess visceral fat tissue that encourages the creation of senescent cells and provides pro-inflammatory signaling of its own; mitochondrial dysfunction that leads to mitochondrial DNA fragments escaping into the cell cytosol to maladaptively trigger mechanisms evolved to sense the presence of foreign DNA; and so forth. The resulting continual, unresolved inflammation is disruptive to tissue structure and function, an important contribution to age-related disease and mortality.

Over the past decade or so, researchers have shown that a number of hunter-gatherer populations exhibit much lower degrees of age-related dysfunction and disease than is the case in the populations of wealthy regions: a slower onset of neurodegeneration, and lower incidence of cardiovascular disease, for example. Hunter-gatherers undertake a great deal of physical activity relative to wealthier populations, and their diet is somewhat different. Today's research materials is a companion to a recent publication on the failure of chronic inflammation to greatly increase with age in Tsimane hunter-gatherers. Here, the same researchers compare the Tsimane and Moseten, near neighbor groups with differing degrees of adoption of modernity. Their data supports the consensus position that some of modernity, particularly the processed dietary options and lack of physical activity, are not so good for us.

Inflammaging is minimal among forager-horticulturalists in the Bolivian Amazon

An increase in chronic systemic inflammation in later life, termed inflammaging, is implicated in health risk. However, it is unclear whether inflammaging develops in all human populations, or if it is the product of environmental mismatch. We assessed inflammaging in Tsimane forager-horticulturalists of the Bolivian Amazon, using serum cytokines in a primarily cross-sectional sample (1,134 samples from n = 714 individuals, age 39-94, 51.3% female).

IL-6 was positively associated with age (β = 0.013). However, other pro-inflammatory markers, including IL-1β and TNF-α, did not increase with age (β = -0.005 and β = -0.001, respectively). We then compared the Moseten, a neighbouring population that has experienced greater market integration (423 samples from n = 380 individuals, age 39-85, 48.2% female). The Moseten also showed a positive age association for IL-6 that attenuated at later ages (age β = 0.025; age2 β = -0.001). Further, IL-1β and TNF-α were both positively associated with age (β = 0.021 and β = 0.011, respectively).

Our results demonstrate minimal inflammaging in the Tsimane, highlighting variation across populations in this age-related process. They also suggest that inflammaging is exacerbated by lifestyle shifts.

Progerin is a truncated form of lamin A, a protein needed to ensure the cell nucleus has a normal structure. In patients with Hutchinson-Gilford progeria syndrome, lamin A mutation leads to a large amounts of progerin, widespread cell dysfunction, the appearance of accelerated aging, and early mortality. In normal aging, progerin is expressed to some degree in some cells, and may or may not be significant; as in all potential contributing mechanisms of aging, it is very hard to assign the degree to which that mechanism is important relative to all of the other ongoing issues. Here, researchers provide evidence for somatic mutations in lamin A that occur in stem cells or progenitor cells, and that thus then expand out into somatic cells in tissue, to arise in chronic kidney disease and contribute to the pathology of that condition.

Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries.

Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.

Link: https://doi.org/10.1038/s43587-025-00882-6

Metabolic syndrome is a consequence of excess fat tissue, being overweight. It is the precursor to type 2 diabetes, and produces the same sort of harmful contributions to age-related conditions via increased chronic inflammation and a range of other mechanisms relating to the disruption of normal metabolism. It should not be surprising to see that metabolic syndrome increases the risk of a neurodegenerative condition like Parkinson's disease, as this class of age-related conditions are well known to involve inflammation in brain tissue.

Metabolic syndrome is defined as having three or more of the following risk factors: excess belly fat, high blood pressure, high blood sugar, higher than normal triglycerides, which are a type of fat found in the blood, and low high-density lipoprotein (HDL) cholesterol, or "good" cholesterol. The study involved 467,200 people with an average age of 57; of those 38% had metabolic syndrome. The participants were followed for a median of 15 years. During that time, 3,222 people developed Parkinson's disease. For people without metabolic syndrome, the incidence rate for Parkinson's was 4.87 cases per 10,000 person-years, compared to 5.21 cases per 10,000 person-years for people who had metabolic syndrome. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

After adjusting for age, smoking status, physical activity, and genes that increase the risk of Parkinson's disease, researchers found that people with metabolic syndrome were about 40% more likely to develop Parkinson's disease than people without the syndrome. The researchers also conducted a meta-analysis of all studies on this topic and confirmed the finding that people with metabolic syndrome have an increased risk of Parkinson's disease. Combining the current study with eight previous studies, the researchers found that people with metabolic syndrome were 29% more likely to develop Parkinson's disease than people without the syndrome.

Link: https://www.aan.com/PressRoom/Home/PressRelease/5278

It is well known that the health of women and aspects of aging worsen in many ways after menopause. The biochemistry of menopause and its role in aging is not as easily researched as it might be, as mice do not naturally exhibit menopause. Menopause can certainly be induced by chemical or surgical means in mice, but these models are all artificial and come with caveats as to the interpretation of results. It was thought that only a few larger mammals exhibit menopause, and this remains the consensus, but in recent years researchers have provided evidence to suggest that most large mammals do in fact undergo menopause. Identifying that this is the case has not been an area of focus, as large mammals are not often used in fundamental research into mechanisms of aging for reasons of cost and time.

In today's open access paper, researchers use an aging clock to assess biological age in women at various stages of menopause. The usual concerns apply for the use of clocks, as to whether they are in fact a good representation of of the accumulated damage and dysfunction of aging in any novel specific context. The only way to determine whether this is the case is to accumulate as much data as possible in many contexts, so researchers here use a well-established clock, one for which there is plenty of existing data to support its ability to measure something useful in this context. Setting that aside, the results are much as one would expect, and show that both entering menopause and undergoing earlier menopause both correlate with an increased biological age.

Menopausal status, transition, and age at menopause with accelerated biological aging across multiple organ systems: findings from two cohort studies

This study aimed to investigate the associations between menopausal factors and both comprehensive and organ-specific biological aging, as well as the modifying role of reproductive history. This study included 37,244 women from the China Multi-Ethnic Cohort (CMEC) and 140,479 from the UK Biobank (UKB). Menopausal factors included menopausal status, menopausal transition, and age at menopause. Comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera-Doubal method and clinical biomarkers and have been shown to predict age-related health outcomes. Multiple linear regression and change-to-change models were applied, with stratified analyses based on reproductive history.

Compared with pre-menopausal women, those who were peri-menopausal or post-menopausal or had undergone hysterectomy or oophorectomy exhibited greater acceleration in comprehensive, liver, metabolic, and kidney BA. In longitudinal change-to-change models, women undergoing menopausal transition showed greater increases in comprehensive BA (CMEC: β = 1.33; UKB: β = 2.60), as well as liver, metabolic, and kidney BAs compared to those remaining pre-menopausal. Earlier age at menopause was associated with accelerated comprehensive BA in UKB (earlier than 40 years: β = 0.69; 40-44 years: β = 0.24). Across organ-specific BAs, liver BA showed the strongest associations with menopausal factors. Reproductive history like age at live birth and number of live births emerged as potential modifiers of these associations.

Menopause, particularly the menopausal transition, was associated with accelerated comprehensive and organ-specific biological aging, with liver aging being most affected. These findings underscore the menopausal transition as a critical window for interventions to enhance women's health and longevity.

Muscle tissue is metabolically active and does produce effects on the rest of the body via signaling. Myokines are signal molecules produced my muscle tissue, while exerkines are signal molecules produced during exercise, and which induce improvements in tissue function, both in muscle and in other organs. This signaling is incompletely mapped and its effects in detail are not well understood outside of a few specific signals that have attracted research attention in past years. The broader topic of how muscle, and muscle use in exercise, influences function in the rest of the body is an area of interest for ongoing research. Researchers would like to produce exercise mimetic drugs, for example, analogous to calorie restriction mimetic drugs, that induce some of the signaling changes induced by exercise. A greater understanding of those signals helps.

Sarcopenia is an unavoidable condition that affects the majority of older adults in their later years. Exercise has been extensively researched as an effective intervention for sarcopenia. In particular, the release of exerkines and myokines during physical activity has beneficial effects on the body, which, as mediators, offer a novel therapeutic strategy for elucidating how exercise enhances skeletal muscle mass and function.

In this review article, we summarize how exerkines exert protective effects on aging skeletal muscle mainly through the following mechanisms: (1) mediating energy diversion to skeletal muscle, ensuring more energy supply to the muscle; (2) enhancing the activity of skeletal muscle satellite cells to promote muscle repair and regeneration; (3) upregulating the expression of genes associated with muscle regeneration and, at the same time, inhibiting the expression of those genes that contribute to the atrophy of skeletal muscle; and (4) improving the function of the neuromuscular junction to improve the neural control of skeletal muscle. These combined effects constitute the protective mechanism of myokines on aging skeletal muscle.

Link: https://doi.org/10.3389/fendo.2025.1592491

A study from a few years ago showed that circulating taurine levels declined with age in mice, and taurine supplementation extended healthy life span. That sparked some interest in the research community in corroborating those findings. Here, researchers show that matters relating to taurine and taurine supplementation are not straightforward, as in their data sets taurine from blood samples does not decline with age, and is not straightforwardly associated with age-related issues. It remains the case that conducting a study in people with low taurine levels would be comparatively simple to carry out, albeit expensive as is the case for any clinical trial, but the choice of what to assess as an outcome is now more complex than it was.

Taurine recently gained popularity as dietary supplement due to recent research that found supplementation with taurine improved multiple age-related traits and extended lifespan in model organisms (worms and mice). However, there is no solid clinical data that shows its supplementation benefits humans.

In a new study, researchers measured taurine concentration in longitudinally collected blood from participants in the Baltimore Longitudinal Study of Aging (aged 26-100), rhesus monkeys (aged 3-32 years) and mice (aged 9-27 months). Taurine concentrations increased with age in all groups, except in male mice in which taurine remained unchanged. Similar age-related changes in taurine concentrations were observed in two cross-sectional studies of geographically distinct human populations, the Balearic Islands Study of Aging (aged 20-85) from the Balearic region of Mallorca, and the Predictive Medicine Research cohort (aged 20-68) from Atlanta, Georgia, as well as in the cross-sectional arm of the Study of Longitudinal Aging in Mice.

Researchers also found that the relation between taurine and muscle strength or body weight was inconsistent. For example, analyses of gross motor function highlight the limitations of considering solely circulating taurine changes as indicative of biological aging, as comparatively low motor function performance can be associated either with high or low concentrations of taurine, whereas in other cases, no relation at all is found between these variables.

Link: https://www.nih.gov/news-events/news-releases/nih-researchers-conclude-taurine-unlikely-be-good-aging-biomarker

The development of cancer is strongly affected by the presence of senescent cells. Cellular senescence is a tool of cancer suppression in the earliest stages at which cancers emerge from cell damage, attempting to halt replication in damaged cells as well as call in the immune system via inflammatory signaling to destroy potentially cancerous cells. Senescent cells are also involved in wound healing and coordination of regeneration, however, and this capacity can be subverted by an established tumor to support its growth. Once a cancer is established, the accumulation of senescent cells in and around tumor tissue creates a more favorable environment for plaque growth via growth factor signaling.

Because of this connection between senescent cells and cancer, many successful chemotherapeutic drugs that were developed before the modern understanding of the relevance of senenscent cells to cancer and aging are turning out to be successful precisely because they kill senescent cells or suppress the pro-inflammatory, pro-growth signaling of senescent cells. The early senolytic drugs demonstrated to selectively kill senescent cells and reverse aspects of aging were all repurposed chemotherapeutics. Researchers continue to identify ever more compounds in the long list of approved and potential chemotherapeutics established over past decades as senotherapeutics that could be repurposed to treat age-related diseases by destroying or suppressing the activities of senescent cells.

Cabozantinib, an Anti-Aging Agent, Prevents Bone Loss in Estrogen-Deficient Mice by Suppressing Senescence-Associated Secretory Phenotype Factors

As the cellular micro-environment changes with age, senescent cells begin to secrete senescence-associated secretory phenotypes (SASPs) factors. These include pro-inflammatory cytokines [e.g., interleukin (IL)-1α, IL-1β, IL-6, and IL8], chemokines [e.g., C-C motif ligand 1 (CCL1), CCL2, and CCL5], proteases (e.g., matrix metalloprotease and serine protease), and growth factors (e.g., PDGF). SASP factors exhibit dual roles: they contribute to tissue regeneration, tumor suppression, and immunosurveillance, but can promote inflammation, tissue damage, and cancer progression. Consequently, extensive research has focused on anti-aging strategies that target senescent cells.

Bone homeostasis is maintained by a delicate balance between bone-forming osteoblasts and bone-resorbing osteoclasts. With aging, particularly post-menopause, this balance is disrupted, leading to impaired bone formation and increased resorption, thereby increasing the risk of osteoporosis and fractures. In aging bone, mesenchymal stem cells are more likely to differentiate into adipocytes rather than osteoblasts. Moreover, SASP factors such as tumor necrosis factor-alpha (TNFα), IL1α, IL1β, IL6, and CCL2 are secreted by senescent cells, fostering a pro-inflammatory microenvironment within bone tissue. TNFα, IL1α, and IL6 specifically impair osteoblast differentiation and enhance osteoclastic bone resorption. These findings highlight the importance of therapeutic strategies targeting senescent cells (senolytics) or modulating SASP activity (senomorphics) to prevent age-related osteoporosis.

In this study, we screened cabozantinib, a tyrosine kinase inhibitor approved for medullary thyroid cancer, for its anti-aging effects in bone-related cells, specifically osteoblasts and osteoclasts. Cabozantinib demonstrated the ability to activate osteoblasts and inhibit osteoclasts by suppressing the secretion of SASP factors from these cells. Additionally, it prevented bone loss in estrogen-deficient, ovariectomized mice. Our findings indicate that targeting senescent osteoblastic and osteoclastic cells using cabozantinib could be a potential therapeutic approach for treating age-related osteoporosis.

Changes in the expression of countless genes takes place with aging. Some of these changes are adaptive, attempts to resist the damaged environment or compensate for other impaired functions. Many are maladaptive and actively cause harm. Researchers here identify a specific maladaptive change in expression in neurons in the brains of aged mice, an increase in FTL1 that appears to produce a range of harm that contributes to loss of cognitive function.

Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline.

Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.

Link: https://doi.org/10.1038/s43587-025-00940-z

A small number of proteins in the body and brain are known to become misfolded or altered in ways that provoke the formation of extensive, harmful protein aggregates. Neurodegenerative conditions in particular are strongly linked to the aggregates of specific proteins, such as amyloid-β, tau, and α-synuclein. Researchers continue to discover new proteins that produce aggregates capable of contributing significantly to forms of age-related disease, however. That TDP-43 aggregates to cause a prominent form of dementia is a comparatively recent discovery, for example. Further, research makes clear that many more proteins, potentially hundreds, can produce aggregates as a result of dysfunction in protein quality control mechanisms. Thus we should probably expect that the present body of knowledge is incomplete with regard to which proteins and aggregates are important in age-related disease.

Protein aggregation is a hallmark of neurodegenerative diseases and is also observed in the brains of elderly individuals without such conditions, suggesting that aging drives the accumulation of protein aggregates. However, the comprehensive understanding of age-dependent protein aggregates involved in brain aging remains unclear. Here, we investigated proteins that become sarkosyl-insoluble with age and identified hyaluronan and proteoglycan link protein 2 (HAPLN2), a hyaluronic acid-binding protein of the extracellular matrix at the nodes of Ranvier, as an age-dependent aggregating protein in mouse brains.

Elevated hyaluronic acid levels and impaired microglial function reduced the clearance of HAPLN2, leading to its accumulation. HAPLN2 oligomers induced microglial inflammatory responses both in vitro and in vivo. Furthermore, age-associated HAPLN2 aggregation was also observed in the human cerebellum. These findings suggest that HAPLN2 aggregation results from age-related decline in brain homeostasis and may exacerbate the brain environment by activating microglia. This study provides new insights into the mechanisms underlying cerebellar aging and highlights the role of HAPLN2 in age-associated changes in the brain.

Link: https://doi.org/10.1371/journal.pbio.3003006

Cellular metabolism is a complex web of connections. For any well known protein that regulates metabolism in ways relevant to aging that can be affected directly by various small molecules, gene therapies, or mutations, there are probably a score of other ways to indirectly affect its expression and activity. The mTOR pathway is well researched, as suppression of mTOR activity is a part of the response to low nutrient levels that adjusts cellular biochemistry in favor of conservation and increased maintenance, such as via an upregulation of autophagy. This tends to slow aging. Even though mTOR and its proximate biochemistry is a relatively well researched area of molecular biology, researchers continue to find new links to other aging-related areas of interest.

In today's open access paper, the authors draw a connection between mild suppression of mitochondrial activity and mTOR activity via a convoluted chain of interactions centered around an uncoupling protein. Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) in an energetic process that produces damaging free radicals as a side-effect. A mild suppression of this mitochondrial activity (whether achieved via mutation, uncoupling, or other approaches) can slow aging in laboratory species, and the resulting changes include reduced mTOR activity. That in turn upregulates autophagy and helps to clear out damaged structures and protein aggregates that can harm cell function. A better understanding of how mitochondria instruct the rest of the cell to improve its function might lead to better ways to artificially induce this behavior.

The mitochondrial aspartate transporter Ucp4a regulates muscle aging and animal lifespan in Drosophila melanogaster

Mitochondria are subcellular organelles that utilize an electron transport chain (ETC) to produce cellular energy and also synthesize numerous metabolites that efflux to the cytosol. Mild knockdown of mitochondrial ETC proteins prolongs lifespan, a phenomenon that has been observed in diverse organisms including C. elegans, Drosophila, and mice. In mammalian cells, ETC perturbation or mitochondrial distress represses the mechanistic target of rapamycin complex 1 (mTORC1) pathway through activation of the transcription factor ATF4. Studies in Drosophila muscle have found ETC perturbation to repress systemic insulin signaling through expression of ImpL2, an inhibitor of Drosophila insulin-like peptides (Dilps). Repression of either mTORC1 or insulin signaling is established to extend lifespan; however, the mechanisms underlying this mitochondrial-distress-mediated life extension are not yet completely understood.

Aspartate (asp), a proteogenic amino acid, is synthesized in the mitochondrial matrix from glutamate and oxaloacetic acid (OAA), a tricarboxylic acid (TCA) cycle metabolite. Of note, asp synthesis requires integral mitochondrial function. In mammalian cells, treatment with an ETC inhibitor depletes asp due to impairment of NADH flux, which is required for integrity of the TCA cycle. Perturbation of asp synthesis impairs cell proliferation, and in endothelial cells impairs the cytosolic mTORC1 pathway.

Here we show that in flies mutation in uncoupling protein 4a (Ucp4a), which encodes a mitochondrial aspartate transporter, can extend lifespan without restricting feeding. Remarkably, the life-extension effect of Ucp4a mutation is specifically due to knockdown of Ucp4a in muscles; knockdown in other tissues was not effective in life-extension. We find that protein aggregates, a characteristic of muscle aging, are reduced by Ucp4a knockdown in muscles. Consistently, Ucp4a mutants and lines with Ucp4a knockdown in muscle maintain healthier muscle than control flies, as suggested by observation of enhanced locomotor activity in aged flies.

Aspartate (Asp) is converted to asparagine (Asn) by the asparagine synthetase (ASNS) enzyme in the cytosol, suggesting that Ucp4a knockdown is likely to reduce cytosolic Asn. This reduction might be a signal that relates to inhibition of the mTORC1 pathway. This possibility is supported by a recent finding that inhibition of glutaminolysis, which is required for asp synthesis, activates the ATF4-mediated pathway to suppress mTORC1 activity through expression of the mTORC1 negative regulators Sestrin2 and Redd1. Ultimately, asp reduction-mediated lifespan extension might require inhibition of the mTORC1 pathway. Further confirmatory research remains required.

The sirtuin family of proteins has attracted research interest for its involvement in mechanisms that may influence the pace of aging. While the overhyped work on the effects of sirtuin 1 on aging unraveled to produce no practical applications, sirtuin 3, sirtuin 4, and sirtuin 5 are localized in the mitochondria and there is a range of more convincing evidence to suggest that they can be manipulated to meaningfully adjust mitochondrial function in later life.

Sirtuins, colloquially termed "longevity proteins," are central regulators in the intricate molecular networks of aging. These proteins function as nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases or adenosine diphosphate (ADP)-ribosyltransferases, operating within multiple cellular regulatory pathways crucial to the aging process. The mammalian sirtuin family comprises seven members (SIRT1-7), with SIRT3, SIRT4, and SIRT5 specifically localized to the mitochondria.

These mitochondrial sirtuins have garnered significant scientific interest due to their potential roles in aging and age-associated disorders, primarily through their involvement in maintaining mitochondrial function and energy metabolism. Through the regulation of mitochondrial metabolism, stress response pathways, and other cellular processes, these proteins contribute to the maintenance of mitochondrial integrity and function, thereby supporting overall cellular homeostasis.

The diverse actions of mitochondrial sirtuins contribute to delaying age-related functional decline in various organs and extending lifespan in model organisms, positioning them as central players in the complex biology of aging. Given their critical roles in regulating aging, a systematic review of SIRT3, SIRT4, and SIRT5 functions in aging and age-related diseases is warranted. This review aims to provide a comprehensive overview of the current understanding of mitochondrial sirtuins, focusing on their involvement in various aging processes and their roles in age-related pathologies.

Link: https://doi.org/10.1093/lifemedi/lnaf019

While modern dentistry offers a range of good-enough approaches to damaged teeth, regeneration of lost enamel remains a much desired capability. Here, researchers show that the application of keratin to damaged tooth enamel provokes the formation of an enamel-like replacement structure. This is quite interesting, and simple enough in implementation that it could emerge as a widespread option in the near future.

Scientists discovered that keratin, a protein found in hair, skin and wool, can repair tooth enamel and stop early stages of decay. Keratin forms a dense mineral layer that protects the tooth and seals off exposed nerve channels that cause sensitivity, offering both structural and symptomatic relief. The treatment could be delivered through a toothpaste for daily use or as a professionally applied gel, similar to nail varnish, for more targeted repair. The team is already exploring pathways for clinical application and believes that keratin-based enamel regeneration could be made available to the public within the next two to three years.

In their study, the scientists extracted keratin from wool. They discovered that when keratin is applied to the tooth surface and comes into contact with the minerals naturally present in saliva, it forms a highly organised, crystal-like scaffold that mimics the structure and function of natural enamel. Over time, this scaffold continues to attract calcium and phosphate ions, leading to the growth of a protective enamel-like coating around the tooth. This marks a significant step forward in regenerative dentistry.

Link: https://www.kcl.ac.uk/news/toothpaste-made-from-hair-provides-natural-root-to-repair-teeth

Translation is the process by which cells manufacture many copies of a protein from one messenger RNA sequence encoding that protein. This takes place in one of the many ribosomes present in the cell, after which a newly assembled protein is folded within the endoplasmic reticulum. Translation is important, and so has evolved to be highly efficient. Errors nonetheless occur, and are corrected by various processes that identify broken, misfolded, and other problem proteins and ensure they are broken down for recycling. Those quality assurance processes have also evolved to be highly efficient. Correctly formed proteins are necessary for cell function, and malformed proteins will tend to cause harm in proportion to their numbers.

Nonetheless, different species exhibit different degrees of efficiency in translation. A range of evidence suggests that these differences provide a meaningful contribution to species life span. For example, naked mole-rats live as much as nine times longer than similarly sized mice, and exhibit exceptionally low rates of translation error. Like most long-lived species, however, naked mole-rats also exhibit many other adaptations that probably influence longevity, and it is ever a challenge to determine the degree to which each each of these distinct characteristics contributes to slowed aging and increased life span.

In today's open access paper, researchers provide an interesting demonstration of the effects of differences in translation error rates on longevity. They used yeast as a model. It is possible to produce thousands of distinct genomes by crossing two yeasts, and people have done this. It is a fairly standard approach if wanting to use small differences in similar organisms as a way to illuminate some aspect of cellular biochemistry. From that starting point, the researchers identified a gene variant that has a sizable effect on translation error rate, and also increases life span by 8%. Yeast, being a lower form of life, tends to respond to interventions with a large change in lifespan; one would expect effect sizes in mice to be smaller, but the next thing to do would be to try a similar genetic change in a mouse lineage and see what results.

Translational fidelity and longevity are genetically linked

A number of theories have been proposed to explain aging from various perspectives. One of the most influential of them is the Error-Catastrophe Theory of Aging, first proposed in 1963. According to this theory, errors that inevitably occur during messenger RNA (mRNA) translation will, sooner or later, happen to the proteins involved in the molecular machinery of translation. Consequently, translational fidelity will be reduced, resulting in a vicious circle towards even more errors, thus the decline of physiological function and eventually the death of the organism.

Based on the Error-Catastrophe Theory of Aging, there are three major directions to test the role of translation error in aging. First, the theory predicts that aged cells will produce more erroneous proteins than young cells. However, this has not been supported by a large body of experimental results from a variety of organisms. Second, the theory predicts a correlation between longevity and translational fidelity, which has been demonstrated by comparisons across species. A third prediction of the theory is that longevity should change accordingly as translational fidelity is manipulated. Early experiments in this direction, in which streptomycin was used to enhance translation error rates, had largely negative results. But more recently, some positive results have been obtained when paromomycin or mutant ribosomal proteins are used to increase translation error rate. While the use of specific antibiotics or artificial mutations might not reflect the natural conditions, these findings demonstrated that increased translational fidelity can indeed enhance longevity, and prompted renewed interest in the theory.

Measuring the lifespan and translational fidelity of a panel of BY x RM yeast recombinant haploid progenies, we validate the fidelity-longevity correlation. Genome-wide quantitative trait loci (QTL) analyses reveal that both fidelity and longevity are most strongly associated with a locus encoding vacuolar protein sorting-associated protein 70 (VPS70). Replacing VPS70 in BY yeast by its RM yeast allele reduces translation error by ~8.0% and extends lifespan by ~8.9% through a vacuole-dependent mechanism. These results collectively demonstrated the genetic basis for the correlation between translation error and aging, which strongly support the role of translational fidelity in intra-specific longevity variations.

Aging is accumulated damage, with age-related disease as the most visible dysfunction that results from that damage. Eventually one of those dysfunctions becomes large enough to cause death. The only way to live longer is to have a lower burden of damage, and thus exhibit lesser degrees of dysfunction. In human populations, this appears to be the case. The study noted here is one of a number to show that centenarians develop fewer and less severe age-related conditions than their peers who fail to live as long. The most interesting observation is that centenarians exhibit a relatively larger incidence of cancer as a fraction of all conditions. One might theorize that this is because their cells are undertaking a greater degree of maintenance activities in the age-damaged tissue environment. Cancer is a numbers game, and the more replication of cells taking place in tissues, particularly stem cells, the greater the odds of a cancer occurring.

Previous research suggests that centenarians reach exceptional ages primarily by avoiding major diseases rather than surviving them. However, how they manage multiple conditions over the life course remains less understood. We conducted a nationwide historical prospective study including all individuals born in Sweden between 1920 and 1922 (n = 274,108), tracking their health from age 70 for up to 30 years. Disease trajectories of centenarians were compared to those of shorter-lived peers using national health registers. We analysed disease burden, the rate of disease accumulation, and patterns of multimorbidity across age groups.

Centenarians had fewer diagnosed conditions and accumulated diseases at a slower rate than non-centenarians. Cardiovascular diseases were the most common diagnoses in all age groups, but contributed less to the overall disease burden among centenarians. In contrast, malignancies accounted for a relatively larger share of their disease profile. Neuropsychiatric conditions were consistently less common among centenarians, showing the largest relative difference across all ages. Centenarians also had fewer co-occurring diseases and were more likely to have conditions confined to a single disease group.

Link: https://doi.org/10.1016/j.eclinm.2025.103396

In recent years, research has indicated that the composition of the gut microbiome is influential on long-term heath and the progression of aging and age-related conditions, perhaps to a similar degree as the better studied influences of weight and exercise. The scientific community has made inroads into correlating specific microbial species and metabolites with specific conditions, and has demonstrated that altering the balance of populations making up the gut microbiome can improve health and extend life in aged animals. Here, researchers review what is known of the ways in which age-related changes in the composition of the gut microbiome can contribute to the progression of heart failure.

Heart failure (HF) occurs in the end stage of various cardiovascular diseases (CVDs), such as hypertension, myocardial infarction, and myocarditis. It is characterized by cardiac remodeling, which involves various structural and functional changes in the myocardium that develop in response to chronic stress or injury to the heart. These changes help maintain heart function to some extent. However, in the long term, they tend to accelerate the progression of CVDs and ultimately lead to HF.

Recently, the role of the gut microbiota in HF has received extensive attention. In HF patients, substantial changes occur in the gut microbiota, characterized by a decline in beneficial bacteria and an overgrowth of potentially harmful bacteria. These changes indicate that gut dysbiosis plays an important role in the development of HF, and therapy targeting the gut microbiota may become a new treatment approach. Furthermore, increasing evidence suggests that microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO), bile acids (BAs), short-chain fatty acids (SCFAs), and amino acids (AAs), may influence the development of myocardial remodeling. Modulating the composition of the gut microbiota appears to help ameliorate myocardial fibrosis and delay the development of HF.

In the past few years, there has been an explosion of reports regarding gut microbiota, and many excellent review articles have summarized the interactions between the gut microbiota and various organs in the body. Here, we focus on the role of gut microbiota in HF and its significance in cardiac remodeling. Although emerging evidence suggests that gut dysbiosis significantly influences the progression of HF, the specific mechanisms remain unclear. We discuss the potential advantages and challenges of novel therapeutic approaches targeting the gut microbiota, aiming to bridge the knowledge gap between gut health and HF, thereby laying a foundation for future research and clinical advancements.

Link: https://doi.org/10.1016/j.gendis.2025.101592

From a starting point of the small list of options to treat aging that are presently accessible to the average individual, if pushed to list the interventions with the most useful human evidence for safety, the most robust and replicated animal data for efficacy, and with relatively well-explored mechanisms of action, then one might start with (a) calorie restriction, (b) exercise, (c) rapamycin, and then (d) the senolytic combination of dasatinib and quercetin. Note that I say nothing of effect sizes when arranging that list. Rapamycin appears better than exercise in mice, but is not as good as calorie restriction when it comes to extending life span. None of those three produce anywhere near the rapid, impressive reversal of measures of aging and age-related disease in mice as have resulted from the use of first generation senolytic treatments, such as dasatinib and quercetin.

Today's open access paper might be read as a companion piece to a recent conservative review of the merits of rapamycin as a treatment to slow aging. When it comes to moving from data obtained in animal studies to data obtained from human clinical trials, well, there is very little human data for the use of rapamycin at the relatively low doses thought to be optimal for slowing aging. The long history of rapamycin use in humans is largely focused on high dose immunosuppression, and we can learn little from that.

This absence of a robust body of evidence was the point made in the above mentioned review, and it is the point made in today's open access paper. We might reasonably expect a calorie restriction mimetic like rapamycin, a drug that upregulates the operation of autophagy, to be capable of producing some degree of benefit in humans. The data to make a compelling case in humans remains absent. We should probably not hold our collective breath awaiting for that human data to arrive, unfortunately. Rapamycin is a generic drug, cheap, hard to monopolize in the way that pharmaceutical companies must in order to justify the vast investment of funds needed for regulators to grant clinical approval. So clinical trials for an age-slowing application of rapamycin are not a priority for the industry, and few other groups have deep enough pockets.

What is the clinical evidence to support off-label rapamycin therapy in healthy adults?

Rapamycin therapy is considered a promising approach for lifespan extension and the delay of age-related disease, with numerous preclinical studies documenting benefit. These benefits have inspired some patients to seek rapamycin therapy from specialty practitioners. Yet, the clinical evidence of benefit associated with low-dose rapamycin use in healthy human adults has not been established, and there may exist signals indicating caution with off-label use at non-immunosuppressive doses.

While the benefit of rapamycin therapy has been demonstrated in non-human models, nonetheless, the clinical evidence for low-dose mTOR inhibitors such rapamycin as a therapy for extending lifespan or delaying the onset of age-related disease in healthy adults remains unestablished. Here, we provide a critical appraisal of studies evaluating low-dose rapamycin therapy in healthy adults and offer considerations for its potential use as an off-label longevity drug in humans.

Longevity data in humans is difficult to acquire. Any well-designed trial that attempts to assess the longevity impact for any drug in people will be time consuming, expensive, and complicated by uncertainties in clinically valid endpoints. Since rapamycin is a generic medication, there is little incentive for any private group to fund such a study, which further complicates acquisition of high quality evidence with regard to low-dose rapamycin therapy. Accordingly, the clinical evidence evaluating low-dose rapamycin, or its analogues, in healthy participants is scant, with less than a dozen known trials exploring a variety of biomarkers, including immune function, protein synthesis, and hematologic parameters.

What emerges is a complex picture that remains insufficient to affirm or negate the longevity and healthspan extending benefits attributed to rapamycin. Despite the preclinical evidence supporting the use of sirolimus to enhance mean and maximal lifespan, the data in humans has yet to establish that rapamycin, or its analogues, is an effective senotherapeutic to delay aging in healthy older adults.

The immune system ages in complex ways, but the result of all of this complexity is chronic inflammation and incapacity, the states of inflammaging and immunosenescence. An aged immune system causes tissue dysfunction on the one hand, while failing to protect against infectious pathogens and malfunctioning cells on the other hand. Focused on one specific part of this big picture, researchers here explore the origins of a dysfunctional population of T cells that emerges in later life to contribute to overall immune dysfunction. They find that fat tissue appears important in encouraging this population to expand from its progenitor cell of origin.

In our previous work using aged mice, we identified a novel population of CD8+ T cells that accumulates across multiple tissues with age. These age-associated CD8+ T cells (TAA cells) are distinct from conventional effector and memory subsets and are also increased in the peripheral blood of older humans. At the transcriptional level, TAA cells are marked by high expression of Gzmk, a granzyme implicated in both cytolytic and non-cytolytic functions, including promotion of pro-inflammatory responses. TAA cells also exhibit co-expression of activation and exhaustion signature.

Although TAA cells make up a significant fraction of the aged CD8+ T cell compartment, the pathway underlying their development remains unknown. In this study, we demonstrate that TAA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Through detailed analysis of TAA cell heterogeneity, we identified a progenitor subpopulation enriched in the aged adipose tissue.

Using heterochronic transplantation, we show that adipose tissue acts as a functional niche, supporting progenitor maintenance and driving the conversion of young CD8+ T cells into the aged phenotype. Taken together, our findings reveal how aging of non-lymphoid tissues orchestrates the reorganization of the CD8+ T cell compartment and highlight adipose tissue as a promising target for therapeutic strategies aimed at modulating immune aging.

Link: https://doi.org/10.1101/2025.07.11.664388

Circulating oxytocin levels decline with age, and researchers have shown that restoring oxytocin to youthful levels has beneficial effects in aged animal models. Oxytocin is produced in the hypothalamus, and thus a range of different delivery mechanisms could work to replace this source. Here, researchers use an intranasal route for the introduction of replacement oxytocin, and show that it produces the expected benefits in aged mice.

While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (older than 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus.

Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression.

TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) knockout mice, compared with age-matched wild type mice, directly confirming a role for OXTR signaling. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.

Link: https://doi.org/10.1111/acel.70198

Antagonistic pleiotropy is a term used to describe a biological mechanism that is helpful in one context, harmful in another. As most often used, this means helpful when young, harmful when old. The concept of antagonistic pleiotropy sits at the heart of any serious discussion of the evolution of aging, as well as the relationships between known mechanisms of aging and hallmarks of aging. The dominant view of aging is that it is a side-effect of natural selection operating more strongly on the characteristics of young individuals than on the characteristics of old individuals, favoring the evolution of mechanisms that enhance early survival and reproductive success at the expense of later survival and reproductive success. Optimizing for initial success no matter the later consequences is a winning strategy for near all ecological niches.

Examples of specific mechanisms and circumstances that illustrate the reality of antagonistic pleiotropy have been established in a number of species. Researchers are very interested in finding examples in humans, however. Given vast genetic and epidemiological databases, researchers have searched for longevity-associated mutations that also affect reproductive success, for example. This is challenging, as longevity-associated mutations with even modest effect sizes and replication in multiple study populations are thin on the ground. There is some debate over whether any of the human data is in fact a good demonstration of antagonistic pleiotropy. Nonetheless, researchers continue to work on the problem, as illustrated by today's open access paper.

Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans

Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited. In this study, Mendelian randomization (MR) was applied to investigate the associations between the ages of menarche or first childbirth and age-related outcomes and diseases. Ingenuity Pathway Analysis was employed to explore gene-related aspects associated with significant single-nucleotide polymorphisms (SNPs) detected in MR analysis. The associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes were validated in the UK Biobank by conducting regression analysis of nearly 200,000 subjects.

Using MR, we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth was also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease, type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease. We identified 158 significant SNPs that influenced age-related outcomes, some of which were involved in known longevity pathways, including insulin-like growth factor 1, growth hormone, AMP-activated protein kinase, and mTOR signaling. Our study also identified higher body mass index as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy.

We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age of 11 and childbirth before 21 significantly accelerated the risk of several diseases and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory.

While all tissues age into dysfunction, the primary cause of human mortality is the aging of the cardiovascular system into heart failure, stroke, and heart attack, combined with the consequences of progressively worsening cardiovascular function in other organs. The way in which cardiovascular aging manifests is well documented, and the underlying processes of aging that contribute to the observed outcomes are also fairly well understood at the high level. The challenge lies in establishing exactly how the low-level mechanisms of aging give rise to changes and loss of function in the heart and vasculature. This is a task that may not even be needed, if instead the research community focused on ways to repair the molecular damage of aging. We don't need to fully understand how exactly any specific harm contributes to cardiovascular disease if we build a means to address it and observe benefits to result from the use of that therapy.

Aging is a slow, progressive, and inevitable process that affects multiple organs and tissues, including the cardiovascular system. The most frequent cardiac and vascular alterations that are observed in older adults (especially patients aged ≥80 years) are diastolic and systolic dysfunction, progressive stiffening of the vascular wall and endothelial impairment usually driven by an excess of extracellular matrix (ECM) and profibrotic substances, reduced levels of matrix metalloproteinases (MMPs), or by amyloid and calcium deposits in myocardium and valves (especially in aortic valves). Moreover, deformation of the heart structure and shape, or increased adipose tissue and muscle atrophy, or altered ion homeostasis, chronotropic disability, reduced heart rate, and impaired atrial sinus node (SN) activity are other common findings.

Interestingly, aging is often associated with oxidative stress, alterations in the mitochondrial structure and function, and a low-grade proinflammatory state, characterized by high concentrations of cytokines and inflammatory cells, without evidence of infectious pathogens, in a condition known as 'inflammaging'. Aging is a well-recognized independent risk factor for cardiovascular disease and easily leads to high mortality, morbidity, and reduced quality of life. Recently, several efforts have been made to mitigate and delay these alterations, aiming to maintain overall health and longevity. The primary purpose of this review was to provide an accurate description of the underlying mechanisms while also exploring new therapeutic proposals for oxidative stress and inflammaging. Moreover, combining serum biomarkers with appropriate imaging tests can be an effective strategy to stratify and direct the most suitable treatment.

Link: https://doi.org/10.31083/RCM27437

Persistent infection via HIV, herpesvirus, or a range of other pathogens capable of evading or subverting the immune system might reasonably be thought of as producing accelerated aging. The dysfunction produced by these infections usually centers around the immune system, but this in turn negatively affects the function of tissues and systems throughout the body. Aging is an accumulation of damage, and persistent infection produces forms of damage that overlap with those generated during the normal course of aging. Here, researchers discuss the range of mechanisms thought to be involved.

Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens - especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites - express proteins and metabolites capable of interfering with host immune signaling, mitochondrial function, gene expression, and the epigenetic environment.

This paper reviews these and other key mechanisms by which infectious agents can accelerate features of human aging. This includes hijacking of host mitochondria to gain replication substrates, or the expression of proteins that distort the signaling of host longevity-regulating pathways. We further delineate mechanisms by which pathogen activity contributes to age-related disease development: for example, Alzheimer's amyloid-β plaque can act as an antimicrobial peptide that forms in response to infection.

Overall, because many pathogens dysregulate mTOR, AMPK, or related immunometabolic signaling, healthspan interventions such as low-dose rapamycin, metformin, glutathione, and NAD+ may exert part of their effect by controlling persistent infection. The lack of diagnostics capable of detecting tissue-resident pathogen activity remains a critical bottleneck. Emerging tools - such as ultrasensitive protein assays, cell-free RNA metagenomics, and immune repertoire profiling - may enable integration of pathogen detection into biological age tracking. Incorporating infection into aging models is essential to more accurately characterize drivers of senescence and to optimize therapeutic strategies that target both host and microbial contributors to aging.

Link: https://doi.org/10.1016/j.arr.2025.102865

A broad range of evidence points to the composition of the gut microbiome providing a similar degree of influence on long-term health as is the case for lifestyle choices in diet and degree of physical activity. The relative proportions of microbial species making up the gut microbiome change with age, and much of this change appears unfavorable. Microbes that manufacture beneficial metabolites necessary for tissue function throughout the body decline in number, while microbes that provoke chronic inflammation or manufacture harmful metabolites increase in number.

Studies involving the transfer of fecal material between young and old individuals, carried out in relatively short-lived species such as killifish and mice, give us some idea as to the importance of the gut microbiome. In killifish, old fish receiving a fecal microbiota transplant from young fish lived an average of ~40% longer than their untreated peers. Effect sizes in very short-lived species are typically much larger than is the case in mammals, but even in mice there are clear signs that transplantation of a young microbiome into an old animal produces a lasting rejuvenation of the gut microbiome and significant improvement in health.

These and other equally interesting results from animal studies in recent years have provoked a serious effort to produce a map of correlations in humans between clearly measurable health metrics and specific differences in composition in the gut microbiome. Even a partial map would pave the way for the development of therapies that use a much simpler composition of microbial species than is the case for a donor microbiome, making it possible to predict, understand, and assess the profile of possible side-effects. Transplanting a standard mix of three (or ten, or twenty) species is a much easier proposition to put in front of regulators than transplanting a varied mix of thousands of species taken from donors, if the goal is ultimately to treat large fractions of the population, a scenario in which a very high bar for safety will be set.

Healthy Ageing and Gut Microbiota: A Study on Longevity in Adults

Many studies have focused on ageing and gut microbiota, but the correlation between gut microbiota and physical function in older adults, especially those with longevity, remains obscure and deserves further exploration. In this study we investigated changes in the gut microbiota and the association between gut microbiota and physical function in adults with longevity. This is a prospective observational study. Fifty-one older adults aged ≥ 60 years (including 27 participants aged 90 years and above) were enrolled. Information on clinical data, physical function including intrinsic capacity by Integrated Care for Older People (ICOPE) tool, and dietary habits of participants was collected and analysed. Gut microbiota structure and functional pathways were analysed by Metagenomics.

Intrinsic capacity (measured as ICOPE scores) of adults' longevity (aged 90-98, LONGE group) was significantly lower than older adults aged 60-89 years (CON group) (5.44 ± 2.15 vs. 6.71 ± 1.46). Gut microbiota of the LONGE group is enriched in Akkermansia and Bifidobacterium, which may be beneficial to health. Gut microbiota was closely related to daily milk consumption, anxiety, and physical function including grip strength by the Short Physical Performance Battery (SPPB).

Bacteroides plebeius and Bacteroides eggerthii were increased in long-living adults with better physical function. Escherichia coli was more abundant in frail young-old adults. Grip strength is positively correlated with the abundance of Roseburia hominis, Eubacterium rectale, Eubacterium eligens, and Roseburia intestinalis. Pathways related to amino acid synthesis that include L-isoleucine, L-valine, and L-threonine were over-presented in long-living adults of better physical function. Adults with longevity showed comparable gut microbiota abundance to younger elderly individuals. The gut microbiota of long-living adults showed higher abundance of potentially beneficial bacteria, and the altered bacteria are closely associated with physical function.

Changes in the gut microbiota may precede clinical indicators during the process of ageing. Gut microbiota may be a potential biomarker for longevity and healthy ageing. Nutrition and emotional state can be important influencing factors.

Researchers here describe a metabolite produced by gut microbes, 10-HSA, that encourages repair of tissue in the intestines and liver. As researchers dig more deeply into the mechanisms by which some configurations of the gut microbiome are more favorable to health than others, one should expect more discoveries of this nature. The research here involves treatment of chemical injury to the intestines and liver of mice, so it would be interesting to see an analogous study carried out in aged mice, to see if the same mechanisms promote a greater function and resilience in age-damaged rather than chemically damaged tissues.

A new study revealed that 10-hydroxy-cis-12-octadecenoic acid (10-HSA), a compound produced by Lactobacillus bacteria, successfully restored gut-liver health in mice exposed to aflatoxin. Aflatoxin is a toxic substance made of mold commonly found in peanuts, corn and other crops. It is known to cause liver injury. The gut and the liver are intricately linked. They communicate through bile acids, immunity responses, and lipid metabolism - a relationship known as the gut-liver axis. When one organ is damaged, the other suffers too. In diseases like metabolic dysfunction-associated steatotic liver disease (MASLD), this connection becomes a key therapeutic target.

Researchers used a mouse model mimicking MASLD. Exposing mice to aflatoxin B1 (AFB1), a toxic compound made by Aspergillus fungi, triggered liver injury, inflammation, and damage to the gut lining. But when these mice were treated with 10-HSA, the researchers saw a dramatic reversal of the liver and gut damage: gut epithelial barrier was restored; key bile acid metabolites like cholesterol and deoxycholate returned to healthy levels; energy metabolism and the detoxification functions in the liver improved; gut immune responses normalized.

Chronic liver diseases like MASLD and cirrhosis are driven in part by the suppression of PPARα signaling. 10-HSA activates PPARα, a protein that regulates lipid metabolism. By activating PPARα, the molecule repaired liver tissue and supported gut health. With strong preclinical evidence and no toxicity concerns, the researchers are preparing for human clinical trials, especially in people with fatty liver disease or metabolic issues.

Link: https://health.ucdavis.edu/news/headlines/uc-davis-scientists-find-a-microbial-molecule-that-restores-gut-and-liver-health/2025/08

Researchers here note that the state of research into the relationships between exercise, physical fitness, and epigenetic aging (or indeed, any other assessment of biological age provided by forms of aging clock) is patchy at best. There are at present too few studies and too little data for researchers to be able to confidently describe the degree to which various levels of exercise and fitness affect aging clocks, as compared to what it is possible to achieve for well-investigated outcomes such as risk of age-related disease and mortality.

The concept of an epigenetic clock is a predictive model based on DNA methylation patterns that provides a more accurate estimate of biological age than chronological age. Physical activity has emerged as a modifiable lifestyle factor that can influence the epigenetic clock and may serve as a geroprotective intervention to extend the health span and possibly the life span. However, some studies have discussed these effects without clearly distinguishing between physical activity, physical fitness, and exercise, which are closely related terms.

These foundational terms - physical activity, exercise, and physical fitness - are often used interchangeably in the general population; however, they have distinct physiological and epidemiological implications, particularly in aging research. For instance, while light-intensity physical activity, such as casual walking, contributes to energy expenditure and general health maintenance, it may not provide a sufficient stimulus to induce the molecular and cellular adaptations typically associated with geroprotective effects. In contrast, structured exercise programs, especially those incorporating moderate-to-vigorous intensity, are more likely to elicit systemic responses such as improved mitochondrial function, enhanced insulin sensitivity, and modulation of epigenetic markers. Furthermore, physical fitness, particularly cardiorespiratory fitness (CRF) and muscular strength, has been shown to be a robust predictor of morbidity and mortality in older adults. It is important to note that while physical activity and exercise are behaviors, physical fitness represents an integrated outcome influenced by genetics, training status, and overall health.

In human studies, one group showed that exercise training helps retain a more youthful methylome and gene expression profile in skeletal muscles. In another study, sedentary middle-aged and older females underwent eight weeks of combined (aerobic and strength) training. The group with a higher epigenetic age prior to the intervention showed a significant decrease in epigenetic age after the intervention. These findings suggest that structured exercise training can effectively reverse or rejuvenate blood- and skeletal muscle-based epigenetic clocks and the aging methylome.

Few studies have examined the relationship between physical fitness obtained through exercise and epigenetic aging. For example, researchers developed DNAmFitAge, which incorporates physical fitness measures into DNA methylation data, and found that bodybuilders had significantly lower DNAmFitAge compared to age-matched controls. These findings suggest that maintaining a high level of physical fitness delays epigenetic aging; however, these studies did not establish a causal relationship.

Link: https://doi.org/10.18632/aging.206278

Mitochondria manufacture the chemical energy store molecule adenosine triphosphate needed to power biochemical processes. They are the distant descendants of ancient symbiotic bacteria, hundreds of mitochondria found in each cell. Mitochondrial function declines with age for a range of complex reasons involving damage, changes in gene expression that affect mitochondrial proteins, and dysfunction in the quality control mechanisms of mitophagy, processes that should promptly remove damaged mitochondria but falter with age. A variety of approaches to improving mitochondrial function in aged tissue have been proposed, but none of the readily available methods can much improve on the effects of exercise.

Today's research materials discuss a novel approach to coercing mitochondria in aged tissues into better performance. Researchers have produced a proof of concept demonstration in mouse models of neurodegenerative disease, showing improved cognitive function following treatment. In brief, researchers have found that forms of G protein-coupled receptors found on mitochondrial membranes can be stimulated to improve mitochondrial function via their interactions with G proteins inside mitochondria. They designed an artificial receptor that can be stimulated in a controlled way by delivery of a small molecule drug, and used mice equipped with this receptor to dial up mitochondrial function and thus reduce age-related dysfunction in tissues.

Since mitochondrial transplantation is an approach under development for the treatment of age-related disease, it is easy to imagine a future in which cultured mitochondria are engineered in various ways prior to transplantation. Artificial receptors on those mitochondrial that allow for boosted mitochondrial function on demand, in response to ingesting a safe drug, may well be one of the more useful of the many possible enhancements to possess.

Neurodegenerative diseases: What if the key lies in the mitochondria?

Neurodegenerative diseases are characterized by a progressive impairment of neuronal functions leading to the death of brain cells. Researchers developed for the first time a tool that allows to temporarily stimulate mitochondrial activity. They hypothesized that if this stimulation led to an improvement of symptoms in animals, this would mean that the impairment of mitochondrial activity precedes the loss of neurons in the context of a neurodegenerative disease.

In previous studies, the research teams already described the specific role of G proteins in the modulation of mitochondrial activity in the brain. In the present paper, the researchers succeeded in generating an artificial receptor, called mitoDreadd-Gs, able to activate G proteins directly in the mitochondria, thereby stimulating mitochondrial activity. The stimulation of mitoDreadd-Gs in the brain led to the normalisation of both mitochondrial activity and memory performance of dementia mouse models.

Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice

Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction.

Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.

Researchers have in the past identified the activities of CaMKII as potential issue in degenerative aging, particularly in muscle tissue. Species differences in its activities are in fact a good example of antagonistic pleiotropy, in that mammalian CaMKII exhibits specific structural differences versus the analogous proteins in lower species that act to produce both better muscle function in youth and worse harms to muscle function in later life. Unfortunately CaMKII has many functions in many different tissues, so it isn't a straightforward target for therapies. Here, researchers use a tissue-specific inhibition in aged muscle to demonstrate that reduced CaMKII expression can reverse some of the characteristic age-related changes in muscle cell biochemistry and improve aspects of muscle function in old mice.

Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)-dependent and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline.

Researchers have in the past identified the activities of Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy.

These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.

Link: https://doi.org/10.1101/2025.07.30.667744

The brain is a plastic organ throughout life, neural networks adapting to use and experience. Many of the changes that occur with age are taking place in response to patterns of use, not just in response to damage and dysfunction. It isn't entirely straightforward to determine which is which. The research noted here doesn't give any particular insight into how to address undesirable changes in the aging brain, but does provide an interesting view into how the brain strives and succeeds to retain function in capacities that receive constant use.

The human cerebral cortex is only a few millimetres thick and arranged in numerous folds. This tissue usually becomes thinner with age. "This is a hallmark of aging. It is attributed, among other things, to the loss of neurons. As a result, some abilities deteriorate. In any case, it is generally assumed that less brain volume means reduced function. However, little is known about how exactly the cortex actually ages. That is why we examined the situation with high-resolution brain scans."

Researchers focused on the primary somatosensory cortex, a part of the cerebral cortex where signals from the tactile sense are processed. Using magnetic resonance imaging (MRI), the researchers were able to map this area of the cerebral cortex with unprecedented accuracy. "Until now, it had not been considered that the primary somatosensory cortex consists of a stack of several extremely thin layers of tissue, each with its own architecture and function. We have now found that these layers age differently. Although the cerebral cortex becomes thinner overall, some of its layers remain stable or, surprisingly, are even thicker with age. Presumably because they are particularly solicited and thus retain their functionality. We therefore see evidence for neuroplasticity, that is, adaptability, even in senior people."

Only the deeper layers of the cerebral cortex showed age-related degeneration: they were thinner in older study participants than in younger ones. "The middle and upper layers of the cortex are most directly exposed to external stimuli. They are permanently active because we have constant contact with our environment. The neural circuits in the lower layers are stimulated to a lesser extent, especially in later life. I therefore see our findings as an indication that the brain preserves what is used intensively. That is a feature of neuroplasticity."

Link: https://www.dzne.de/en/news/press-releases/press/the-cerebral-cortex-ages-less-than-thought

Immunosenescence is the name given to the age-related decline in the capacity of the immune system to carry out its duties: defend against pathogens; destroy senescent and cancerous cells; participate in normal tissue maintenance. Inflammaging, a chronic inflammatory stage characteristic of aging that arises from maladaptive reactions to damage, the presence of senescent cells, and other causes, is considered by some researchers to be an aspect of immunosenescence, while others think of it as a distinct phenotype. Both immunosenescence and inflammaging are important contributions to degenerative aging. Infectious disease and cancer are far more dangerous for the old precisely because the immune system is diminished in capacity, while the chronic inflammation of aging contributes to all of the common age-related diseases.

The research and development communities are well aware of the damage done by immune aging, and many projects have aimed and continue to aim at producing therapies that can improve immune function in older individuals. Among the more promising approaches are the various ways to restore a more youthful capacity of hematopoietic stem cell populations to generate functional immune cells in the right proportions, or regrow the atrophied thymus to restore a youthful supply of new T cells of the adaptive immune system, or selectively destroy one or more of the small, dysfunctional subpopulations of immune cells that cause harm in the aging body. It is a very interesting, active area of development, but it remains to be seen as to how rapidly viable therapies can be introduced into widespread clinical use.

Immunosenescence: signaling pathways, diseases and therapeutic targets

Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels.

Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials.

In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.

The practice of calorie restriction involves eating fewer calories while still obtaining at least adequate levels of micronutrients. Mild calorie restriction might be a 10% reduction from recommended calorie levels, but as much as 40% is possible given sufficient diligence and attention to the details. Calorie restriction induces sweeping metabolic changes that collectively act to improve cell and tissue function. The present consensus is that the most important of these changes is enhanced autophagy. Autophagy is a collection of maintenance processes responsible for recycling damaged proteins and structures in the cell. In near all species assessed to date, calorie restriction slows aging and improves health.

Diet influences disease progression, yet the effects of fasting on acute kidney injury (AKI) and its transition to chronic kidney disease (CKD) remain unclear. This study evaluated fasting-mimicking diet (FMD) cycles versus ad libitum feeding in murine models of AKI and CKD induced by aristolochic acid or folic acid.

FMD significantly reduced serum creatinine, kidney injury, and maladaptive repair marker expression, and promoted faster recovery. It also lowered renal cytokines and pro-fibrotic genes, reduced CCL2 levels, and decreased monocyte recruitment while favoring protective monocyte phenotypes. Cycles of caloric restriction yielded similar nephroprotection. Initiating FMD at the peak of AKI enhanced repair and attenuated inflammation.

Inhibition of CCR2 abolished FMD's protective effects, implicating the CCL2/CCR2 axis in mediating its benefits. However, broader anti-inflammatory actions may also contribute, and reduced CCL2 may reflect downstream effects. These findings highlight the potential of dietary interventions to modulate kidney injury and inflammation in AKI and CKD.

Link: https://doi.org/10.1016/j.isci.2025.113094

In the near term, the field of tissue engineering aims to produce artificial tissue structures that can support cells and integrate with native tissue when implanted into an injury, promoting regeneration that would not otherwise have taken place. In the longer term, the goal is to produce entirely artificial, fully functional organs - but first things first. Producing large sections of pseudo-tissue that can reliably promote regeneration is still a work in progress, with many projects at varying stages of development. As this paper makes clear, the fine details involved in sufficiently replicating tissue structural properties can be a challenge.

Myocardial Infarction (MI) occurs when blood flow to the heart is restricted, causing cardiomyocyte death, scar tissue formation, and myocardial remodeling. These changes reduce the heart's efficiency, increasing the mechanical load on surrounding tissue and causing the infarcted region to thin. In severe cases, this leads to myocardial rupture, which requires immediate surgical intervention. Here, cardiac patches made from biological (bovine pericardium), synthetic materials (polytetrafluoroethylene or polyester fiber) are implanted to stabilize the heart. However, these materials do not degrade, contract, or integrate into the myocardium. Furthermore, these patches undergo undesirable biological interactions such as calcification, thrombosis, and inflammation. These drawbacks hinder the application of cardiac patches in pediatric patients, impairing long-term recovery and safety in many cases.

An ideal cardiac patch would be implantable, easy to handle surgically and provide short-term mechanical support while promoting biological regeneration of the damaged myocardium. Such a patch would fully integrate with native tissue, degrade in a controlled manner, and avoid triggering an immune response or other adverse effect. Tissue-engineered cardiac patches, or engineered heart tissues (EHTs), offer a potential solution to these challenges. Previous research has shown that large, clinically relevant cardiac tissues can be fabricated and engrafted onto animal hearts, where they maintain their structural and electrical properties, undergo vascularization, and improve cardiac function. However, tissue-engineered cardiac patches are primarily applied to the epicardial surface of the heart, and few examples of intraventricular implantation exist.

In this work, we developed an implantable, intraventricular cardiac patch by reinforcing EHTs with 3D-printed polycaprolactone (PCL) materials. A key challenge in designing intraventricular cardiac patches is balancing the biological compatibility of soft materials with the mechanical robustness required for implantation. To address this, we utilized volumetric 3D printing (VP) to fabricate a porous PCL metamaterial that could be infiltrated with a cell-laden hydrogel and provide tunable mechanical properties that match the myocardium. We combined our metamaterial with a hydrogel-infiltrated melt-electrowritten (MEW) mesh, which reduces permeability and enables patch implantation via suturing. This multi-material design enabled the patch to be implanted in an acute large animal trial, where it withstood intraventricular pressure, prevented bleeding, and enabled hemodynamic restabilization (partial restoration of blood pressure and heart rate), demonstrating its potential for myocardial defect repair.

Link: https://doi.org/10.1002/adma.202504765

Stretches of nuclear DNA can adopt a broad range of transient structural forms, guided by the complex feedback loops of epigenetic marks, decorating molecules added to and removed from DNA. Epigenetics as a form of control over gene expression is all a matter of structure: which regions are packaged up and inaccessible, which are accessible. Other processes can also have their effects on local structure of the DNA, however. Some of the resulting structural forms can be problematic, and might be thought of as damage or dysfunction or an unwanted side-effect of those processes operating on DNA. This is all fairly well described by the scientific community, with an established nomenclature for different structural features.

In this context, an R-loop is a structure in which a length of double-stranded nuclear DNA has a RNA sequence stuck to it, perhaps the consequence of a failure of transcription, the first step of gene expression. In today's open access paper, researchers provide evidence for R-loops to result in leakage of nuclear DNA fragments from the nucleus into the cytosol. This triggers inflammatory signaling via the cGAS/STING system that evolved to detect inappropriately localized nucleic acids, such as that belonging to viruses and bacteria. Unfortunately, forms of cell damage related to aging and disease will result in mislocalized fragments of the cell's own nucleic acids, generating a maladaptive inflammatory reaction on the part of cGAS/STING that further contributes to the progression of aging and disease.

Targeted Inhibition of cGAS/STING signaling induced by aberrant R-Loops in the nucleus pulposus to alleviate cellular senescence and intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is a significant contributor to chronic low back pain and disability worldwide, yet effective treatment options remain limited. Through integrative analysis of single-cell RNA-seq data from intervertebral discs (IVDs), we have firstly uncovered that the aberrant accumulation of R-Loops - a type of triple-stranded nucleic acid structure - can result in the cytoplasmic accumulation of double-stranded DNA (dsDNA) and activate cGAS/STING signaling and induce cellular senescence in nucleus pulposus cells (NPCs) during IVDD. Restoring the R-Loop state significantly mitigated both the activation of the cGAS/STING pathway and NPC senescence. Additionally, we identified ERCC5 as a critical regulator of the R-Loop state and cellular senescence.

Thus, we developed an NPC-targeting nano-delivery platform (CTP-PEG-PAMAM) to deliver small interfering RNA for ERCC5 (si-Ercc5) to the NP region of the IVDD. This approach aims to modulate the abnormal R-Loop state and inhibit the activation of cGAS/STING signaling in NPCs for IVDD treatment. CTP-PEG-PAMAM demonstrated excellent targeting capability towards NPCs and NP tissue, and achieved effective silencing of the Ercc5 gene without causing systemic organ complications. Both in vitro and in vivo experiments revealed that CTP-PEG-PAMAM-siERCC5 significantly inhibited cGAS/STING signaling activated by aberrant R-Loops, alleviated cellular senescence and promoting cell proliferation, thereby delayed IVDD in a puncture-induced rat model.

In conclusion, the ERCC5-R-Loop-cGAS/STING axis in NPCs represents a promising therapeutic target for delaying IVDD, and the designed CTP-PEG-PAMAM/siRNA complex holds great potential for clinical application in the treatment of IVDD.

Aging clocks can be manufactured using machine learning techniques from any sufficiently complex set of biological data obtained from people of different ages. An algorithm is found that maps age-related changes in the data to chronological age, on average. When that algorithm is applied to an individual not in the data set, the predicted age is called a biological age. Higher biological ages predicted by a clock usually correlate fairly well to risk of disease and mortality. Given the relatively low cost involved in creating clocks, new clocks are being produced at a rapid pace. It remains to be seen as to which of the many clocks created over the past decade or so prove to be useful enough in some context to be broadly adopted.

Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly correlate with age. In principle, we can use these estimators to find novel targets for aging research, which can then be used for developing drugs that can extend the healthspan. However, methylation-based clocks do not provide direct mechanistic insight into aging, limiting their utility for drug discovery.

Here, we describe a method for building tissue-specific bulk RNA-seq-based age-estimators that can be used to identify the ageprint. The ageprint is a set of genes that drive baseline healthy aging in a tissue-specific, developmentally-linked fashion. Using our age estimator, SkeletAge, we narrowed down the ageprint of human skeletal muscles to 128 genes, of which 26 genes have never been studied in the context of aging or aging-associated phenotypes. The ageprint of skeletal muscles can be linked to known phenotypes of skeletal muscle aging and development, which further supports our hypothesis that the ageprint genes drive (healthy) aging along the growth-development-aging axis, which is separate from (biological) aging that takes place due to illness or stochastic damage. Lastly, we show that using our method, we can find druggable targets for aging research and use the ageprint to accurately assess the effect of therapeutic interventions, which can further accelerate the discovery of longevity-enhancing drugs.

Link: https://doi.org/10.1101/2025.07.28.667277

Some long-lived proteins (such as components of nuclear pore structures) in some long-lived cells (such as neurons) may never be replaced across a normal life span, or at the very least have lifetimes of years. That suggests that damage to these molecules may be important in aging and age-related disease. Some research has taken place on this topic, but as noted here, issues of measurement ensure that damage to long-lived molecules remains a more speculative contribution to degenerative aging. It may be important relative to other mechanisms, or it may not.

Neurons, unlike most other cell types, do not divide and are not replaced over an organism's lifetime. This lack of turnover necessitates robust mechanisms to maintain cellular integrity and function across prolonged periods of time, up to many decades. One key aspect of neuronal longevity is protein homeostasis, or proteostasis, which involves the balance between protein synthesis, folding, and degradation. Advances in metabolic labeling techniques have provided unexpected insights into protein turnover rates in neurons, and identified long-lived proteins (LLPs) in the brain. In addition to proteins, recent studies assessing the longevity of RNA have led to the identification of long-lived RNAs (LLRs) in the brain, challenging the prevailing consensus that RNA molecules are unstable.

Investigating the mechanisms underlying the long-term maintenance of these long-lived molecules - and the consequences of their dysfunction during brain aging or in the pathogenesis of age-related disease - is crucial to understanding their pathophysiological roles. However, due to limitations in measurement sensitivity and the lack of tools to selectively manipulate long-lived molecules, current proposals regarding their roles in brain aging remain largely speculative. In this opinion article, we discuss recent developments in characterizing LLPs and LLRs, as well as advances in emerging technologies to detect long-lived molecules in the brain. We also examine the mechanisms underlying the maintenance of long-lived molecules and these molecules' potential physiological roles. We finally delineate future directions to improve current understanding of the biological roles of long-lived molecules in brain aging and longevity.

Link: https://doi.org/10.1016/j.tins.2025.07.004

There is some debate over whether GLP-1 receptor agonist drugs such as semaglutide can affect mechanisms relevant to aging independently of weight loss. GLP-1 receptors are present in many organs, including the brain, so it is not unreasonable to think that other outcomes may result from GLP-1 receptor agonism over and above reduced appetite and calorie intake. But do those outcomes slow aging to a meaningful degree in comparison to the effects of weight loss? That is where we should be appropriately skeptical.

Compelling mechanistic and epidemiological data indicates that excess visceral fat tissue accelerates aging, such as via the increased accumulation of senescent cells and the induction of a harmful diabetic metabolism. The effect size is fairly large. Losing weight should reduce biological age, so any data on GLP-1 receptor agonist drug use and biological age in overweight populations, as is the case in today's open access paper, cannot be used to argue that there is something other than weight loss going on - the weight loss effects get in the way.

The most compelling evidence for GLP-1 receptor agonists to affect pace of aging independently of loss of visceral fat tissue comes from a study in mice using low doses of the drug exenatide, too low to cause weight loss. The researchers nonetheless noted effects on aging, and their evidence suggests that this is specifically due to GLP-1 receptor agonism in the hypothalamus, and downstream effects from there. Recall that the hypothalamus is influential on many aspects of metabolism, and research has suggested that changes in hypothalamic function do affect pace of aging.

Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial

People with HIV (PWH) represent a unique population exhibiting accelerated biological aging, characterized by premature onset of age-related conditions, persistent low-grade inflammation, and metabolic dysfunction, even when HIV replication is effectively suppressed by antiretroviral therapy. A common metabolic complication in this population is HIV-associated lipohypertrophy, defined by excessive accumulation of visceral and ectopic adipose tissue, which further exacerbates aging processes. Within the geroscience framework, the accelerated-aging phenotype in PWH provides an ideal clinical model to evaluate candidate geroprotective therapies.

In a completed phase 2b, randomised, double-blind, placebo-controlled trial (semaglutide n = 45; placebo n = 39), we tested whether once-weekly semaglutide can slow epigenetic aging in people with HIV-associated lipohypertrophy, a population marked by visceral adiposity (average BMI = 32.86) and accelerated epigenetic age. Using paired peripheral-blood methylomes collected at baseline and 32 weeks, we conducted a post-hoc analysis spanning 17 DNA-methylation clocks.

After adjustment for sex, BMI, hsCRP, and sCD163, semaglutide significantly decreased epigenetic aging: PCGrimAge (-3.1 years), GrimAge V1 (-1.4 years), GrimAge V2 (-2.3 years), PhenoAge (-4.9 years), and DunedinPACE (-0.09 units, ≈9 % slower pace). Semaglutide also lowered the multi-omic OMICmAge clock (-2.2 years) and the transposable element-focused RetroAge clock (-2.2 years). Eleven organ-system clocks showed concordant decreased with semaglutide, most prominently inflammation, brain and heart, whereas an Intrinsic Capacity epigenetic clock was unchanged. These findings provide, to our knowledge, the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of aging, justifying further evaluation of GLP-1 receptor agonists for health-span extension.

People who do not put on a lot of excess weight, and the excess visceral fat tissue that goes with it, are very unlikely to develop type 2 diabetes. It is a metabolic disease in which the primary, addressable cause is the presence of too much visceral fat. Adoption of a low calorie diet and undergoing the consequent weight loss is a curative strategy, and can reverse the course of type 2 diabetes even in late stages of the condition. With all that said, typically, overweight people develop type 2 diabetes later in life. It takes a great deal of visceral fat tissue to push someone into type 2 diabetes in earlier adulthood. So clearly the mechanisms and dysfunctions of degenerative aging do play a role. Here, researchers focus specifically on the aging of the immune system and its interaction with the metabolic dysfunction that leads to type 2 diabetes.

Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR), inflammation, and dysregulation in glucose metabolism. The disease is spreading globally, partly due to aging, which can damage the immune system and speed up the progression of the metabolic disorder. This review primarily delves into the triggers for T2D within the framework of the ominous octet, which emphasizes 8 principal factors that contribute to high blood glucose and associated metabolic disorders. The octet includes impaired insulin secretion, diminished incretin effect, increased lipolysis, heightened hepatic glucose production (HGP), neurotransmitter dysfunction, augmented renal glucose reabsorption, reduced glucose uptake in muscle, and inflammation-driven IR in adipose tissue (AT).

We further discuss the interplay of hyperinsulinemia, mitochondrial dysfunction (MD), and endoplasmic reticulum (ER) stress with immune aging in driving disease progression affecting each component of the octet. MD and ER stress can result in defects in insulin signaling, ultimately leading to pancreatic β-cell death. Chronic inflammation associated with aging, also known as inflammaging, especially affects older adults by worsening IR and glucose regulation, which creates a continuous sequence of metabolic problems. Thus, the "ominous octet" framework provides fundamental knowledge to develop personalized treatment approaches that target metabolic dysfunction together with ER stress, MD, and immune system imbalances. These strategies show promising potential to improve treatments for T2D and may lead to better health outcomes for older adults dealing with this condition.

Link: http://doi.org/10.14218/ERHM.2025.00018

The hundreds of mitochondria present in every cell are responsible for generating the chemical energy store molecule adenosine triphosphate to power cell processes. Dysfunction in the mitochondrial population is characteristic of aging and thought to be a meaningful contribution to loss of tissue function. This dysfunction arises in part because the quality control mechanisms that cull damaged mitochondria become less effective. When functioning correctly, the processes of mitophagy identify and flag damaged mitochondria, which are then conducted to a lysosome, engulfed, and broken down. The remaining mitochondria replicate to make up their numbers. Many interventions known to modestly slow aging or aspects of aging, exercise included, improve the operation of mitophagy and consequently improve mitochondrial function. How much of the overall benefit arises from improved mitophagy versus other mechanisms is a hard question to answer, however.

Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise confers these protective effects remain incompletely understood.

In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB-related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved.

Link: https://doi.org/10.3390/metabo15070472

Constant, unresolved inflammatory signaling is a feature of aging. It occurs in absence of the usual provocations of infection and injury, and is disruptive to tissue structure and function. Normal, short-term inflammation is useful and necessary, but long-term inflammation is harmful. It changes cell behavior for the worse, causes the normal processes of tissue maintenance to run awry, degrades the effectiveness of the immune system, encourages growth of cancers, and contributes to the onset and progression of all of the common fatal diseases of aging.

Much of this unwanted inflammation of aging is caused by the reaction of inflammasomes to the molecular damage present in an aged cell. Inflammasomes are protein complexes that evolved to react to the presence of molecules characteristic of infectious agents such as viruses by inducing inflammatory signaling that will then be amplified by the immune system. Unfortunately, this means that they will also react to age-related cell dysfunction that leads to the escape of fragments of nuclear DNA from the nucleus and mitochondrial DNA from mitochondria into the body of the cell. Analogous maladaptive activation of inflammasomes also takes place as a result of other dysfunctions that occur in aged cells.

Researchers are interested in targeting inflammasomes to prevent this induction of inflammation in aged tissues. The challenge here is that, so far, it appears that distinguishing between unwanted activation and desirable activation will be challenging. Efforts to suppress inflammatory signaling will not just suppress the harmful chronic inflammation, but also suppress useful short-term inflammation, further impairing immune function. It remains to be seen as to whether there are clever ways around this problem; one or two possible paths forward have been found in recent years, but these approaches may or may not work out. It is too early to say.

Potential Role of Inflammasomes in Aging

Inflammaging is a term used to describe the physiological changes in the immune system associated with aging that play a significant role in the onset and progression of complex aging-related diseases. These changes affect various conditions, including skin aging, cardiovascular disease, neurodegenerative disease, periodontal disease, and other chronic illnesses. Molecular and cellular mechanisms linking aging and chronic inflammation have been studied extensively, focusing on increased cytokine expression related to inflammasomes and their sustained activation in inflammatory diseases.

Inflammasomes are protein complexes observed within the cell cytoplasm, serving as critical molecular platforms that induce inflammatory responses. Inflammasomes recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, as well as the initiation of pyroptosis, a form of cell death. The activation of inflammasomes involves various sensors, including nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptor (NLR) proteins, pyrin, absent in melanoma 2 (AIM2), and gamma-interferon-inducible protein Ifi-16 (IFI16). These sensors activate the protease enzyme caspase-1, which cleaves pro-IL-1β and pro-IL-18, generating mature IL-1β and IL-18. Furthermore, inflammasome activation leads to the cleavage of gasdermin-D, resulting in N-terminal fragments that form pores in the cell membrane. This process induces pyroptosis while releasing various DAMPs and cytokines.

Inflammasomes play a fundamental role in enhancing innate immune responses and promoting pathogen clearance and tissue repair. However, their activation can be context-dependent, and excessive activation may exacerbate inflammatory conditions. Conversely, insufficient cytokine activation could contribute to chronic inflammation. Therefore, the precise regulation of inflammasome activity is essential for maintaining physiological homeostasis.

The targeting of inflammasomes offers a promising avenue for mitigating inflammaging and age-related diseases. Given the distinct yet overlapping roles of various inflammasome sensors, the development of selective and broad-spectrum inflammasome inhibitors is critical. While many studies have focused on NLRP3 inhibition, the involvement of other inflammasomes in inflammaging suggests that a more comprehensive approach is necessary. Each inflammasome sensor responds to different activation signals, meaning that a single-target strategy may be insufficient to fully mitigate chronic inflammation and its systemic effects in aging. Further research is needed to determine how targeting multiple inflammasomes simultaneously could impact the inflammaging process and whether dual or multi-inflammasome inhibition can provide synergistic benefits without compromising immune surveillance.

Synucleinopathies are neurodegenerative conditions characterized by the aggregation of misfolded α-synuclein, a form of protein aggregation that drives much of the pathology of these diseases. The most prominent synucleinopathy is Parkinson's disease, but it may well be that α-synuclein plays a role in the aging of the brain more generally. Synucleinopathies are exaggerated versions of a damaging process that operates to some degree in every older person. Here, researchers suggest that aspects of DNA damage and DNA repair play a noteworthy role in synucleinopathies - altered in some way by the presence of α-synuclein aggregates, and in turn driving a significant fraction of the chronic inflammation of brain tissue that is a feature of these and other neurodegenerative conditions. Modulating the DNA repair process can help, at least in animal models of α-synuclein aggregation.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach.

Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks.

In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy.

Link: https://doi.org/10.3390/biom15070907

Urolithin A is one of a number of molecules regulated as supplements that is known to modestly improve mitochondrial function. A number of companies are working on deriving drugs from modified forms of urolithin A, while the research community is more focused on trying to understand how exactly it improves mitochondrial function. The effect size is not large, as is the case for better understood approaches to improve mitochondrial function in aged tissues, such as the various ways to increase NAD+ in mitochondria, and delivery of forms of mitochondrially targeted antioxidant. These various molecules tend to produce results that are smaller than those resulting from greater exercise and greater physical fitness, where there is data to compare directly, and have collectively failed to move the needle on diseases in a range of clinical trials. Nonetheless, there remains considerable interest in all of these approaches, largely because they cost little and are immediately available for use.

Urolithin A (UA) is a natural compound produced through a multi-step metabolic process by gut microbiota, derived from dietary precursors such as ellagitannins (ETs) and ellagic acid (EA). These polyphenols are abundant in foods like pomegranates, berries, and tea. Extensive preclinical research highlights UA's diverse biological effects, including anti-inflammatory, antioxidant, anti-senescence, anti-apoptotic, and promoting mitophagy. Randomized clinical studies further validate UA's ability to upregulate proteins linked to mitophagy and oxidative phosphorylation (OXPHOS) in muscle tissue while reducing plasma inflammatory markers, such as C-reactive protein (CRP).

Regarding safety, clinical trials have confirmed UA's tolerability at doses up to 1000 mg daily, with no serious adverse effects reported in interventions lasting up to four months. Notably, UA is the first compound shown in human trials to induce mitochondrial-related gene expression without significant side effects. The U.S. FDA has granted UA Generally Recognized as Safe status as a food additive.

UA has been extensively investigated in preclinical models of various central nervous system (CNS) disorders. This review systematically integrates preclinical evidence for UA's therapeutic potential in CNS disorders and elucidates its biosynthesis, pharmacokinetic properties, key bioactivities, and recent clinical trials involving UA. Although clinical trials targeting UA treatment for CNS disorders have not yet been initiated, multiple clinical trials have demonstrated that UA possesses favorable safety and pharmacokinetic profiles and have validated some of the biological effects observed in in preclinical studies. Importantly, this review provides an in-depth analysis of the challenges encountered in the clinical translation of UA for the treatment of CNS disorders.

Link: https://doi.org/10.3390/biomedicines13071553

When continually stimulated, as occurs in persistent viral infections and cancer, T cells of the adaptive immune system become exhausted. This state is characterized by an inability to attack and kill pathogens and harmful cells. As with any other aspect of the immune system, however, exhaustion is not a well-defined and simple binary state, but rather a broad category that contains many different subtypes of exhausted cell, degrees of exhaustion, and distinct biochemistries contributing to exhaustion. Cellular biochemistry is complicated at every level.

Researchers want to find effective ways to reprogram T cells to exit exhaustion or resist the onset of exhaustion. This seems possible in principle, and a number of technology demonstrations exist to demonstrate that at least some manipulation of T cell exhaustion can be accomplished. Turning those initial research results into useful therapies is very different matter, of course. Today's research materials report on new discovery that may help to make exhaustion less of a problem in cancer and persistent infection. The researchers have identified GFI1 as a regulator of the degree to which exhaustion prevents T cells from generating a useful response to pathogens and cancerous cells, and GFI1 inhibitors may prove to be a useful class of drug.

Reinvigorating exhausted T cells in cancer and chronic viral infections

Killer immune cells destroy cancer cells and cells infected by virus. However, in chronic viral infection and cancer, the killer cells often lapse into "exhausted" CD8+ T cells that no longer can stem disease. Exhausted CD8+ T cells are a complex population of subsets composed of progenitor cells and "effector-like" or "terminally exhausted" cells. Effector-like cells still retain some killer ability.

Researchers used mice infected with a chronic virus to describe four subsets in the population, including a previously under-described Ly108+CX3CR1+ subset that expresses low levels of Gfi1, while other established subsets have high expression. This Ly108+CX3CR1+ subset is transitory and develops to terminally exhausted cells and effector-like cells, which retain some tumor killing ability. This process depends on low levels of Gfi1.

"Considering Gfi1 downregulation is associated with the active differentiation of CD8+ T cell progenitors, we argue that transient and intermittent inhibition of Gfi1 with lysine-specific histone demethylase may facilitate the differentiation of progenitors to Ly108+CX3CR1+ cells and then to effector-like cells, thereby improving the control of chronic infections and tumors/"

Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer

During chronic infection and tumor progression, CD8+ T cells lose their effector functions and become exhausted. These exhausted CD8+ T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8+ T cells.

During chronic LCMV Clone 13 infection, a previously under-described Ly108+CX3CR1+ subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108+CX3CR1+ cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8+ T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-4-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8+ T cells.

Metabolic dysfunction-associated steatohepatitis (MASH) follows a fatty liver, largely a consequence of obesity, but made worse by aging, in which fat-induced dysfunction of liver tissue maintenance leads to an increasing burden of fibrosis and loss of function. In fibrosis, the normal mechanisms of tissue maintenance run awry and excessive collagen is deposited to form scar-like structures that disrupt tissue function. At present fibrosis is largely irreversible, despite some potentially promising lines of research and development.

In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging.

In conclusion, there is a close bidirectional relationship between MASLD/MASH and aging. After aging, the prevalence, severity, and mortality of MASLD/MASH all increase. At the same time, MASLD/MASH can exacerbate liver aging, leading to the senescence of liver cells and affecting the normal functions of the liver. However, the detailed mechanisms by which aging contributes to the development of MASLD/MASH and why aging is exacerbated by this disease remain unclear. Moreover, the causal relationship between the two is not explained in detail, which one comes first and which one comes next. Future studies should further explore the specific mechanisms of this relationship and develop targeted preventive and therapeutic strategies to mitigate the impact of liver disease on the aging process and delay the progression of liver disease in the elderly population.

Link: https://doi.org/10.1007/s11684-025-1133-7

Researchers continue to search for circulating factors present in young blood fractions that might produce beneficial effects on cells in aged tissues. Transfusion of blood fractions from young donors to aged recipients has failed to produce compelling data, but it remains possible that specific factors could be manufactured and delivered in larger amounts to produce benefits. The paper here is one example of many early stage discovery projects presently taking place, in which researchers produce in vitro cell and tissue models to cost-effectively assess the effects of varied young blood fractions and specific factors. Their data suggests that factors from young blood fractions could produce benefits by altering the behavior of immune cells derived from the bone marrow that are present in tissues throughout the body.

Aging is a complex process that significantly contributes to age-related diseases and poses significant challenges for effective interventions, with few holistic anti-aging approaches successfully reversing its signs. Heterochronic parabiosis studies illuminated the potential for rejuvenation through blood-borne factors, yet the specific drivers including underlying mechanisms remain largely unknown and until today insights have not been successfully translated to humans.

In this study, we were able to recreate rejuvenation of the human skin via systemic factors using a microphysiological system including a 3D skin model and a 3D bone marrow model. Addition of young human serum in comparison to aged human serum resulted in an improvement of proliferation and a reduction of the biological age as measured by methylation-based age clocks in the skin tissue. Interestingly, this effect was only visible in the presence of bone marrow-derived cells.

Further investigation of the bone marrow model revealed changes in the cell population in response to young versus aged human serum treatment. Using proteome analysis, we identified 55 potential systemic rejuvenating proteins produced by bone marrow-derived cells. For seven of these proteins, we were able to verify a rejuvenating effect on human skin cells using hallmarks of aging assays, supporting their role as systemic factors rejuvenating human skin tissue.

Link: https://doi.org/10.18632/aging.206288

A common approach taken by researchers when investigating how a specific aspect of cellular biochemistry functions is to disable genes one by one to observe whether they are necessary or not. This isn't exactly straightforward, as cells typically have several ways of achieving a given goal, and removing one of those ways may or may not appear to do anything, depending on how exactly the researcher chooses to measure the outcome. This is the curse of engaging with complex systems. Nonetheless, sometimes one does find that one gene is critical, and that usually helps to advance the understanding of how the biochemistry of interest functions.

Today's open access paper is an example of this sort of research applied to calorie restriction, an incremental advance in the understanding of how beneficial effects result from a lowered calorie intake. Calorie restriction induces the activation of cell maintenance processes to produce improved resilience, health, and longevity. This response to starvation evolved very early in the history of life on earth, and is thus remarkably similar in organisms ranging from yeast to worms to mice to humans. In all of these species, it produces sweeping changes to the operation of cellular biochemistry, making it a challenge to pick out the controlling mechanisms and important outcomes. Over the years, researchers have established that autophagy is required for calorie restriction to extend life, and have identified some important regulatory genes, such as mTOR.

There is much left to discover. But it seems plausible that this sizable focus of research, and the development of calorie restriction mimetic drugs that follows, will be only a footnote to the future extension of the healthy human life span. Calorie restriction has nowhere near the same effect on longevity in long-lived species as it does in short-lived species. Calorie restricted mice can live as much as 40% longer, but humans probably gain only a few years in the same circumstances. Why this is the case remains an open question, but it may be that long-lived species are long-lived because they already possess most of the metabolic improvements induced by the practice of calorie restriction in short-lived species.

Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy

Sestrins were identified two decades ago as stress-responsive proteins that play an important role in regulating cellular homeostasis. Vertebrate genomes showcase three Sestrin genes (SESN1-3), while invertebrates feature just one. Numerous stressors, ranging from hypoxia and oxidative stress to DNA damage and nutrient deprivation, induce Sestrin expression in mammalian cells. The orchestration behind this expression involves several transcription factors, notably p53, FOXO, ATF4, and NRF2. Highlighting evolutionary conservation, the same signalling pathways trigger the activation of dSesn in D. melanogaster. Consequently, Sestrins play pivotal roles in the regulation of cellular viability under various stress conditions, such as hypoxia, oxidative stress, DNA damage, and glucose deprivation.

Earlier research from our team established Sestrins as antioxidant proteins that play a critical role in inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) kinase. mTORC1 is an intricate environmental sensor that integrates signals from nutrients, growth factors, and stresses to regulate cell fate decisions. Remarkably, mTORC1 plays a key role in lifespan and aging regulation across various species. Application of specific mTORC1 inhibitors, like rapamycin, has been shown to enhance lifespan in different organisms from yeast to mice. Similarly, caloric restriction (CR), a well-documented longevity enhancer across many species, also represses mTORC1 activity, further cementing the role of this kinase in aging control.

This study aimed to elucidate the influence of the sesn-1 gene on lifespan modulation during caloric restriction (CR) in the nematode model organism C. elegans. Our findings reveal that sesn-1 mediates lifespan extension under CR, primarily through the repression of mTORC1 kinase and activation of autophagy. Moreover, we identified an essential role for sesn-1 in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated sesn-1's interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between sesn-1 and the FOXO pathway. Overall, our research underscores the profound implications of Sestrins in aging and stress resistance, shedding light on possible therapeutic avenues for prevention and treatment of age-associated disorders.

Senescent cells accumulate with age and contribute to degenerative aging by provoking inflammation and disrupting tissue structure and function. Targeting cellular senescence for the treatment of age-related disease is presently in the slow, optimistic phase of research and development that comes after the initial hype has died down, but before a large number of attempts have been made at definitive, sizable clinical trials. This can last for years. The clinical development of new therapies is a very slow business. It has been something like fifteen years since the first flush of real excitement about senescent cells as a mechanism of aging captured the research community, and while a dozen or more life science companies are developing drugs to destroy or alter the behavior of senescent cells in patients, only a few small clinical trials have been conducted to date.

With the intensification of global aging, the incidence of age-related diseases (including cardiovascular, neurodegenerative, and musculoskeletal disorders) has been on the rise, and cellular senescence is identified as the core driving mechanism. Cellular senescence is characterized by irreversible cell cycle arrest, which is caused by telomere shortening, imbalance in DNA damage repair, and mitochondrial dysfunction, accompanied by the activation of the senescence-associated secretory phenotype (SASP).

In this situation, proinflammatory factors and matrix-degrading enzymes can be released, thereby disrupting tissue homeostasis. This disruption of tissue homeostasis induced by cellular senescence manifests as characteristic pathogenic mechanisms in distinct disease contexts. In cardiovascular diseases, senescence of cardiomyocytes and endothelial cells can exacerbate cardiac remodeling. In neurodegenerative diseases, senescence of glial cells can lead to neuroinflammation, while in musculoskeletal diseases, it can result in the degradation of cartilage matrix and imbalance of bone homeostasis.

This senescence-mediated dysregulation across diverse organ systems has spurred the development of intervention strategies. Interventional strategies include regular exercise, caloric restriction, senolytic drugs (such as the combination of dasatinib and quercetin), and senomorphic therapies. However, the tissue-specific regulatory mechanisms of cellular senescence, in vivo monitoring, and safety-related clinical translational research still require in-depth investigation.

Link: https://doi.org/10.3390/biomedicines13071727

The introduction of cheap accelerometers via the mobile phone industry had the side-effect of allowing the research community to accurately assess the effects of varying low levels of physical activity on long-term health. Self-reporting is particularly inaccurate in this range of exertion, and thus the use of accelerometers in studies enabled a much more accurate determination of the lower end of the dose-response curve for exercise. The results demonstrated that even small amounts of exercise are very much better than no exercise. Double the small amount of exercise is better yet. The paper here is an example of this sort of dose-response gradient at lower levels of exercise, focused on fast walking in older people.

While the health benefits of daily walking are well-established, limited research has investigated effects of factors such as walking pace on mortality. Data from the Southern Community Cohort Study were used, including information from nearly 85,000 predominantly low-income and Black individuals recruited during 2002-2009 across 12 southeastern US states. Participants provided baseline information on daily walking pace and time, demographic information, lifestyle factors, and health status. Mortality data were collected until December 31, 2022.

Over a median follow-up of 16.7 years, 26,862 deaths occurred. Significant associations were found between all-cause mortality and daily fast walking time. Fast walking as little as 15 minutes a day was associated a nearly 20% reduction in total mortality (hazard ratio, HR: 0.81), while only a 4% reduction in mortality (HR: 0.96) was found in association with more than three hours of daily slow walking. Fast walking was independently associated with reduced mortality, regardless of the leisure-time physical activity levels. The inverse association was more pronounced for mortality due to cardiovascular diseases than cancers. Participants with baseline comorbidities had larger risk reductions compared to their generally healthy counterparts, although all individuals benefited from fast walking.

Link: https://doi.org/10.1016/j.amepre.2025.107738

The innate immune cells known as macrophages are found in tissues throughout the body, and their activities are important in tissue maintenance and regeneration. Macrophages can adopt different packages of behavior in response to circumstances. There are a number of ways to define these behaviors, but researchers usually refer to (a) M1 macrophages that are inflammatory and aggressive, focused on destroying pathogens and errant cells, versus (b) M2 macrophages that are anti-inflammatory and more focused on tissue maintenance. This split of activities becomes particularly important in aged, damaged, or cancerous tissue. Cancers are known to reprogram and subvert immune cells in order to fuel growth, and the macrophages present in cancerous tissue, known as tumor-associated macrophages, are front and center in that process.

In today's open access paper, the authors discuss how cellular senescence in tumor-associated macrophages is particularly important in determining how these macrophages accelerate tumor growth. One of the useful activities undertaken by senescent cells in normal tissue is to coordinate regeneration from injury, and the senescence-associated secretory phenotype (SASP) generated by senescent cells is as much pro-growth as it is pro-inflammatory. A tumor evolves to encourage macrophage senescence, which in turn supports unchecked replication of tumor cells.

The research community is very interested in the application of senotherapeutics to cancer. Indeed, many successful chemotherapeutic drugs of past years have turned out to be senotherapeutic in the light of more recent knowledge. That these drugs are capable of destroying senescent cells or changing their behavior explains their success. Separately, researchers are also very interested in manipulating tumor-associated macrophages to make tumors less aggressive, such as via attempts to force M2 macrophages in tumor tissue to adopt an M1 state, or otherwise stop supporting cancer growth in favor of attacking cancerous cells. These two areas of research interest dovetail well with one another.

Senescent macrophages in cancer: roles in tumor progression and treatment opportunities

Macrophages play critical roles in the tumor microenvironment (TME), where they influence tumor progression through their remarkable plasticity and environmental adaptability. Typically, pro-inflammatory M1 macrophages (classically activated macrophages) are found in healthy tissues; in contrast, the macrophages in the TME predominantly adopt a pro-tumorigenic M2 (alternatively activated macrophages) phenotype, which facilitates tumor progression via extracellular matrix remodeling, angiogenesis, and immune suppression. Consequently, tumor-associated macrophages (TAMs) are central to promoting tumor growth, invasion, and metastasis through paracrine signaling and other mechanisms.

The role of cellular senescence in tumor development, particularly the effects of senescent macrophages in the TME, has garnered increasing attention. Cellular senescence was initially considered a tumor-suppressive mechanism. However, senescence paradoxically promotes tumor progression, particularly via senescent macrophages. Senescent macrophages, after exposure to specific intrinsic and extrinsic stimuli, undergo cellular aging. These cells are typically characterized by upregulation of p16 Inhibitor of Cyclin-Dependent Kinase 4a (p16INK4a) and distinct features associated with the senescence-associated secretory phenotype (SASP). Through intrinsic senescence, therapeutic interventions, or external stimuli, senescent macrophages exhibit functional impairments including chronic inflammation, decreased antigen presentation, and impaired phagocytosis. These changes foster an immunosuppressive environment conducive to tumor growth.

Key in this process is the SASP, comprising cytokines, chemokines, proteases, and growth factors that disrupt the immune environment and enhance tumorigenesis. Notably, IL-6 is a prominent SASP factor contributing to a pro-inflammatory, tumor-promoting milieu. Emerging evidence highlighting that senescent macrophages exacerbate tumor progression through SASP secretion and immune dysregulation has underscored the importance of understanding their mechanisms. Therapeutic strategies targeting senescent macrophages, including senolytics, senomorphics, and senoreverters, as well as immunotherapies such as Chimeric Antigen Receptor T-cell (CAR-T) cells, offer promising avenues for halting tumor growth and reversing the harmful effects of the aging TME. Future research is expected to focus on optimizing these treatments and elucidating the interactions between senescent macrophages and tumor cells to improve clinical outcomes.

The evidence for persistent viral infection by herpesviruses and others to be a significant cause of Alzheimer's disease is mixed and contradictory. There are clear and well understood mechanisms by which persistent infection can in principle contribute to neurodegeneration, but only some epidemiological data supports the a role for viral infection in Alzheimer's disease. It may be that the contribution is small, or emerges very slowly over a long time, or it may be that only a subset of patients exhibit the necessary biochemistry for persistent infection to play a major role in neurodegenerative disease. Once clinical trials start to show that no beneficial effect results from antiviral treatment, however, further investigations will likely slow to a minimal level of effort.

Various studies have found connections between herpes infections and Alzheimer's, including an autopsy study that found HSV1 DNA was often associated with amyloid plaques in the brains of people diagnosed with Alzheimer's. Additional studies have found that people treated for herpes infections were less likely to be later diagnosed with Alzheimer's than HSV-positive people who received no antiviral treatment. This raised hopes that herpes treatments could slow progression of Alzheimer's symptoms among patients. But the first clinical trial to test that theory has found that a common antiviral for herpes simplex infections, valacyclovir, does not change the course of the disease for patients in the early stages of Alzheimer's.

The trial included 120 adults, age 71 on average, all diagnosed with early Alzheimer's disease or mild cognitive impairment with imaging or blood tests that indicated Alzheimer's pathology. All participants had antibodies revealing past herpes infections (mostly HSV1, some HSV2). The participants were randomly assigned to take daily pills containing either valacyclovir or a placebo. The researchers measured the patients' memory functions and imaged the brain to look for amyloid and tau deposits associated with Alzheimer's and other structural changes. After 18 months, the researchers found that patients taking the placebo performed slightly better on cognitive tests than the valacyclovir group, but no other measures were significantly different.

"Our trial suggests antivirals that target herpes are not effective in treating early Alzheimer's and cannot be recommended to treat such patients with evidence of prior HSV infection. We do not know if long-term antiviral medication treatment following herpes infection can prevent Alzheimer's because prospective controlled trials have not been conducted."

Link: https://www.cuimc.columbia.edu/news/antiviral-treatment-fails-slow-early-stage-alzheimers

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that have their own DNA, replicate to maintain their numbers, and are responsible for generating the chemical energy store molecule adenosine triphosphate (ATP) to power the cell. Mitochondria, like all cell structures, are constantly damaged. Damaged and dysfunctional mitochondria are removed via the cell maintenance process of mitophagy. With age, this quality control falters, while the expression of genes necessary for mitochondrial function change for the worse. Mitochondrial DNA becomes damaged in ways that further degrade function. As a result, cell and tissue function also becomes disrupted, contributing to the many manifestations of degenerative aging. The focus here is on muscle tissue, but analogous stories can be told for any tissue in the aging body.

As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults.

A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.

Link: https://doi.org/10.1186/s11658-025-00771-1

Medicine is the collective, warring, practical implementation of some of our most fundamental, important views on the human condition. What do we think can and should be done about the existence of suffering? What is the purpose of life? What do we do about death and its consequences? The development and provision of medical services inevitably requires these questions to be answered at some point by most of the people involved. Why start a career in medicine or medical development? Why continue it? What to focus on? Where does meaning arise in this life choice?

Medicine is largely a response to suffering. But it cannot only be a response to suffering, because there are two paths to alleviating suffering, as we all know. The first path requires no medicine in its simplest implementations, and is to bring as quick as possible an end to the life of the suffering individual. Medicine exists because this is rarely an individual's first impulse. Few indeed follow that path down to the nihilist's logical conclusion that all entities capable of suffering should be prevented from coming into being or persuaded into destruction. Faced with situations in which an end to life is the rational choice because there is no other option, emotions ranging from dissatisfaction to rage drive the creation of individual and collective initiatives to find another option.

Nonetheless, death happens regardless. Medicine cannot yet prevent people from dying in all too many scenarios, largely those associated with aging. Even though the medical community has come around to trying to do something about aging, it remains the case that someone, somewhere, at any given time is thinking about how to make inevitable death less terrible. This is the sort of thing that medical communities do when they cannot yet solve the problem. They chew on it, measure it, try to do something, anything that can be done now to reduce the suffering associated with the intractable problem, even if that means considering the paths that none of us like to consider.

Measuring and monitoring the quality of dying in the UN Decade of Healthy Ageing

To monitor and evaluate the UN Decade of Healthy Ageing (2021-30), the World Health Organization has proposed a set of indicators of healthy ageing, based on functional ability and intrinsic capacity of older people. Functional ability is defined as the health-related attributes that enable people to be and to do what they have reason to value. This definition could include individuals who are dying; however, specific indicators for this stage have yet to be developed. Mortality rates and life expectancy are important outcome indicators used to assess health-care system performance, with health-care interventions typically aimed at reducing avoidable mortality. Nonetheless, death is inevitable, and the importance of how we die has been widely recognised, for example, by the Lancet Commission on the Value of Death. The period preceding death forms a part of the ageing trajectory and requires targeted actions to ensure that it is lived with the highest level of health and dignity. Dying well constitutes an integral component of healthy ageing.

Measuring the quality of dying can guide care and support for individuals who are dying and their families, inform clinical decision making, shape health and care delivery, support policy development and evaluation, facilitate comparisons across institutions and countries, and track changes over time across settings where people are dying and where end-of-life care should be accessible to them. However, in attempting to identify such measures, numerous questions arise. How should a good death be defined? Who should report on the quality of dying? Over what timeframe should the evaluation occur? Which descriptors should be used? Should the assessment be performed prospectively or retrospectively? How do we take account of widely varying contexts, individual preferences, and sociocultural diversities? How can measurement and monitoring be implemented worldwide?

This article explores these challenges, identifying potentially measurable indicators and ambiguities in their use, and offers recommendations towards a practical measurement framework. We aimed to define a concise, meaningful, and pragmatic set of indicators that could be collected and applied universally across countries and over time. We define a logic model of candidate variables at different conceptual levels and describe an empirical exercise for prioritising and operationalising these variables for measurement.

It is well known that the formation of fat deposits within muscle tissue is a feature of aging, and is also associated with a variety of muscle disorders. Here, researchers explore how exactly this infiltration of fat into muscle harms muscle function, with a focus on regenerative capacity. At present physical activity is the most reliable approach to prevent or reduce fat infiltration of muscle tissue, but it seems likely that at least some of the growing number of weight loss drugs in development, many of which improve upon GLP-1 receptor agonists by neither reducing calorie intake nor causing loss of muscle mass, will also be effective.

Adipose tissue acts as an energy storage as well as an endocrine organ. However, different fat depots, such as subcutaneous (SAT), visceral (VAT), and intramuscular adipose tissue (IMAT), have stark metabolic and phenotypic differences. IMAT, the accumulation of adipocytes between individual myofibers within skeletal muscle, is a pathological hallmark of muscular dystrophies, but it is also present in a spectrum of metabolic disorders, including diabetes, obesity, and sarcopenia. The progressive infiltration of IMAT within muscle tissue has been closely associated with loss of muscle mass, metabolic dysfunction, disease progression, and impairment of patient mobility.

The cellular origin of IMAT is a population of stem cells located in the muscle interstitium, called fibro-adipogenic progenitors (FAPs). In a healthy muscle, FAPs are critical in maintaining muscle mass during homeostasis and playing a central role in muscle regeneration. FAPs secrete pro-myogenic factors to aid the cellular origin of muscle fibers, muscle stem cells (MuSCs), in their differentiation process toward myofibers. With age and disease, however, FAPs can also differentiate into either adipocytes, leading to IMAT formation or myofibroblasts, giving rise to fibrosis.

To understand the influence of IMAT on skeletal muscle, we created a conditional mouse model, termed mFATBLOCK that blocked IMAT formation by deleting peroxisome proliferator-activated receptor gamma (Pparγ) from FAPs. This deletion had no effect under normal conditions but successfully prevented IMAT accumulation after an adipogenic injury. Mechanistically, our data argues that IMAT acts as a physical barrier and prevents new nascent myofiber formation during early regeneration, as well as myofiber hypertrophy during the later regenerative phase. Consequently, this results in a functionally weakened muscle that has both fewer and smaller myofibers.

Link: https://doi.org/10.1016/j.celrep.2025.116021

The high blood pressure of hypertension is harmful to tissues throughout the body. Pressure damage directly damages tissue structure, disrupts tissue function, and alters cell behaviors for the worse. This is particularly harmful to the brain, as brain tissue has only a limited capacity for regeneration following rupture of small blood vessels and consequent cell death. More subtly, increased pressure disrupts the normal operation of the blood-brain barrier that lines blood vessels passing through the brain. This allows leakage of inappropriate cells and molecules into the brain to provoke persistent inflammation, an important contribution to neurodegenerative conditions.

Hypertension increases the risk for cognitive impairment and promotes vascular and renal inflammation. We tested if immune cell infiltration occurs in the brain during hypertension and if it is associated with cognitive impairment. Male C57Bl/6 mice were administered angiotensin II or aldosterone as an experimental model of hypertension. This increased blood pressure and promoted blood-brain barrier dysfunction, leukocyte accumulation in the brain, and impairment of working memory.

When co-administered with angiotensin II, the antihypertensive medication hydralazine prevented the development of these changes. In a separate cohort of mice in which angiotensin II-induced changes were first established, intervention with hydralazine lowered blood pressure but did not reverse brain inflammation or cognitive impairment. Finally, angiotensin II infusion altered the transcriptomic profile of the whole brain, as well as specifically within the hippocampus, and co-treatment with hydralazine modulated these changes.

In conclusion, experimental hypertension leads to brain inflammation and was associated with impaired working memory. Cognitive impairment that develops during hypertension can be inhibited, but not readily reversed, by anti-hypertensive therapy.

Link: https://doi.org/10.1016/j.bbih.2025.101059

Fruit flies are used as a model of intestinal aging primarily because this aspect of aging drives mortality in that species. We can say that flies die from intestinal dysfunction in the same way that we can say that humans die from cardiovascular dysfunction; it isn't the whole story by any means, but it is a sizable chunk of the story and the most common cause of mortality. So whenever one reads research materials on the topic of the aging of intestinal tissue, it is reasonable to expect fruit flies to be involved in that work at some point.

In today's open access paper, researchers present an interesting finding regarding mechanisms of intestinal tissue maintenance and aging. Because enterocyte cells in the intestinal epithelium do not turn over all that rapidly, an early life injury that provokes greater turnover for a time has the side-effect of making a fly more resilient to later age-related damage and dysfunction. The intervention doesn't have to be injury, as fasting also provokes greater turnover of enterocytes. Anything that allows some degree of replacement of enterocytes in adult life will lead to a long-term resilience to age-related intestinal dysfunction.

Age mosaic of gut epithelial cells prevents aging

Similar age-related structural and functional declines have been reported in the aging mammalian and Drosophila intestines. The Drosophila midgut epithelium has emerged as a model system for the study of aging genetically, and contributes to the understanding of the mechanisms of mammalian intestinal aging. The Drosophila midgut epithelium is a monolayer tissue composed of self-renewing intestinal stem cells (ISCs) that divide asymmetrically to give rise to enteroblasts (EBs) that differentiate into absorptive polypoid enterocytes (ECs) or enteroendocrine progenitor cells that give rise to a pair of enteroendocrine cells (EECs). In old flies, the midgut epithelium exhibits hyperplasia and barrier disruption, which associates with fly death.

However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we show that early midgut injury prevents the abrupt onset of aging hyperplasia and extends lifespan in flies. Daily transcriptome profiling and lineage tracing analysis show that the abrupt onset of aging hyperplasia is due to the collective turnover of developmentally generated "old" enterocytes (ECs). Early injury introduces new ECs into the old EC population, forming the epithelial age mosaic. Age mosaic avoids collective EC turnover and facilitates septate junction formation, thereby improving the epithelial barrier and extending lifespan. Furthermore, we found that intermittent time-restricted feeding benefits health by creating an EC age mosaic. Our findings suggest that age mosaic may become a therapeutic approach to reverse aging.

Cerebral small vessel disease is the term given to a noteworthy level of dysfunction in the small blood vessels of the brain, a big tent category that includes endothelial dysfunction, blood-brain barrier leakage, stiffening of vessels, and the damage left by minor vessel rupture. Clinicians diagnose small vessel disease in the brain typically as a result of scans in hypertensive patients who had a stroke or exhibit cognitive dysfunction and for whom imaging shows a sizable burden of hyperintensity lesions, small volumes of dead and damaged brain tissue resulting from the rupture of small vessels.

Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia. Ageing, hypertension, hyperglycaemia, and smoking make up the biggest risk factors for cSVD. They individually or collectively increase the levels of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases, decrease the bioavailability of nitric oxide, and, in the process, compromise the structural integrity and function of the vascular endothelium, blood-brain barrier, and brain parenchyma. These then appear as white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and atrophy in cerebral imaging.

As there is currently no curative therapy for cSVD, prevention or delay of cSVD remains of particular importance to preserve quality of life for as long as possible. Bearing that in mind, this review explores whether drugs used for other neurovascular conditions may prevent neuroinflammation and oxidative damage and effectively maintain endothelial function and blood-brain barrier integrity. It also examines whether potential benefits may be extended to cSVD. The list of drugs includes anti-anginal drugs, acetylcholine esterase inhibitors, β-hydroxy β-methylglutaryl-CoA reductase inhibitors, lithium drugs, phosphodiesterase inhibitors, oral antihyperglycaemic drugs, and tetracycline antibiotics. This review discusses the mechanisms of action of these agents and critically evaluates preclinical, translational, and clinical research pertaining to cSVD.

Link: https://doi.org/10.3390/cimb47040232

Specific receptors on the surface of immune cells enable these cells to ingest and clear specific forms of metabolic waste. Receptors are proteins that are produced via the usual mechanisms of gene expression. The amount produced can change with age and circumstances, as epigenetic regulation of gene expression changes, and this will affect the ability of immune cells to act against specific targets. Researchers here report on the ability of the innate immune cells known as microglia to clear excess amyloid-β from the brain, and show that it is dependent on expression of the ADGRG1 receptor. In severe Alzheimer's disease, microglia lack sufficient ADGRG1 to effectively clear plaque. Whether this is a contributing cause of Alzheimer's disease rather than a side-effect remains to be demonstrated conclusively, but this is far from the only data suggesting that microglial dysfunction is important in neurodegenerative conditions.

In Alzheimer's disease, proteins like amyloid beta form clumps, known as plaques, that damage the brain. But in some people, immune cells called microglia break down these proteins before they can cause harm. This leads to fewer and smaller clumps - and much milder symptoms. Researchers identified a protein called ADGRG1 that enables microglia to gobble up and digest plaques. When the researchers removed this protein, which is a kind of receptor, from mice, their microglia barely nibbled on the plaques. This led to the rapid buildup of plaques, neurodegeneration and problems with learning and memory.

When the researchers reanalyzed a prior study of gene expression in the human brain, they found that individuals who died while exhibiting mild Alzheimer's had microglia with lots of these receptors, and mild cognitive impairment - implying that the microglia ate well and kept the disease in check. But in those who died of severe Alzheimer's, the microglia had very few of the receptors, and the plaques proliferated. ADGRG1 is part of a large family of receptors, called G protein-coupled receptors, that are routinely targeted in drug development. This bodes well for a rapid translation of the discovery into new therapies.

Link: https://www.ucsf.edu/news/2025/07/430411/immune-cells-eat-molecular-trash-to-keep-alzheimers-bay

In today's open access paper, researchers report on correlations between phenotypic age and cognitive function in older adults. Phenotypic age is an aging clock that uses a small number of blood chemistry measures as its inputs, such as portions of a complete blood count, creatine, C-reactive protein, and so forth. The big advantage of this approach over epigenetic clocks is that one can look at what changed following an intervention and theorize a little about what that means. Did C-reactive protein levels go down in the course of a reduction in phenotypic age, for example? That indicates positive effects on the chronic inflammation characteristic of later life. This sort of reasoning remains impossible for epigenetic clocks at the present time. One can see what changed, which CpG sites on the genome are differently methylated in the sample, but there is no connection from there to the rest of our biochemistry. It is a dead end.

The most interesting outcome reported in today's study is that chronological age fails to correlate with cognitive function. We might take this as hopeful. Cognitive decline is not inevitable in a normal human life span, even given the universal operation of mechanisms of degenerative aging, and even given the paucity of interventions to slow aging beyond exercise and lifestyle choice. Accelerated phenotypic age does correlate with a decline in cognitive function in the study population, and we might take this as the usual cautionary tale about taking better care of one's long-term health. The data suggests that these differences are largely a matter of exercise and physical fitness.

Aging acceleration, not chronological age, is associated with cognitive performance in older adults: A cross-sectional study on the protective role of physical activity

Cognitive decline in older adults is a growing public health concern, and traditional measures such as chronological age are insufficient for accurately assessing cognitive function. Phenotypic age (PhenoAge) and phenotypic age acceleration (PhenoAgeAccel), which reflect biological age and aging acceleration, may be better predictors of cognitive decline. Additionally, physical activity (PA) has been recognized for its protective effects on aging and cognitive health. This study explored the role of PhenoAge and PhenoAgeAccel in cognitive performance and investigated whether PA moderates this relationship.

We used data from the National Health and Nutrition Examination Survey, which analyzed 1,298 participants aged 60 years and older. PhenoAge was calculated using 10 biomarkers, and PhenoAgeAccel was derived as the difference between chronological age and PhenoAge. Cognitive performance was assessed using the Digit Symbol Substitution Test. The relationship between PhenoAge, PhenoAgeAccel, and low cognitive performance was analyzed using weighted logistic regression models. Subgroup and sensitivity analyses were conducted, and the interactions between PhenoAgeAccel and PA were evaluated.

Both PhenoAge and PhenoAgeAccel scores were significantly associated with low cognitive performance. The highest quartiles of PhenoAge (odds ratio = 3.22) and PhenoAgeAccel (odds ratio = 2.31) were associated with higher odds of low cognitive performance. By contrast, chronological age did not show a significant relationship with cognitive performance. PA was found to moderate the association between PhenoAgeAccel and cognitive performance. Higher levels of PA attenuated the impact of PhenoAgeAccel on cognitive decline. Receiver operating characteristic curve analysis showed that PhenoAge (area under the curve [AUC] = 0.562), PhenoAgeAccel (AUC = 0.589), and chronological age (AUC = 0.513) were significantly different. In conclusion, PhenoAgeAccel and PA are significant predictors of cognitive decline, with PA offering a protective effect against the impact of accelerated aging on cognition.

A number of variants of the FOXO3 gene are associated with greater longevity, which researchers believe may be due to an altered distribution of different forms of the FOXO3 protein. Here, researchers note a study in which a human pluripotent cell line was engineered with a favorably altered FOXO3 sequence and differentiated into mesenchymal progenitor cells. These cells were injected into aged monkeys, producing an across the board improvement in measures of health and function. This is much as one would expect from a good stem cell therapy repeated over time, but it is unclear as to whether the mechanisms involved go beyond a suppression of age-related chronic inflammation. Generally, transplanted cells die quickly. Beneficial effects are derived from the signals that they produce, favorably altering the behavior of native cells for a time. The most reliable outcome is reduced inflammation.

FOXO3 is a well-established regulator of longevity, stress resistance, and stem-cell maintenance. In a pioneering effort to reprogram aging-related genetic circuits, researchers introduced two phospho-null mutations (S253A and S315A) to eliminate phosphorylation sites into the FOXO3 locus, generating engineered human embryonic stem cells that, upon mesenchymal differentiation, gave rise to progenitor cells with enhanced stress resilience and self-renewal capacity - designated as senescence-resistant cells (SRCs).

Administering SRCs intravenously to aged cynomolgus monkeys over a 44-week period led to a cascade of restorative changes. Compared to wild-type mesenchymal cells, SRCs more effectively reversed age-related changes across the brain, immune system, bone, skin, and reproductive tissues. Multi-modal assessments-behavioral, histological, transcriptomic, and methylomic-consistently indicated biological age reversal.

Notably, SRC-treated monkeys exhibited improved cognitive function, restored cortical architecture, and enhanced hippocampal connectivity. Bone density increased, periodontal degeneration was mitigated, and immune cell transcriptional profiles shifted toward a youthful state. At the molecular level, transcriptomic aging clocks showed an average reversal of 3.34 years with SRCs, while DNA methylation clocks corroborated these effects in multiple tissues. Furthermore, the authors observed the restoration of reproductive system health. In both male and female monkeys, SRC treatment reduced senescent markers, enhanced germ cell preservation, and reversed transcriptional aging clock across ovaries and testes. Single-cell transcriptomics revealed that oocytes, granulosa cells, and testicular germ cells responded particularly well, rejuvenating by up to 5-6 years.

Link: https://doi.org/10.1093/lifemedi/lnaf022

Cartilage is a poorly regenerative tissue, one of the reasons why cartilage damage is a feature of aging and persistent consequences of joint injury. Nonetheless, cartilage is formed during development so in principle there must exist programs of regeneration that might be activated via suitable forms of therapy. Here, researchers use a targeted nanoparticle approach to deliver a therapeutic cargo into chondrocytes in damaged cartilage tissue. This caused an improvement in both mitochondrial function and capacity for regeneration.

Treating osteoarthritis (OA) presents a significant challenge due to the fact that conventional intra-articular injections only achieve superficial penetration and uncontrolled drug release. Here, amino-modified cationic mesoporous silica nanoparticles were covalently conjugated with cartilage-targeted peptides to form a Trojan horse-like architecture for enveloping the prochondrogenic fucoidan.

The hydrogel microsphere, consisting of photocurable gelatin methacryloyl (GelMA) and chondroitin sulfate methacryloyl (ChSMA), were fabricated using a microfluidic platform for cargo delivery. The cationic targeting nanoparticle-hydrogel microsphere@fucoidan (CTNM@FU) possess three-step programmable characteristics that enable responsive transport toward injured cartilage, effective penetration of the cartilage extracellular matrix and selective entry into chondrocytes, escape from lysosomes, and release of bio-activators.

The impaired cartilage metabolism was significantly reversed upon co-culturing with CTNM@FU. Intra-articular administration of CTNM@FU not only mitigated cartilage degeneration but also expedited de novo cartilage formation. Mechanistically, CTNM@FU protected cartilage by activating SIRT3, enhancing mitochondrial energy and countering aging. Collectively, a spatiotemporally guided strategy enables more precise treatments for degenerative joint disorders.

Link: https://doi.org/10.1016/j.xinn.2025.100913

An infrequently discussed topic in aging circles is the point that we should probably expect any therapy that improves tissue maintenance and regeneration in old people to also increase cancer risk. There isn't much in the way of evidence to support that position, but it seems worthy of consideration. Cancer is a numbers game, and the greater the activity undertaken by stem cells and progenitor cells, the greater the likelihood of cancerous mutations. The only exceptions are interventions that act to improve the function of the immune system in addition to any other benefits that they produce; such treatments could lead to a net reduction in cancer risk, due to improved immunosurveillance of potentially cancerous cells. A plausible example of this type of treatment is telomerase gene therapy, though it remains to be demonstrated that improved immune function is the mechanism by which cancer risk is reduced in animal studies.

With this in mind, researchers here show that too much klotho can increase cancer risk in cancer survivors. Cancer survivors exhibit a greater risk of later cancer mortality than other age-matched individuals. This is in part due to the risk of recurrence of the treated cancer, but also because chemotherapy and radiotherapy stress cell populations to produce an increased burden of cellular senescence in these patients. Greater levels of klotho correlate with greater longevity in the population at large, but to the degree that greater longevity goes hand in hand with increased cell activity, regenerative capacity, and tissue maintenance, then it will also increase the risk of cancer. It should be easier to quantify that risk in the epidemiological data for cancer survivors than in the general population, and hence this study.

Circulating Klotho and mortality patterns among US cancer survivors: A cohort study

Klotho, a longevity hormone, exerts diverse anticancer activities. However, evidence regarding the association between serum Klotho and mortalities among cancer survivors is lacking. We examined the association between serum Klotho and the risks of all-cause and cancer mortalities among 1602 cancer adults from the National Health and Nutrition Examination Survey (NHANES) (2007-2016) using multivariate Cox proportional hazard models. The nonlinear relationship was determined using the likelihood ratios test, and the inflection points and 2-piecewise Cox proportional hazards regression models were computed.

After a median follow-up period of 84.0 months, U-shaped associations between circulating Klotho and all-cause and cancer mortality were observed, with identified inflection points (pg/mL) of 765.5 for all-cause and 767.6 for cancer mortality. Klotho below these thresholds was inversely associated with all-cause mortality (Hazard ratio, HR = 0.72) and cancer mortality (HR = 0.61; Klotho above the threshold showed a trend of positive associated with cancer mortality (HR = 1.22). Effect modification of age was apparent; Klotho was associated positively with cancer mortality risk among participants aged under 60 (HR = 1.50). The U-shaped associations between serum Klotho and all-cause and cancer mortality indicate that maintaining an ideal Klotho level in cancer patients could reduce mortality risks.

When people talk about klotho, they usually mean α-klotho, and specifically the soluble fragment of α-klotho that is secreted by cells to circulate in the body. Researchers have demonstrated in animal studies that high levels of α-klotho slow aging to extend life while low levels accelerate aging to shorten life. In humans, higher circulating levels of α-klotho correlate with a lower risk of age-related disease and longer life expectancy, and vice versa. Enumerating the mechanisms by which α-klotho affects the pace of aging, and determining which are more or less important than the others, remains a work in progress. The research noted here is an example of this ongoing work, and is focused on the effects that α-klotho has on muscle tissue.

Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness.

Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation.

RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.

Link: https://doi.org/10.1101/2025.06.11.659129

Humans tend to die from cardiovascular aging, while flies tend to die from intestinal aging. The intestines of humans age and become dysfunctional, as they do in flies, of course. But intestinal aging usually isn't a severe enough cause of issues in and of itself to win out over cardiovascular disease, pulmonary disease, and the other more common causes of death. It may well contribute meaningfully to all of those other causes of mortality! The converse can be said for the aging of the cardiovascular system in flies; the consequences are usually less severe than those of intestinal aging in that species. Nonetheless, researchers spend a good deal of time with flies in the study of intestinal aging, as this review paper makes clear.

Intestinal aging is central to systemic aging, characterized by a progressive decline in intestinal structure and function. The core mechanisms involve dysregulation of epithelial cell renewal and gut microbiota dysbiosis. In addition to previous results in model organisms like Drosophila melanogaster, recent studies have shown that in mammalian models, aging causes increased intestinal permeability and intestinal-derived systemic inflammation, thereby affecting longevity. Therefore, anti-intestinal aging can be an important strategy for reducing frailty and promoting longevity.

There are three key gaps remaining in the study of intestinal aging: (1) overemphasis on aging-related diseases rather than the primary aging mechanisms; (2) lack of specific drugs or treatments to prevent or treat intestinal aging; (3) limited aging-specific dysbiosis research. In this review, the basic structures and renewal mechanisms of intestinal epithelium, and mechanisms and potential therapies for intestinal aging are discussed to advance understanding of the causes, consequences, and treatments of age-related intestinal dysfunction.

Link: https://doi.org/10.1016/j.apsb.2025.05.011