Fight Aging!

Mitochondria are power plants, hundreds of these organelles in every eukaryotic cell, descended from ancient symbiotic bacteria, and now repurposed to generate the chemical energy store molecule adenosine triphosphate (ATP) that is used to power cell processes. Beneath this simple overview lies a very complex and incompletely understood biochemistry. Mitochondria influence many core cell processes, and are influenced in turn. The oxidative byproducts generated by ATP production are both damaging and a signal that can be beneficial. Mildly impairing mitochondrial function can be beneficial to health, if accomplished in certain ways. And so forth. It is clearly the case mitochondria become dysfunctional in cells in aged tissues, as measured in many different ways, and this appears to be an important contribution to the aging process. What to do about it is unclear, however.

The best of presently available pharmacological and supplement based approaches that improve mitochondrial function or improve the quality control process of mitophagy responsible for clearing damaged mitochondria struggle to much improve on the benefits of exercise. It is also quite unclear in most cases as to how exactly they function to achieve this outcome, and bear in mind that the relevant biochemistry is itself still incompletely mapped out and understood. The most impressive results instead emerge in animal studies of partial reprogramming on the one hand, to reset expression of proteins necessary for mitochondrial function to youthful levels, and mitochondrial transplantation on the other, delivering functional young mitochondria for cells to make use of. Both of these technologies remain in relatively early stages of development, still far from the clinic.

Mitochondrial dysfunction in the regulation of aging and aging-related diseases

Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence.

In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responses that are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence.

Senescent cells accumulate in the aged body, generating a potent mix of pro-inflammatory signaling known as the senescence-associated secretory phenotype (SASP) that is disruptive to tissue structure and function. Over the last decade or so, researchers have devoted an increasing amount of time and effort into firstly understanding these cells, and secondly finding potential ways to reduce their contribution to age-related disease and mortality. While most efforts are directed towards the selective destruction of senescent cells via senolytic therapies, a growing number of projects are identifying senomorphic therapies that might reduce the SASP, and thereby reduce the harmful impact of lingering senescent cells. Such therapies would have to be taken continuously versus the intermittent use of senolytics, but nonetheless papers such as the one noted here are emerging on a regular basis.

Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age-related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored.

By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment.

Together, our study supports the feasibility of exploiting a redox-active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof-of-concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age-related conditions. Prospective efforts are warranted to determine long-term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.

Link: https://doi.org/10.1111/acel.70138

Researchers have investigated the favorable effects of hydrogen sulfide (H2S) on cell metabolism in the context of aging. An increased presence of H2S appears to modestly improve mitochondrial function and autophagy to some degree, thereby reducing oxidative stress and inflammation characteristic of aging. This functions via post-translational modification of important proteins via S-sulfhydration, changing their function. Like most approaches to metabolic manipulation, the effect size is not as large as we might like it to be, and the underlying biochemistry may overlap to some degree with responses to exercise and calorie restriction.

Hydrogen sulfide (H2S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial biosynthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.

The age-related decrease in endogenous H2S synthase leads to a decline in the level of S-sulfhydration modification of cysteine residues in target proteins, which ultimately promotes the accumulation of reactive oxygen species (ROS) in an age-dependent manner, thereby triggering DNA damage. Moreover, the reduction in intracellular protein S-sulfhydration is correlated with an age-related secretory phenotype, characterized by heightened secretion of inflammatory factors and chemokines, as well as impairment of the autophagy-lysosomal pathway. This leads to the onset of systemic chronic inflammation and ultimately contributes to inflammaging.

To date, numerous studies have emphasized the potential role of protein S-sulfhydration in addressing age and stress-related inflammatory disorders. In disease models such as arthritis and myocardial ischemia reperfusion injury (IRI), supplementation with exogenous H2S donors can effectively counteract cell senescence by promoting the nuclear entry of KEAP1/NRF2, reducing the membrane stability of the receptor RAGE, inhibiting the S-sulfhydration of the NF-κB p65 subunit, and decreasing oxidative stress along with the release of inflammatory factors. Nevertheless, there is a paucity of effective therapeutic interventions targeting age-related pathways. In this review, we offer a comprehensive overview of the current understanding of S-sulfhydration and its role in combating oxidative-inflammatory stress and cellular aging.

Link: https://doi.org/10.1016/j.jare.2025.06.038

Beyond killing cancerous cells, one of the major goals in traditional chemotherapy and radiotherapy treatment approaches has been to induce senescence in those cells that a therapy fails to kill outright. A senescent cell no longer replicates, and it is the uncontrolled replication of cancerous cells than makes cancer so dangerous. Therefore shutting down that replication was seen as a beneficial outcome, even if the cell survives. Over time, a greater understanding of senescent cells in the broader context of aging and age-related disease has led to a more nuanced view of therapy induced senescence in the context of cancer.

Senescent cells secrete inflammatory signals to attract the immune system, to make it pay attention to the local environment. But senescent cells also secrete pro-growth signals as a result of their role in regeneration following injury. The presence of some senescent cells for a short period of time is generally beneficial. The presence of many senescent cells for a lasting period of time is generally harmful. In the context of cancer, a small number of senescent cancer cells can help to engage the immune system in the process of killing cancerous cells. Too many senescent cancer cells can actually help the cancer by encouraging its growth and disrupting the operation of the immune system with excessive inflammatory signaling.

The established cancer therapies of chemotherapy and radiotherapy leave a burden of lingering senescent cells in cancer survivors. This is literally accelerated aging, and contributes to the higher risk of subsequent cancer and all cause mortality in those patients. It seems clear that the use of senolytic drugs to selectively destroy those lingering senescent cells should be beneficial, even though this has yet to be established as the standard of care. It is far less clear that using senolytic drugs during cancer therapy to kill senescent cells as they are created will be reliably beneficial. Whether it helps or hinders likely depends on factors that will be hard to determine and vary from patient to patient even for similar cancers.

When therapy-induced senescence meets tumors: A double-edged sword: A review

At present, it is widely recognized that conventional treatments for diseases such as cancer, including chemotherapy and radiation therapy, induce high levels of DNA damage in patient cells and lead to the secretion of numerous senescence-associated secretory phenotype (SASP) factors, thereby culminating in cellular senescence. This phenomenon is referred to as "therapy-induced senescence (TIS)." Chemotherapy, radiation therapy, and targeted therapies can promote cellular senescence in the tumor microenvironment (TME), affecting both cancer cells and their surrounding stromal cells. Prior investigations have shown that 31% to 66% of cancer tissues subjected to different types of chemotherapy display TIS. In addition, TIS has been quantified not only in malignant and nonmalignant fractions of tumor tissues but also in healthy tissue specimens after chemotherapy or radiation therapy. TIS is a common response to traditional cancer treatments. It was once considered a beneficial outcome of cancer therapy, and is currently regarded as a potential target for developing novel therapeutic approaches to inhibit cancer cells.

Tumor disease development, metastasis, medication resistance, and immunological evasion were all significantly influenced by the TME. It was used to assess the overall clinical outcomes of cancer treatment. Pharmacological induction may induce senescence in both malignant and nonmalignant tumor cells. In brief, TIS may affect the long-term prognosis of cancer by affecting TME. Significantly, the process of senescence triggers the activation of many pleiotropic cytokines, chemokines, growth factors, and proteases, which are together referred to as the SASP. This activation results in continuous arrest of tumor cells and remodeling of the tumor immune microenvironment. On the one hand, SASP can promote antitumor immunity and therapeutic efficacy; on the other hand, it can promote the infiltration of immune-suppressive cells, contributing to immune evasion by tumor cells. However, the specific effects of SASP in this context remain unclear.

The concept of a "one-two punch" approach for cancer treatment has been proposed, wherein the initial step involves the use of a drug to stimulate senescence in cancer cells and the second step involves the use of another drug (such as a senolytic) to eliminate senescent cancer cells. Cancer therapies stimulate senescence in both tumors and healthy tissues. Senescent cells are subsequently cleared through immune surveillance but may accumulate following cancer treatment. Despite the combination of traditional anticancer drugs and senolytics remaining in the early stages of research, reports have validated their effectiveness in suppressing tumor cells. Optimizing the beneficial effects of the SASP on the TME while mitigating its harmful effects, combined with therapeutic strategies that incorporate anticancer drugs, senolytics, and senomorphics, offers a promising new approach for future clinical treatments.

Of all of the pharmaceutical approaches to slowing aging, rapamycin has the best, most robust, largest body of evidence from animal studies. Rapamycin is an mTOR inhibitor, mimicking some of the beneficial effects of calorie restriction on metabolism, long-term health, and life span. The most important outcome is thought to be improved autophagy, the cell maintenance process responsible for recycling unwanted proteins and structures in the cell. While rapamycin has been widely used for a long time at relatively high doses, there remains comparatively little human data at lower, anti-aging doses. Still, what data there is paints the picture of a safe drug with few to no side-effects.

Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension from two such compounds, rapamycin and metformin, remains inconclusive, particularly in vertebrates. Here, we conducted a meta-analysis comparing lifespan extension conferred by rapamycin and metformin to DR-mediated lifespan extension across vertebrates. We assessed whether these effects were sex- and, when considering DR, treatment-specific.

In total, we analysed 911 effect sizes from 167 papers covering eight different vertebrate species. We find that DR robustly extends lifespan and, importantly, rapamycin - but not metformin - produced a significant lifespan extension. We also observed no consistent effect of sex across all treatments and log-response measures. Furthermore, we found that the effect of DR was robust to differences in the type of DR methodology used. However, high heterogeneity and significant publication bias influenced results across all treatments. Additionally, results were sensitive to how lifespan was reported, although some consistent patterns still emerged. Overall, this study suggests that rapamycin and DR confer comparable lifespan extension across a broad range of vertebrates.

Link: https://doi.org/10.1111/acel.70131

The protein α-synuclein misfolds and spreads from neuron to neuron in the nervous system to cause the pathology of Parkinson's disease. In Parkinson's patients, it has been found that T cells exhibit increased reactivity to α-synuclein. That may contribute to inflammation and disease progression, but here researchers show that this reactivity exists and is measurable before evident symptoms of Parkinson's disease emerge. Thus it may serve as the basis for a blood test to detect Parkinson's in its earliest stages.

A role of the immune system in Parkinson's disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells in the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and α-synuclein (α-syn), two Lewy body-associated proteins. Further, T cell reactivity towards α-syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown.

Here, we investigated T cell responses towards PINK1 and α-syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.

Link: https://doi.org/10.1038/s41531-025-01001-3

DNA damage is involved in degenerative aging, though there remains some debate over exactly how it can contribute meaningfully to widespread tissue dysfunction over and above the increased risk of cancer. Near all mutational damage to DNA is promptly repaired, while most of the lasting mutations occur in unused regions of the genome, in somatic cells with few divisions remaining. While most mutations can thus produce little harm, one possible path to broader damage results from mutations occurring in stem cells, which can spread widely throughout tissue to form overlapping patterns of mutations known as somatic mosaicism. There is some initial evidence for this to contribute to age-related conditions and loss of function. A more radical possibility is that repeated efforts to repair more severe forms of DNA damage, regardless of whether successful or not, deplete factors needed to maintain youthful control over genome structure and gene expression, and this gives rise to the characteristic changes observed in cells in aged tissues.

What can be done about stochastic DNA damage occurring in different places in different cells? Repairing this damage seems challenging, a project for the more distant future. Slowing down the accumulation of unrepaired damage seems more feasible, largely a matter of identifying crucial proteins in DNA repair machinery and providing more of them. Today's open access paper is an example of this approach. If, however, it is the case that even successful repair efforts inexorably give rise to changes in genome structure and cell behavior, this may not be all that effective in slowing aging. Reducing cancer incidence, yes, as that is absolutely driven by the burden of unrepaired mutational damage, but perhaps not so great for the rest of aging.

The Redox Activity of Protein Disulphide Isomerase Functions in Non-Homologous End-Joining Repair to Prevent DNA Damage

DNA damage is a serious threat to cellular viability, and it is implicated as the major cause of normal ageing. Hence, targeting DNA damage therapeutically may counteract age-related cellular dysfunction and disease, such as neurodegenerative conditions and cancer. Identifying novel DNA repair mechanisms therefore reveals new therapeutic interventions for multiple human diseases.

In neurons, non-homologous end-joining (NHEJ) is the only mechanism available to repair double-stranded DNA breaks (DSB), which is much more error prone than other DNA repair processes. However, there are no therapeutic interventions to enhance DNA repair in diseases affecting neurons. NHEJ is also a useful target for DNA repair-based cancer therapies to selectively kill tumour cells.

Protein disulphide isomerase (PDI) participates in many diseases, but its roles in these conditions remain poorly defined. PDI exhibits both chaperone and redox-dependent oxidoreductase activity, and while primarily localised in the endoplasmic reticulum it has also been detected in other cellular locations. We describe here a novel role for PDI in DSB repair following at least two types of DNA damage. PDI functions in NHEJ, and following DNA damage, it relocates to the nucleus, where it co-localises with critical DSB repair proteins at DNA damage foci. A redox-inactive mutant of PDI lacking its two active site cysteine residues was not protective, however. Hence, the redox activity of PDI mediates DNA repair, highlighting these cysteines as targets for therapeutic intervention.

The therapeutic potential of PDI was also confirmed by its protective activity in a whole organism against DNA damage induced in vivo in zebrafish. Hence, harnessing the redox function of PDI has potential as a novel therapeutic target against DSB DNA damage relevant to several human diseases.

Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body, but with a portfolio of duties that also includes assisting in the maintenance and function of neural networks. With age, microglia become more inflammatory and active, and this contributes to the onset and progression of neurodegenerative conditions. There are many known contributing causes, one of which is the mitochondrial dysfunction that occurs in cells throughout the body.

The best way to determine just how much of the problem of inflammatory microglia is downstream of mitochondrial dysfunction is to fix that dysfunction, but the presently available approaches that improve mitochondrial function in aged tissues (vitamin B3 derivatives, mitoQ, urolithin A, and so forth) are not powerful enough to make a sizable difference. It may be that mitochondrial transplantation therapies will be needed in order to robustly determine whether fixing mitochondria can slow or reverse neurodegenerative conditions to a useful degree.

Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neuro­degenerative diseases, such as Alzheimer's disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases.

Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function.

This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.

Link: https://doi.org/10.3164/jcbn.24-202

Senescent cells serve a useful function in younger life when they emerge transiently in response to injury and forms of cell stress and damage. Such cells are rapidly cleared by programmed cell death or by the immune system. Unfortunately the aging of the immune system and rising levels of cell and tissue damage ensures that senescent cells accumulate with age to disrupt tissue structure and function with their inflammatory secretions. Based on animal study evidence, this appears to be an important contribution to degenerative aging. In mice, clearing senescent cells produces rapid rejuvenation of many aspects of aging and reversal of many forms of age-related disease.

Cellular senescence occurs at all stages of life and is an important physiological mechanism of tissue remodeling during embryogenesis, antitumor protection, and wound healing. At the same time, increasing numbers of senescent cells in tissues is associated with aging of the organism, and senescence is also a pivotal determinant in the development and progression of chronic age-related diseases. Macromolecular damage accumulating in senescent cells leads to dysfunction of organelles, disruption of the secretory activity of the cell with the development of the senescence-associated secretory phenotype (SASP), and structural changes in cells. In turn, SASP factors induce the senescence of microenvironmental cells through paracrine and endocrine pathways.

Since it is well-known that the accumulation of senescent cells is associated with aging and the development of age-associated diseases, targeting of senescent cells is now considered as the most promising strategy for longlife intervention. Geroprotective preparations are represented by small-molecule compounds exhibiting cytotoxicity toward senescent cells (senolytics) and therapeutics inhibiting oxidative stress and harmful effects of SASP (senomorphics). Novel anti-aging approaches include immunotherapy directed at surface antigens specifically upregulated in senescent cells; in particular, chimeric antigen receptor (CAR) therapies and senolytic vaccines.

Senescent cells exhibit considerable heterogeneity, which complicates the development and implementation of geroprotective therapy. The hallmarks of senescent cells depend on tissue type and the phenotype of senescent cells. However, among the variety of bioactive substances, signaling pathways, and structural rearrangements associated with cellular aging, it is difficult to identify a universal marker of senescent cells. Given the complexity of detecting senescent cells, further studies should be conducted to reveal features of cellular aging using modern methods based on omics technologies with bioinformatics data analysis to develop relevant models for the assessment of cellular senescence.

Link: https://doi.org/10.3390/ijms26115390

The creation of effective regenerative therapies for the aging heart is an area of active research and development. Cell therapies based on delivery of cardiomyocytes proved to be challenging, as just as in every other early approach to cell therapy, near all transplanted cells fail to survive. More recently researchers have engineered tissue patches made up of cardiomyocytes and supporting artificial extracellular matrix structures made of hydrogels and other materials. When such a patch is applied to injured heart tissue, it allows more of the transplanted cells to survive, resulting in the generation of healthy tissue.

The natural extracellular matrix of the heart undergoes change with age. This aging of the extracellular matrix is nowhere near as well studied as the aging of cells, yet it is considered important as a contributing factor in the age-related disruption of tissue function. Given the efforts to generate engineered tissue to repair aged hearts, there is a growing interest in better understanding the aging of the extracellular matrix and how the various signals involved might be relevant to building better tissue patches. Today's open access paper is illustrative of this line of research and development.

Hybrid hydrogel-extracellular matrix scaffolds identify biochemical and mechanical signatures of cardiac ageing

Cardiac fibroblasts (CFs) are the resident cells largely responsible for the remodelling of heart tissue and are known to be mechanosensitive. In healthy tissue, CFs largely remain in a quiescent state, but external stimuli, including biochemical, structural, and mechanical cues, are able to activate quiescent CFs, leading to their differentiation into a proto-myofibroblast phenotype and subsequently into a mature myofibroblast phenotype when these stimuli are impactful and persistent. The process of CF activation and proper myofibroblast maturation are essential for extracellular matrix (ECM) deposition and the maintenance of matrix homeostasis but can also lead to fibrosis and result in functional consequences. This is important in ageing tissues, as alterations in the ECM can be vast and multifaceted, thereby leading to the activation of CFs and subsequent aberrant tissue remodelling.

Indeed, it has been shown that myofibroblasts are more abundant in aged versus young hearts and directly induce changes to the tissue geometry. Although in vitro material systems have identified individual properties of the ECM that play distinct roles in CF function, it remains a challenge to vary these properties independently. In most scaffold platforms, tuning the mechanical properties will alter the ligands and/or architecture. A handful of novel material systems have been described that are capable of independent tunability, yet the incorporation of native ECM properties is still lacking. Thus, our understanding of the specific contributions stemming from ECM cues is currently limited. We, therefore, sought to develop a native ECM-based scaffold in which we could individually tune the mechanics and faithfully mimic the in vivo cardiac environment - both composition and architecture - allowing for the identification of ECM-specific roles in age-related CF activation, mechanosensing, matrix remodelling, and senescence.

Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid scaffold that independently confers two distinct matrix properties - ligand presentation and stiffness - to cultured cells in vitro, allowing for the identification of their specific roles in cardiac ageing. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, whereas its mechanical properties can be independently tuned to mimic young or aged tissue stiffness. Seeding these scaffolds with murine primary cardiac fibroblasts, we identify distinct age- and matrix-dependent mechanisms of cardiac fibroblast activation, matrix remodelling, and senescence. Importantly, we show that the ligand presentation of a young extracellular matrix can outweigh the profibrotic stiffness cues typically present in an aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent ageing dysfunction and promote rejuvenation.

One of the primary goals in the field of comparative biology is to produce a sufficient understanding of the proficient regeneration exhibited by species such as salamanders and zebrafish to enable similar feats of complete regeneration from severe injury in mammals. Progress has been slow, as it is a challenging problem. While a number of lines of evidence suggest that mammals still possess the molecular machinery necessary to regenerate organs, such as the exceptional regenerative capacity of MRL mice, it remains unclear as to why this machinery is inactive in near all circumstances.

Tissue regeneration requires a complex cellular choreography that results in restoration of missing structures. Salamander limb regeneration is no exception, where mesenchymal cells, including dermal fibroblasts and periskeletal cells, dedifferentiate into a more embryonic-like state and migrate to the tip of the amputated limb to form a blastema. Mesenchymal cells within the blastema contain positional information which coordinates proximodistal (PD) pattern reestablishment in the regenerating limb, enabling autopod-forming blastema cells to distinguish themselves from stylopod-forming blastema cells.

It has been proposed that continuous values of positional information exist along the PD axis and that thresholds of these values specify limb segments. These segments are genetically established by combinations of homeobox genes including Hox and Meis genes, and each limb segment contains a unique epigenetic profile around these homeobox genes. However, a mechanistic explanation for how continuous values of positional information are established and differentially interpreted by limb segments during limb regeneration is lacking.

Here, we show that retinoic acid (RA) breakdown via CYP26B1 is essential for determining RA signaling levels within blastemas. CYP26B1 inhibition molecularly reprograms distal blastemas into a more proximal identity, phenocopying the effects of administering excess RA. We identify Shox as an RA-responsive gene that is differentially expressed between proximally and distally amputated limbs. Ablation of Shox results in shortened limbs with proximal skeletal elements that fail to initiate endochondral ossification. These results suggest that PD positional identity is determined by RA degradation and RA-responsive genes that regulate PD skeletal element formation during limb regeneration.

Link: https://doi.org/10.1038/s41467-025-59497-5

The exposome is the omics-styled name given to the full breadth of environmental factors that impact health, aging, and the operation of our biochemistry in general. Well studied aspects of the exposome include particulate air pollution, heavy metal exposure, and a broad range of diet and lifestyle choices. This short review paper provides a high level overview of present thought on the role of exposome components in the onset and progression of age-related conditions.

The exposome encompasses all the environmental factors that a person encounters in its lifetime affecting biological processes and the overall health of the individual. The exposomes range from air- and water-polluting agents to diet and lifestyle choices and occupational hazards. Such environmental components, if prolonged, may lead to accelerating cellular aging, the disruption of metabolism, or an increase in chronic diseases including cardiovascular diseases, diabetes, or cancer. Environmental toxins and lifestyle factors are also associated with the later development of neurodegenerative diseases such as Alzheimer's and Parkinson's.

This review describes how the exposome influences aging with emphasis on mechanistic focus and offers potential strategies to counteract the adverse effects of the exposome on health. First, we provide a basic structure, concerning environmental exposure and its impact on aging. Next, we examine the role of oxidative stress, inflammation, and epigenetic modifications. Then we discuss advancement in exposome research and how the exposome is related to neurodegenerative diseases. We eventually propose future directions and preventive strategies that will reduce the risk of exposomes and aging positively.

Link: https://doi.org/10.4103/jpbs.jpbs_599_25

Exercise to maintain physical fitness remains one of the most cost-effective approach to slowing aging. It clearly works, and even if the effect size is smaller than we'd all like it to be, it costs little more than time and effort. Of the various other approaches to achieving slowed aging or rejuvenation that have an established body of robust animal data, only calorie restriction, first generation senolytics to clear senescent cells, and mTOR inhibition as a calorie restriction mimetic strategy improve on the results of physical activity.

The dose-response curve for exercise is particularly steep when moving from no physical activity to some physical activity. Human epidemiological data suggests that there is a sizable difference between being sedentary and undertaking 30 minutes of moderate exercise once a week. Today's study is essentially a comparison between (a) people who undertake little to no exercise and (b) people who undertake at least some exercise. The little to no exercise group is evidently worse off.

Physical Activity Is Associated With Decreased Epigenetic Aging: Findings From the Health and Retirement Study

Epigenetic aging measures or clocks are DNA methylation-based indicators of biological aging, linked to health outcomes and disease risk. Physical activity and exercise may influence epigenetic aging, suggesting a pathway through which it promotes healthier aging and reduces chronic disease burden. In this study, we assessed the association between self-reported moderate-to-vigorous physical activity and epigenetic age acceleration (EAA) in participants of the Health and Retirement Study, followed biennially for 12 years from 2004 to 2016.

Leukocyte DNA methylation was measured from venous blood samples collected in 2016 and second-generation epigenetic clocks (GrimAge, PhenoAge, and DunedinPACE) were used to assess EAA. Physical activity was assessed at each wave, with participants reporting vigorous activity at least once per week or moderate activity more than once per week or more categorized as 'physically active'.

In 2016, 58% of the participants were classified as physically active. In cross-sectional analysis, physically active participants had lower EAA than inactive participants: -1.26 years for GrimAge acceleration, -1.70 years for PhenoAge acceleration, and -0.05 years per chronological year for DunedinPACE.

Our findings highlight physical activity as a robust factor associated with slower epigenetic aging, with both accumulation and concurrent physical activity as the strongest predictors. These results underscore the role of physical activity in promoting healthier biological aging, suggesting its potential as a target for interventions aimed at mitigating age-related health decline.

The progressive blindness of glaucoma arises from pressure damage to the retina, the proximate cause being the presence of too much aqueous humor in the eye. The underlying causes are more complex and less well understood. As is the case for raised blood pressure, however, there are any number of ways to influence relevant mechanisms in order to control pressure without actually addressing the root cause damage and dysfunction of aging. Here, for example, researchers interfere in the expression of proteins critical in the production of aqueous humor, resulting in reduced pressure in the eye.

Glaucoma is a major global cause of irreversible vision loss. It is marked by elevated intraocular pressure (IOP) and the loss of retinal ganglion cells (RGC). While there are medical and surgical therapies for glaucoma aiming to reduce aqueous humor production or enhance its drainage, these treatments are often inadequate for effectively managing the disease.

In this study, we developed a targeted therapy for glaucoma by knocking down two genes associated with aqueous humor production (aquaporin 1, AQP1, and carbonic anhydrase type 2, CA2) using Cas13 RNA editing systems. We demonstrate that knockdown of AQP1 and CA2 significantly lowers IOP in wild-type mice and in a corticosteroid-induced glaucoma mouse model. We show that the lowered IOP results from decreasing aqueous production without affecting the outflow facility; this treatment also significantly promotes RGC survival as compared with untreated control groups.

Therefore, CRISPR-Cas-based gene editing may be an effective treatment to lower IOP for glaucomatous optic neuropathy.

Link: https://doi.org/10.1093/pnasnexus/pgaf168

The activities and interactions of insulin, growth hormone, and insulin-like growth factor 1 (IGF-1) signaling are collectively one of the better studied influences on the pace of aging in animal models. Impaired IGF-1 signaling slows aging and extends life, affecting pathways known to be involved in the calorie restriction response, such as those involving mTOR. Sabotaging growth hormone signaling has even more dramatic effects. Here, researchers link these benefits to mitochondrial quality by showing that mice with impaired mitochondrial function due to excessive mitochondrial DNA mutations do not benefit from reduced IGF-1 signaling. The positive influences on pace of aging deriving from reduced IGF-1 signaling require intact and functional mitochondria. Since mitochondria become damaged and dysfunction with age, this is an interesting finding.

A large body of evidence supports the idea that instability of the mitochondrial genome (mtDNA) leads to a progressive decline in mitochondrial function, which accelerates the natural aging process and contributes to a wide variety of age-related diseases, including sarcopenia, neurodegeneration, and heart failure. A similar body of work describes the role of IGF-1 signaling in the aging process. IGF-1 regulates the growth and metabolism of human tissues, and reduced IGF-1 signaling can not only extend mammalian lifespan, but can also confer resistance against various age-related diseases, including neurodegeneration, metabolic decline, and cardiovascular disease. However, how mitochondrial mutagenesis and IGF-1 signaling interact with each other to shape mammalian lifespan remains unclear.

We found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Link: https://doi.org/10.1101/2025.06.03.656903

A peroxisome is one of the many different varieties of membrane-bound organelle found in eukaryotic cells, a feature of organisms ranging from nematode worms to flies to mice to humans. The peroxisome is involved in oxidative reactions and lipid metabolism, such as conducting beta-oxidation of fatty acids, and both manufacture and scavenging of oxidative molecules such as hydrogen peroxide. Core cell functions of this nature are well understood in isolation, but the program of mapping out how these functions change with age, how they all interact with one another, and the degree to which they are relevant to age-related dysfunction in cells, tissues, and organs, is both much more challenging and at a much more rudimentary stage.

In today's open access preprint paper, the authors note that the peroxisome is particularly understudied in the context of aging. They have demonstrated that the number of peroxisomes in cells declines systemically in early aging in nematode worms. Interfering in this process to maintain the presence of peroxisomes in cells into later life improves health and slows aging. Interestingly, it appears to do so by maintaining youthful mitochondrial structure and function. Why this is the case is an open question; clearly expression levels of mitochondrial proteins are favorably altered, but it is unclear as to what about the continued presence of peroxisomes in the cells of aged animals achieves that outcome.

Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria

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

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

Our data supports a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

As a general rule, the organizers of clinical trials for the treatment of age-related diseases do all they can to focus on the least aged people possible. In this they are following the incentives placed upon them by regulators and investors, to try to avoid medical issues and deaths that occur for reasons unrelated to the treatment under assessment. One unlucky death or serious medical issue can sink an early stage trial, a program, or a company, regardless of cause, and very old people exhibit a high risk of such outcomes. So industry and academia ends up in the interesting position of not actually assessing potential age-slowing and rejuvenation therapies in the people who are most in need of such treatments. This seems a hard problem to fix, given the reasons why it exists.

Despite the growing numbers, older people remain systematically underrepresented in clinical trials (CTs) - creating what may be the most significant evidence gap in modern medicine. Systematic exclusion of older adults with multimorbidity, frailty, cognitive impairment, or those in long-term care settings creates a critical gap whereby clinicians must extrapolate treatment decisions from evidence derived predominantly from younger, healthier populations. This evidence gap cascades into inadequate clinical practice guidelines and suboptimal care standards, ultimately compromising care quality and patient safety for the very populations who most need evidence-based interventions.

Even when CTs do include older adults, they often employ restrictive eligibility criteria that exclude those with common geriatric conditions. The Systolic Blood Pressure Intervention Trial (SPRINT) exemplifies these limitations. Despite including participants aged ≥75 years with dedicated subgroup analyses, SPRINT excluded individuals with diabetes, prior stroke, heart failure, dementia, polypharmacy, and nursing home residence - conditions prevalent among older adults. This selective recruitment yielded a study population divergent from real-world older patients, potentially compromising external validity when extrapolating findings to broader older populations.

Link: https://doi.org/10.1016/j.jnha.2025.100597

In the matter of the aging of the brain, researchers are increasingly turning their attention to inflammatory dysfunction in the immune system of the central nervous system, particularly the innate immune cells known as microglia, analogous to macrophages elsewhere in the body. Neurodegenerative conditions are characterized by excessive unresolved inflammation in brain tissue, a state that is disruptive to tissue structure and function, altering cell behavior for the worse. As the paper noted here illustrates, research into how this inflammation arises, and how dysfunction emerges in microglia, is proceeding one gene at a time, looking for important regulatory mechanisms and points of intervention.

There is little understanding of how aging serves as the strongest risk factor for several neurogenerative diseases. Specific neural cell types, such as microglia, undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear.

The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function.

We show that TIMP2 deletion exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, increased microgliosis, and increased levels of stress and inflammatory proteins measured in the brain extracellular space by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increased microglial activation and altered myelin phagocytosis.

Treating aged mice with TIMP2 reversed several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a key modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

Link: https://doi.org/10.1101/2025.05.20.655226

Genes consist of exon sequences and intron sequences that, once transcribed into RNA, are spliced together to form the final RNA molecule. Exons are usually included and introns usually excluded, but many genes can encode for multiple different RNA molecules via alternative splicing arrangements. The regulation of RNA splicing is complex, and like all complex aspects of our biochemistry it becomes dysfunctional with advancing age. The proportions of normal versus alternative splicing are altered, and outright incorrect RNA molecules can be formed as well.

It remains an open question as to the degree to which RNA splicing dysfunction is an important contribution to degenerative aging. Clearly it can cause harm, but as is the case for much of aging, it is hard to assess whether this harm is meaningful in comparison to other causes of damage, dysfunction, and cell stress. Today's open access paper is one example of a range of evidence that supports a greater rather than lesser role for RNA splicing dysfunction in aging. While focused on one tissue only, if harms can be shown in one location in the body it is reasonable to think they are occurring elsewhere as well.

A related open question is whether it is worth attempting to find ways to directly correct the operation of RNA splicing in aged cells versus attempting to identify and fix the underlying causes of RNA splicing dysfunction. One might expect RNA splicing dysfunction to be downstream of epigenetic changes characteristic of aging, as epigenetic change can cause a reduction in the production of critical molecular machinery or imbalances in the relative numbers of specific molecules needed for RNA splicing. There is the hope that success in developing therapies based on partial reprogramming will address RNA splicing dysfunctions and many other issues by resetting epigenetic marks into a more youthful state. But this remains to be seen, and a number of groups are pursing other approaches that may improve the operation of RNA splicing to some degree.

Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice

Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries.

Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, mitochondrial genes were disproportionately affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a truncated isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased reactive oxygen species (ROS) production.

Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.

Researchers here process epidemiological data to arrive at an estimate of the contribution of cytomegalovirus infection to age-related disease. This assumes causation to arrive at these numbers, comparing infection status with presence or absence of specific age-related conditions. Cytomegalovirus is a very prevalent form of persistent herpesvirus infection, with upwards of 90% of older individuals testing positive for its presence. It is thought that cytomegalovirus infection is disruptive to the aged adaptive immune system, either generating excess inflammatory signaling, or driving expansion of memory T cells dedicated to this virus at the expense of T cells capable of responding to novel threats. This in turn contributes to a faster onset and progression of age-related conditions.

Cytomegalovirus (CMV) infection has been indicted in the etiology of multiple aging-related diseases. We aimed to quantify the proportion of diseases that could be prevented with a potential CMV treatment among US older individuals. We analyzed disease prevalence among 8,934 eligible individuals from the US Health and Retirement Study (HRS) in 2016-2020. In our hypothetical intervention, the treatment would improve immune control of CMV and shift the distribution of continuous CMV IgG antibody levels from the highest quartile to the lower 3 quartiles. We estimated top-quartile CMV level attributable fractions for 7 outcomes: heart diseases, stroke, high blood pressure, high cholesterol, cancers, diabetes, and difficulty with Activities of Daily Living using a novel logistic regression-based approach.

In the study sample, a hypothetical intervention that decreased CMV IgG below the highest quartile level in 2016 would result in a 3.57 percentage points reduction of diabetes cases and a 1.81 percentage points reduction of high blood pressure cases among Non-Hispanic White (NHW) women. Among NHW men, the same intervention would lead to a 2.43 percentage points reduction of diabetes, a 2.89 percentage points reduction of heart diseases and a 2.52 percentage points reduction of high blood pressure. Our findings provide initial evidence for the potential population health impact of CMV intervention, specifically on high blood pressure, diabetes, and heart diseases.

Link: https://doi.org/10.1016/j.lana.2025.101122

Researchers here report on the differences in epigenetic aging between mice kept in standard laboratory facilities versus mice allowed to roam a more natural habitat with minimal supervision. The laboratory mice aged more slowly, which one might theorize has to do with greater degrees of care and attention from the laboratory staff. However, the researchers argue that the natural habitat imposes greater stresses upon the mice in various ways, and that in turn accelerates the epigenetic changes characteristic of aging.

We examined differences in age-associated methylation changes between traditionally laboratory-reared mice and "rewilded" C57BL/6J mice, which lived in an outdoor field environment with enhanced ecological realism. Our results lead us to two conclusions. First, the rate of epigenetic changes in the most used biomedical model organism is highly dependent on environmental context, with laboratory-reared animals showing a global bias toward slower rates of epigenetic aging compared to field-reared animals. Second, this more rapid aging of the epigenome is particularly pronounced in sites that gain methylation with age, which are enriched for genes associated with insulin regulation, DNA damage repair, and CTCF and cohesin binding. From the current data, it remains unclear if rewilded mice also show accelerated senescent phenotypes, including early onset disease development and behavioral declines, compared to those in the laboratory.

Our data hold some possible insights into the mechanisms by which animals may display accelerated epigenetic aging in the field compared to the laboratory. From an environmental perspective, animals in the field are exposed to a wide range of different environmental challenges and opportunities, including (1) social competition and potential resource scarcity in males, (2) homeostatic challenges resulting from dynamic weather experiences, (3) social instability when animals die or are born, and (4) reproductive effort in the form of mating and territorial defense in males and pregnancy and reproduction in females. Each of these environmental experiences - which are faced to an extent by all natural populations of vertebrates, including humans - may have contributed to short-term or chronic physiological stress, with downstream impacts on epigenetic aging rates.

Link: https://doi.org/10.1111/acel.70098

Given a body of human epidemiological data, one can typically only draw conclusions on correlations rather than causations: biomarkers A and B correlate with age-related condition X, but may or may not be involved in causing that condition. The research community designs animal studies to produce data on causation, and in many cases it is quite reasonable to lean on the results of those studies as support for the same path of causation in humans, but one can't run those same causation-focused studies in humans.

Thus the research community has developed strategies to tease out support for causation from correlational human data. Mendelian randomization brings in data on genetic variants that are known to affect specific biomarkers or outcomes of age-related disease. When segmenting the human data by these variants changes the outcomes, segment by segment, that suggests a causative relationship between biomarker and age-related disease. Linkage disequilibrium score regression is an analogous approach developed to try to break apart the individual contributions of multiple effects to a given outcome by adding data on genetic variants as a point of comparison.

Today's open access paper is an example of the application of these strategies to the challenge of gaining insight into causation between the aging of the gut microbiome and onset and progression of age-related conditions. The composition of the gut microbiome can be measured accurately via sequencing, and researchers now have a great deal of data to correlate specific changes with specific age-related conditions. Proof of causation has been obtained from animal studies in which restoration of a youthful gut microbiome composition improves health and extends life. Now, researchers would like to see more human data along the same lines.

Causal Analysis Between Gut Microbes, Aging Indicator, and Age-Related Disease, Involving the Discovery and Validation of Biomarkers

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this study integrates machine learning algorithms to explore the potential of MR and LDSC methods for biomarker screening.

Gut microbiota is found to be a potential risk factor for 14 age-related diseases. The causal effects of gut microbiota on chronic kidney disease, cirrhosis, and heart failure are partially mediated by aging indicators. Additionally, gut microbiota identified through MR and LDSC methods exhibit biomarker properties for disease prediction (average area under curve, AUC = 0.731). These methods can serve as auxiliary tools for conventional biomarker screening, effectively enhancing the performance of disease models (average AUC increased from 0.808 to 0.832).

This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery. These findings may help to develop new approaches for healthy aging detection and intervention.

Researchers here focus on a signaling mechanism that is diminished with age, the interaction between circulating prostaglandin E2 (PGE2) and its receptor EP4 on muscle stem cells. Levels of both PGE2 and its receptor decline with age, and this appears to broadly impair muscle stem cell function. The proof of that point is that delivering more PGE2 to aged mice improves muscle stem cell function, leading to an improved response following muscle injury.

Researchers examined the effects of circulating prostaglandin E2 (PGE2) and its receptor EP4 on muscle tissue. Their prior research had established that PGE2 signals during muscle injury trigger muscle stem cells to regenerate the muscles of young mice. In aged mice, the team found that EP4 expression on aged muscle stem cells are either lacking or reduced by half of those found in young stem cells. "PGE2 levels in muscle also decline with age, so we see blunted signaling from reductions in both the messenger and receiver. PGE2 is an alarm clock to wake up the stem cells and repair the damage. Aging essentially reduces the volume of the alarm and the stem cells have also put on ear plugs."

It is possible, however, to overcome the effects of aging and reset the intensity of this cellular signal. Researchers gave a stable form of PGE2 to aged mice after muscle injury and in conjunction with exercise. The treated mice gained more muscle mass and were stronger compared to untreated ones. The study revealed that PGE2 treatment restores stem cell function by modulating the activity of key transcription factors which reversed many of the age-related changes that the researchers observed. "The evidence suggests that PGE2 is not just acting on one mechanism. We've previously shown that PGE2 can also benefit the muscle fiber, and neurons that innervate the muscle. PGE2 has been implicated in the regenerative process and signaling for the intestine, liver, and several other tissues, potentially opening up an approach that could restore the renewing capacity of other aged tissues."

Link: https://sbpdiscovery.org/press/turning-back-time-on-muscle-stem-cells-to-prevent-frailty-from-aging/

The core hypothesis of this paper is that epigenetic changes characteristic of aging are all adaptive, beneficial attempts by cells to resist damage and dysfunction. This seems dubious. Looking into the aging body, we can point to any number of maladaptive, harmful changes in function; reactions that would be beneficial in youth, or when operating only temporarily, but become harmful in the aged tissue environment, or when sustained over time. Think of the way the immune system reacts to the age-damaged environment to generate chronic inflammation, for example. Why should epigenetic regulation be exempt from such maladaptive change?

Methylation clocks have found their way into the community of aging research as a way to test anti-aging interventions without having to wait for mortality statistics. But methylation is a primary means of epigenetic control, and presumably has evolved under strong selection. Hence, if methylation patterns change consistently at late ages it must mean one of two things. Either (1) the body is evolved to destroy itself (with inflammation, autoimmunity, etc.), and the observed methylation changes are a means to this end; or (2) the body detects accumulated damage, and is ramping up repair mechanisms in a campaign to rescue itself.

My thesis herein is that both Type 1 and Type 2 changes are occurring, but that only Type 1 changes are useful in constructing methylation clocks to evaluate anti-aging interventions. This is because a therapy that sets back Type 1 changes to an earlier age state has stopped the body from destroying itself; but a therapy that sets back Type 2 changes has stopped the body from repairing itself. Thus, a major challenge before the community of epigenetic clock developers is to distinguish Type 2 from Type 1.

The existence of Type 1 epigenetic changes is in conflict with conventional Darwinian thinking, and this has prompted some researchers to explore the possibility that Type 1 changes might be a form of stochastic epigenetic drift. I argue herein that what seems like directed epigenetic change really is directed epigenetic change. Of five recent articles on "stochastic methylation clocks," only one is based on truly stochastic changes. Using the methodology from this paper and a methylation database, I construct a measure of true methylation drift, and show that its correlation with age is too low to be useful.

Link: https://doi.org/10.18632/aging.206245

Reprogramming of adult cells occurs early in embryonic development, changing the adult germline cell into a pluripotent embryonic stem cell. This also removes epigenetic changes characteristic of age to rejuvenate cell functions, such as mitochondrial activity. A recipe for recreating this reprogramming process in any cell was discovered 20 years ago, and involves increased expression of the four Yamanaka factors. Over time, the interest of the scientific community has expanded from initial efforts to use reprogramming in order to generate patient-matched induced pluripotent stem cells for research and cell therapies. Now, researchers are equally interested in partial reprogramming that can produce epigenetic and functional rejuvenation in tissues without erasing cell type.

Researchers have expected these two aspects of reprogramming, dedifferentiation to pluripotency versus epigenetic rejuvenation, to be regulated separately. That underneath the regulatory layer of the Yamanaka factors, there would be other regulatory layers that distinctly produce dedifferentiation versus epigenetic rejuvenation. So far progress towards concretely identifying these hypothetical lower levels of regulation has been slow. Today's news from the Shift Bioscience team is a claim to an effective way to induce rejuvenation without dedifferentiation, by altering the expression of a single gene. The preprint does not identify the gene, of course, given that this is a corporate rather than an academic research group, but that information will emerge with time. One caution is that the researchers have validated the effects in a few cell types, but it may or may not generalize to all cell types.

A single factor for safer cellular rejuvenation

Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: OSK(M)) have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use.

To overcome this therapeutic barrier, we screened for novel factors by optimising directly for age reversal rather than for pluripotency. We trained a transcriptomic ageing clock, unhindered by the low throughput of bulk DNA methylation assays, to enable a screen of unprecedented scale and granularity.

Our platform identified what we here designate as SB000, the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.

In recent years, researchers have established correlations between the state of the gut microbiome and development of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. The balance of microbial populations making up the gut microbiome shifts with age to promote greater inflammation and dysfunction throughout the body, though one can also argue that the aging of the immune system promotes both this gut dysbiosis and neurodegeneration. Assessing the degree to which specific mechanisms are responsible for specific conditions is challenging, given the complexity of aging and its consequences. Nonetheless, there is good reason to think that an aged gut microbiome is actively harmful. Here, researchers note that inappropriate migration of oral bacteria into the gut may also be involved in the aging of the gut microbiome and its impact on the aging of the brain.

The human microbiome is increasingly recognized for its crucial role in the development and progression of neurodegenerative diseases. While the gut-brain axis has been extensively studied, the contribution of the oral microbiome and gut-oral tropism in neurodegeneration has been largely overlooked. Cognitive impairment (CI) is common in neurodegenerative diseases and develops on a spectrum. In Parkinson's Disease (PD) patients, CI is one of the most common non-motor symptoms but its mechanistic development across the spectrum remains unclear, complicating early diagnosis of at-risk individuals.

Here, we generated 228 shotgun metagenomics samples of the gut and oral microbiomes across PD patients with mild cognitive impairment (PD-MCI) or dementia (PDD), and a healthy cohort, to study the role of gut and oral microbiomes on CI in PD. In addition to revealing compositional and functional signatures, the role of pathobionts, and dysregulated metabolic pathways of the oral and gut microbiome in PD-MCI and PDD, we also revealed the importance of oral-gut translocation in increasing abundance of virulence factors in PD and CI. The oral-gut virulence was further integrated with saliva metaproteomics and demonstrated their potential role in dysfunction of host immunity and brain endothelial cells.

Our findings highlight the significance of the oral-gut-brain axis and underscore its potential for discovering novel biomarkers for PD and CI.

Link: https://doi.org/10.1080/19490976.2025.2506843

The research community continues to create aging clocks based on omics data at a fair pace. At this point, there are scores of clocks one might chose from if conducting studies on potential therapies to slow or reverse aspects of aging. Yet the primary challenge remains knowing whether any given clock will accurately reflect future outcomes following a specific form of treatment, meaning reduced risk of age-related disease and lowered mortality. Because there is no detailed map linking the omics data making up a clock to underlying mechanisms of aging or outcomes in aging, researchers do not know in advance how an aging clock will react to changes in the mechanisms targeted by a potential treatment for aging, and whether those reactions are useful. The clock might overestimate the impact, it might underestimate the impact. The only way to find out in certainty is to calibrate the clock against the therapy in long-running, expensive studies, and that somewhat defeats the point of having an aging clock.

The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We addressed this by developing a proteomics-based signature of healthspan, termed the Healthspan Proteomic Score (HPS), using proteomic data from the Olink Explore 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2,920 proteins).

A lower HPS was associated with higher mortality risk and several age-related conditions, such as chronic obstructive pulmonary disease, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation.

The external validity was evaluated using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explore 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies.

Link: https://doi.org/10.1073/pnas.2414086122

At a high level, it is fair to say that high blood glucose accelerates aging. The various forms of diabetes involve an excessively dysregulated glucose metabolism, and diabetics do exhibit accelerated aging. In the past, prior to the present greater focus on aging, researchers have even used diabetic mice as stand-ins for naturally aged mice to save time and funding. In comparison to mammals, birds have high blood glucose and relatively long life spans for their size. Is there anything to be learned from the comparative biology of birds and mammals in this context?

In today's open access paper, researchers discuss what the data on bird blood glucose might mean in terms of underlying mechanisms. It seems likely that birds possess mechanisms not present in mammals that allow them to resist the negative consequences of high blood glucose. Obviously this sort of review of the data is a very early starting point on the road to discovery and understanding of those mechanisms, even prior to any assessment regarding whether there is a useful basis for the production of therapies to bring that resistance to humans. One should not expect this research to move rapidly, given the slow pace of progress in other portions of the comparative biology field with much greater interest and funding, such as naked mole rat resistance to cancer.

Variation in albumin glycation rates in birds suggests resistance to relative hyperglycaemia rather than conformity to the pace of life syndrome hypothesis

The pace of life syndrome (POLS) hypothesis suggests that organisms' life history and physiological and behavioural traits should co-evolve. In this framework, how glycaemia (i.e. blood glucose levels) and its reaction with proteins and other compounds (i.e. glycation) covary with life history traits remain relatively under-investigated, despite the well-documented consequences of glucose and glycation on ageing, and therefore potentially on life history evolution. Birds are particularly relevant in this context given that they have the highest blood glucose levels within vertebrates and still higher mass-adjusted longevity compared to organisms with similar physiology as mammals.

We thus performed a comparative analysis on glucose and albumin glycation rates of 88 bird species from 22 orders in relation to life history traits (body mass, clutch mass, maximum lifespan, and developmental time) and diet. Glucose levels correlated positively with albumin glycation rates in a non-linear fashion, suggesting resistance to glycation in species with higher glucose levels. Plasma glucose levels decreased with increasing body mass, but, contrary to what is predicted in the POLS hypothesis, glucose levels increased with maximum lifespan before reaching a plateau. Finally, terrestrial carnivores showed higher albumin glycation compared to omnivores despite not showing higher glucose, which we discuss may be related to additional factors as differential antioxidant levels or dietary composition in terms of fibres or polyunsaturated fatty acids.

These results increase our knowledge about the diversity of glycaemia and glycation patterns across birds, pointing towards the existence of glycation resistance mechanisms within comparatively high glycaemic birds.

Most discussion of protein aggregation is focused on the few proteins that can excessively aggregate to form solid deposits and an associated toxic biochemistry, such as amyloid-β, α-synuclein, tau, and so forth. But many proteins can aggregate to much lesser degrees, particularly when the normal processes of quality assurance and clearance are impaired. Is this broad aggregation of hundreds of specific proteins in cells in aged tissues a sufficiently important contribution to dysfunction to be worth addressing distinctly from the underlying changes in environment and epigenetic regulation of gene expression that cause this issue? That is an interesting question.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging. We engineered bioorthogonal tools which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia.

We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal 'aggregome' encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia.

These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1101/2025.05.20.654652

Near everything that happens in the cosmetics "anti-aging" space is, and has long been, garbage products coated in a layer of marketing, pretty lies that mimic the output of actual science to the degree needed to succeed. At some point this mess will largely go away because topical therapies that actually address mechanisms of aging will emerge, coupled to assessments that demonstrate these therapies to achieve results that the garbage products cannot. Meanwhile, the present state of the market is actively hostile to that progress, as product success has everything to do with marketing and very little to do with whether or not it actually works. What does productive change look like? It might start with calls to action such as the one noted here.

The field of anti-aging research has made remarkable strides with the identification of geroprotectors - compounds capable of extending healthspan and lifespan in animal models - presenting promising implications for human longevity. Building on these advances, we propose a novel product category: longevity cosmeceutical actives and products. Unlike conventional anti-aging products that primarily target superficial signs of aging, longevity cosmeceuticals address the molecular hallmarks of aging, fundamentally enhancing skin health and longevity.

To clearly distinguish these scientifically validated products from marketing-driven claims, we define, for the first time, longevity cosmeceutical actives and products based on stringent criteria: (1) they must directly target and modulate established hallmarks of skin aging; (2) they must demonstrably extend "skinspan" over time, reflected by improved skin viability, structure, and functional integrity; and (3) their efficacy must be validated through clinical trials, preferably with post-trial skin biopsies to evaluate aging hallmark biomarkers, along with comprehensive safety assessments.

This review explores molecular hallmarks of skin aging, highlights geroprotective compounds with potential cosmeceutical applications, and recommends essential biomarkers for assessing prevention of rapid biological aging. Additionally, we propose methodologies for skinspan assessment and emphasize the importance of robust clinical trial designs. By establishing these scientifically rigorous standards, we aim to drive innovation, substantiate longevity claims, and transform the cosmetic industry toward meaningful biological improvements in skin health.

Link: https://doi.org/10.3389/fragi.2025.1586999

Senescent cells grow in number in tissues throughout the body with advancing age. Cells become senescent throughout life, largely as a result of reaching the Hayflick limit on replication, but it can also happen in response to injury, or various forms of cytotoxic stress. These cells are removed by the immune system or programmed cell death and do not accumulate. Only later in life when there are greater levels of damage and cell stress on the one hand, and a failing immune system on the other hand, does creation outpace clearance to allow senescent cells to linger and grow in number.

The research and development communities are pursuing the development of senolytic therapies to selectively destroy senescent cells. To a lesser degree, there are also programs aimed at senostatic approaches to slow the creation of senescent cells or senomorphic approaches to alter the behavior of senescent cells to make them less harmful.

The expansion of these latter two approaches is in part driven by reservations in portions of the research community to the use of senolytics. Today's open access paper touches on most of those concerns, some more hypothetical than others. A few are the usual concerns for new classes of therapy: is the target well enough understood, is there enough knowledge to apply therapies effectively. Some are specific to senescent cells, however, in particular the question of whether senescent cells in any specific circumstance or tissue are actually needed despite the problems they cause, and thus could only be replaced slowly rather than cleared outright.

Is Senolytic Therapy in Cardiovascular Diseases Ready for Translation to Clinics?

Aging is a predominant risk factor for cardiovascular diseases. There is evidence demonstrating that senescent cells not only play a significant role in organism aging but also contribute to the pathogenesis of cardiovascular diseases in younger ages. Encouraged by recent findings that the elimination of senescent cells by pharmacogenetic tools could slow down and even reverse organism aging in animal models, senolytic drugs have been developed, and the translation of results from basic research to clinical settings has been initiated. Because numerous studies in the literature show beneficial therapeutic effects of targeting senescent cells in cardiomyopathies associated with aging and ischemia/reperfusion and in atherosclerotic vascular disease, senolytic drugs are considered the next generation of therapies for cardiovascular disorders.

According to the current research in the literature, we could conclude that senescent cells exhibit two faces in cardiovascular disease and aging, i.e., they have either detrimental effects or beneficial effects. Although the reasons for these contradictory results are not clear, the following considerations may provide hints for explanation and point towards further research directions.

First, it has been demonstrated that not all senescent cells have the same functions. For example, with the development of mouse models for genetic tracing and the manipulation of p16ink4+ cells, specific depletion of senescent cell types, such as endothelial cells and macrophages, and other cell types becomes possible. Moreover, senescent cells derived from the same cell type are not homogenous even in the same disease microenvironment. At least two groups of senescent cells might exist, i.e., pro-inflammatory tissue destructive and anti-inflammatory tissue reparative senescent cells, depending on the profile of the senescence-associated secretory phenotype (SASP).

Second, it therefore seems that the effects of senolytic therapy, whether beneficial or detrimental, are context-dependent in specific diseases. In cardiac diseases, e.g., myocardial infarction, heart failure, or age-related cardiac dysfunction, removal of senescent cardiomyocytes could be detrimental if survived or available cardiomyocytes under the condition are not adequate or not sufficient to support the pumping function of the heart. On the other hand, the elimination of senescent cardiomyocytes will be beneficial if the remaining cardiomyocytes are adequate to compensate for the heart pumping function and the detrimental paracrine effects of cardiomyocytes on other non-myocyte cells, such as fibroblasts, endothelial cells, and immune cells, could be removed.

Moreover, the SASP factor profiles from senescent cells might be different depending on the stimuli that induce cell senescence. Replicative senescent vascular endothelial cells or the endothelium from aged mouse exhibit a pro-inflammatory phenotype, while the SENEX gene induced premature endothelial senescence, revealing an anti-inflammatory phenotype. These observations implicate that senescent cells in different pathological conditions, such as atherosclerosis, insulin resistance, diabetes, hypertension, etc., and natural aging may have different profiles of SASP factors, which may also influence the effects of senolytic and/or senomorphic therapies.

Anti-senescence therapies or senolytic and senomorphic drug therapies are attractive and promising future therapeutic modalities for the treatment of cardiovascular diseases, and they represent a novel research direction for cardiovascular aging and age-associated cardiovascular diseases. However, we shall be cautious not to endorse clinical use of senolytics for the prevention or treatment of cardiovascular diseases or other age-associated chronic diseases until the roles of cell senescence in specific disease development are well-studied and the safety and efficacy of the drugs in well-designed clinical trials are investigated.

Type 2 diabetes is condition produced by excess weight in the vast majority of patients, and losing weight can reverse the progression of the condition even in later stages. Separately, researchers have demonstrated that excess visceral fat tissue promotes a greater burden of cellular senescence in older individuals. Senescent cells contribute to the chronic inflammation of aging, disruptive to tissue structure and function. Here, researchers note that type 2 diabetes patients exhibit a greater burden of cellular senescence, as determined by a range of measures - not all that surprising. Interestingly, other investigations have suggested that senescent cells in the pancreas drive dysfunction in both type 1 diabetes and type 2 diabetes, an important common mechanism in conditions with very different root causes.

Although animal studies have linked cellular senescence to the pathogenesis and complications of type 2 diabetes mellitus (T2DM), there is a paucity of corroborating data in humans. Thus, we measured a previously validated marker for senescent cell burden in humans, T-cell expression of p16 mRNA, along with additional biomarkers, to compare the senescence phenotypes of postmenopausal control (lean, N = 37) and T2DM (N = 27) participants. To control for effects of obesity alone, we included a third group of obese but non-diabetic women (N = 29) who were matched for body mass index to the T2DM participants. In addition, given the increase in fracture risk in T2DM despite preserved or even increased bone mineral density, we related these senescence biomarkers in the T2DM participants to skeletal microarchitectural parameters.

Relative to the lean participants, T-cell p16 and p21Cip1 expression was increased in the T2DM, but not the obese, non-diabetic participants. Expression of p16 and p21Cip1 was positively associated with HbA1c and an index of skin advanced glycation end-products. T2DM was also associated with an increase in a number of SASP factors. Among participants with T2DM, women in the highest tertile for T-cell expression of p16 had significantly reduced tibial cortical area and thickness as compared to those in the lower two tertiles. Overall, our studies link cellular senescence to metabolic and skeletal alterations in T2DM and point to the need for further studies evaluating the role of cellular senescence in mediating skeletal fragility, as well as potentially other complications in T2DM.

Link: https://doi.org/10.1111/acel.70120

Cell reprogramming as a basis for the treatment of aging involves inducing the expression of Yamanaka factors for a short period of time, ideally resulting in a shift in cell epigenetic state to a more youthful configuration without disruption of cell function or the creation of potentially harmful pluripotent stem cells. While early efforts focused on gene therapy technologies, there is a branch of research focused on small molecules that might achieve sufficient Yamanaka factor expression to be interesting. A number of combinations of small molecules have been explored, and the one assessed in mice here has been called the 2c cocktail by other authors. While small molecules have the advantage of effective delivery to the whole body, a goal that remains impossible for adult gene therapies, side-effects remain a sizable concern for the known small molecule reprogramming agents.

Targeting partial cellular reprogramming pathways through specific small molecule combinations holds promise for lifespan extension in model organisms. Chemical cocktails like RepSox and tranylcypromine (TCP) may induce beneficial age-related changes without the risks of full reprogramming. Female C3H mice were divided into two age groups: "old" (16-20 months) and "senior" (10-13 months). They received intraperitoneal injections of RepSox (5 mg/kg) and TCP (3 mg/kg) or DMSO (control) every 72 h for 30 days.

In the "old" group, treated mice showed enhanced neurological status, fur and skeletal health, and increased cortical angiogenesis, though with some adverse histological changes in the liver and brain. In the "senior" group, treated mice displayed a plateau in mortality after month seven, while deaths continued in controls. Although overall survival was not significantly different, maximum lifespan significantly increased in treated mice. Histological findings revealed localized adaptive changes rather than major toxic effects. These results suggest that the combination of RepSox and TCP exerts protective effects on aging phenotypes and may potentially slow systemic aging processes in C3H mice.

Link: https://doi.org/10.1002/brb3.70573

Cholesterol attached to LDL particles leaves the liver to be transported in the bloodstream to tissues throughout the body. Along the way, this is expected to contribute to development of atherosclerosis in blood vessel walls via deposition of excessive cholesterol in some locations. Patients with homozygous familial hypercholesterolemia, who exhibit loss of function mutations in the LDL receptor and enormously elevated LDL cholesterol in blood, demonstrate that past a certain point there is a dramatic acceleration of atherosclerosis resulting from too much transported cholesterol. Untreated, these patients typically die in their 30s from heart attack or stroke.

What about the rest of the population with a more normal varied range of LDL cholesterol levels, however? The consensus on lowering LDL cholesterol as the dominant approach to reduce atherosclerotic cardiovascular disease risk is not without its challengers. Physicians note that most of the aged patients who present with a first heart attack or stroke do not have elevated LDL cholesterol. Epidemiologists note that the data suggests that the mechanisms of atherosclerosis vary considerably across the population. People respond very differently to cholesterol levels and pharmacological strategies to reduce them. This is one of the reasons why very large trials are needed to see effect sizes resulting from lowered LDL cholesterol.

Today's open access paper is an example of the body of literature that challenges the consensus on the practice of setting targets for LDL cholesterol levels, and the relevance of LDL cholesterol to disease. A reasonable view of the situation is that some fraction of the population does suffer when LDL cholesterol is too high, and thus does benefit from the therapeutic strategy of lowering LDL cholesterol - but at present there is no good way to identify in advance whether any given individual is in that group. The underlying biochemistry is not fully understood, and outcomes arise only slowly over time, a situation in which producing greater understanding is necessarily expensive, and thus few groups are willing to make the effort.

Is Targeting LDL-C Levels Below 70 mg/dL Beneficial for Cardiovascular and Overall Health? A Critical Examination of the Evidence

Over the past two decades, the strategy for managing cardiovascular disease (CVD) risk with lipid-lowering therapy has changed significantly. LDL-cholesterol (LDL-C) targets in guidelines have been progressively lowered from 100 mg/dL (2.6 mmol/L) or less to 70 mg/dL (1.8 mmol/L) or less for high-risk patients and 55 mg/dL (1.4 mmol/L) or less for very high-risk patients. The reduction in target LDL-C levels was stated as justified based on the appearance that intensive lipid-lowering therapy offered additional cardiovascular benefits compared to the standard regimens.

The establishment of low LDL-C targets in CVD prevention was based on the premise that there is a linear relationship between LDL-C levels and CVD risk. However, this premise faces several challenges: (1) The supposed direct correlation between LDL-C levels and atherosclerosis progression is questionable; (2) The systematic reviews that provided the foundation for this assumption have several limitations, including extrapolation of results for LDL-C levels beyond observed data; (3) Potential bias due to the ecological fallacy stemming from meta-regression results based on study-level rather than patient-level analyses; (4) Inconsistent findings from trials specifically designed to investigate the relationship between LDL-C targets and CVD risk; (5) Research documenting greater longevity of elderly individuals with familial - as well as non-familial - hypercholesterolemia contradicts the premise that lower LDL-C levels are ideal.

In this paper, we address these challenges point by point, providing evidence to support each argument. We also point out that LDL-C is a hybrid measure composed of heterogeneous particles, with varying atherogenicity depending on the size of the particles. Finally, we address evidence that pleiotropic effects of lipid-lowering therapies, particularly statins, may contribute to cardiovascular benefits, independent of LDL-C reduction. This paper, therefore, presents evidence to challenge current LDL-C targets of 70 mg/dL or less in patients at high CVD risk.

Mitochondria are power plants, hundreds of them in every cell. A mitochondrion is descended from symbiotic bacteria, essentially a wrapper around the electron transport chain, which is a complex system that produces either heat or molecules of adenosine triphosphate (ATP), a chemical energy store used to power the cell. It also produces reactive oxidative molecules as a side-effect of its energetic process of operation, which the cell treats as both a source of damage to be repaired and a signal to adjust operations. Improving mitochondrial function slows aging. Interesting, so does mild sabotage of the electron transport chain, causing the cell to react to the reduced supply of ATP and increased generation of oxidative molecules by increasing its maintenance and defense efforts - the benefits outweigh the harms. This is all very complex, however; any change cascades to produce second order effects, and it is hard to predict in advance whether a novel mitochondrially targeted intervention will be beneficial or harmful in aggregate. Once the results are demonstrated it is then hard to understand why it is beneficial or harmful.

Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical - and, in the case of metformin, clinical - longevity benefits.

More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress.

Link: https://doi.org/10.3390/biom15050614

β-hydroxybutyrate is also known as 3-Hydroxybutyrate. An increase in the circulating levels of this compound is thought to mediate some of the beneficial effects of exercise and calorie restriction. Here researchers supplement with β-hydroxybutyrate in mice, starting in mid-life, and observe an increase in median life span that is perhaps larger than one might expect for this intervention, similar to the outcome of rapamycin treatment. The researchers dive into some of the mechanisms involved, but one might think that an intervention of this sort will change most aspects of metabolism; it isn't necessarily the case that those noted here are the most important.

Aging is a significant risk factor for chronic diseases and disability, yet effective anti-aging interventions remain elusive. We explored the potential of 3-hydroxybutyrate (3HB), an endogenous metabolite with established safety, to modulate longevity in mice. In this study, we employed cell models, a yeast model, and naturally aging mouse models to investigate the effects of 3HB on aging in various systems. Additionally, we utilized RNA sequencing and metabolomics technologies to explore the potential mechanisms underlying the action of 3HB.

Our findings demonstrate that 3HB supplementation effectively delays cellular senescence, extending yeast lifespan by 51.3% and the median lifespan of naturally aged mice by 21.0%. Notably, 3HB prolonged healthy lifespan in mice while mitigating age-related tissue morphology changes and organ senescence. Mechanistically, we identified that 3HB's anti-aging properties are mediated through its ability to delay cellular senescence and metabolic reprogramming, while promoting the production of beneficial metabolites like trigoneline and isoguvacine. These findings highlight the promising therapeutic potential of 3HB as an anti-aging intervention and provide novel insights into its underlying mechanisms.

Link: https://doi.org/10.3390/nu17101647

The gut microbiome is made of thousands of microbial species in various proportions, some helpful, some harmful. The development of means to accurately measure the composition of the gut microbiome, by sequencing the 16S rRNA gene that exhibits characteristic species-level differences, has enabled the scientific community to connect changes in the gut microbiome to aging, health, and disease. This mapping of the gut microbiome as a contributing factor in aging and age-related diseases is still in the relatively early stages, but as the field progresses we should expect to see increased interest in the development of novel, improved means to alter the gut microbiome as form of therapy.

The composition of the gut microbiome is fairly resilient to short-term changes induced by diet, present probiotic and prebiotic supplements, mild antibiotic use, and the like. It will bounce back. Over decades of life, however, changes do occur in the balance of microbial populations, and they are not favorable. Inflammatory microbes grow in number at the expense of microbes that generate metabolites necessary for optimal tissue function. Some of this is a consequence of long-term shifts in diet in older individuals, some of it is the decline of the immune system in its role as gardener of the gut microbiome, some of it is other factors. The relative importance of each of these items has yet to be concretely determined.

Fortunately there are ways to permanently change the gut microbiome. Flagellin immunization will direct the immune system to more aggressively remove problem microbes, reshaping the whole microbiome into a more favorable configuration of populations. Fecal microbiota transplantation from a young donor to an old recipient will rejuvenate the balance of populations, and has been shown to produce health and longevity benefits in animal studies. The problem there is that it is unclear as to what exactly constitutes a beneficial microbe, and so it seems likely that fecal microbiota transplantation will be discarded in favor of culturing specific known mixes of microbes that can be delivered once via enteric capsules or similar to achieve a similar but more controlled outcome.

The gut microbiota and aging: interactions, implications, and interventions

Aging is associated with notable shifts in the composition and function of the gut microbiota. Research indicates a decrease in microbial diversity and changes in the abundance of specific bacterial groups in older individuals compared to younger counterparts. For instance, there tends to be an increase in Escherichia coli and other Proteobacteria and a decrease in beneficial bacteria like Bacteroides and Bifidobacterium, essential for gut health and overall wellbeing. Centenarians, a unique subset of elderly individuals, serve as a fascinating model for studying longevity and investigating gut microbiota alterations that could potentially facilitate healthier aging. Centenarians exhibit a noteworthy trend: an elevation in genera such as Akkermansia, which holds potential implications for longevity.

These alterations in the gut microbiota are influenced by several factors, including dietary changes, reduced physical activity, increased medication use, and physiological changes in the gastrointestinal tract such as decreased gut motility. The decline in beneficial bacteria and the proliferation of potentially pathogenic microbes contribute to an imbalanced gut environment, often referred to as dysbiosis. Dysbiosis in the elderly has been associated with various age-related conditions, like inflammaging, cognitive decline, neurodegeneration, insulin resistance, type 2 diabetes mellitus, cardiovascular disease, and cancer.

Given the critical role of the gut microbiota in aging and age-related diseases, there is a growing interest in microbiota-targeting interventions to promote healthy aging. In addition to dietary modifications, probiotics, non-viable probiotics (paraprobiotics), prebiotics, synbiotics, and microbial soluble factors (postbiotics) have garnered significant attention for their potential to modulate the gut microbiota and enhance the health of the elderly. Although still in the experimental stages for age-related conditions, fecal microbiota transplantation (FMT) has shown promise in restoring a healthy microbiota and improving metabolic and immune functions in older adults, based on animal studies.

Rupture of the atherosclerotic plaque that grows in arteries leads to the death of more than a quarter of humanity via heart attack and stroke. It is the single largest cause of human mortality. Imaging approaches for characterizing size and composition of atherosclerotic plaques have improved immensely over the past twenty years, but remain expensive enough in clinical practice to ensure they are used far less often then they might be. The average older individual in wealthier parts of the world may know that he or she has plaque, has been imaged within the past few years, but is unlikely to keep apace of how exactly that plaque is changing. As researchers note here, plaque doesn't just grow over time, it quietly changes composition to form more dangerous, unstable structures.

Atherosclerotic plaques are accumulations of fat, cholesterol, and other substances in the arteries, and over time these plaques can calcify. The degree of calcification is thought to promote plaque stability, which then potentially reduces the risk of possible rupture. Ruptured plaques can lead to the formation of a blood clot and possible stroke. "It is important to remember that plaques that don't yet cause symptoms can rapidly evolve in ways that make them more dangerous. One of the key findings of our work is that calcified plaques may not be as harmless as once thought, since these plaques were found to be at risk of intraplaque bleeding, which in itself is the most important cause of plaque rupture and subsequent stroke."

For the study, researchers followed 802 patients from the Rotterdam Study - an ongoing large-scale, population-based study - aged 45 years and older with subclinical carotid artery atherosclerosis. Baseline MRIs of carotid plaque compositions were conducted and then repeated after six years. All participants were in pre-symptomatic stages of their disease.

Over the course of the research, plaques became more complex, developing multiple components such as calcification, bleeding, and fatty deposits. Changes towards more complex plaque composition were more common in men than in women. The study showed that compared to plaques without calcification, plaques that already had calcification were twice as likely to develop internal bleeding, which is a key indicator of plaque vulnerability and potential rupture. The researchers also did a simulation to predict plaque evolution beyond the six years. A simulated 30-year evolution showed that more than half of the participants who had single component plaques would develop into complex multicomponent plaques by the age of 70. "Even if there are no symptoms, early signs of plaque in your carotid arteries can quietly become more dangerous over time."

Link: https://www.rsna.org/news/2025/june/carotid-plaque-may-pose-danger

Researchers here assess a compensatory approach to the neurodegeneration of Alzheimer's disease, meaning an enhancement of the ability of cells to operate in the face of damage rather than addressing the damage itself. This can inevitably only slow progression of the condition, and is not a path to a curative therapy. Nonetheless, tinkering with cell metabolism in order to slow disease progression is arguably the dominant approach to the development of new therapies. The research community needs to do better than this if we're to see major advances in the treatment of aging and age-related conditions.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive synaptic loss and cognitive decline. Gene therapy that augments intrinsic neuroprotective pathways offers a promising strategy to mitigate neurodegeneration and prevent further cognitive loss. Caveolin-1 (Cav-1), a membrane lipid raft (MLR) scaffolding protein, regulates multiple pro-growth and pro-survival signaling pathways within plasmalemmal microdomains. Previously, we showed that AAV9-Synapsin-promoted Cav-1 (SynCav1) delivered to presymptomatic AD mice preserved cognitive functions and MLR-associated neurotrophic signaling. However, the therapeutic potential of SynCav1 delivered at the symptomatic stage of AD had not been tested. Therefore, the current study investigated the effect of hippocampal SynCav1 delivery at symptomatic age in two distinct preclinical AD models of amyloid pathology: PSAPP and APPKI mice.

Our results demonstrated that SynCav1 delivery to PSAPP and APPKI mice at symptomatic age consistently preserved hippocampal-dependent memory. Transcriptome profiling revealed that PSAPP-SynCav1 mice exhibited a similar transcript profile to age-matched wild-type mice. Gene Ontology enrichment analysis indicated downregulation of neurodegeneration-specific pathways and upregulation of synaptic and cognitive-related pathways in PSAPP-SynCav1 mice. In vitro, SynCav1-transfected mouse primary cortical neurons exhibited increased p-CaMKII and p-CREB expression, suggesting that SynCav1 may protect the central nervous system by enhancing neuronal and synaptic activity. Furthermore, activity-dependent neuroprotective protein (ADNP) was identified as a potential candidate mediating SynCav1's neuroprotective effects on cognition. Subcellular membrane fractionation revealed that SynCav1 preserved MLR-localized pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R), a well-known regulator of ADNP expression. Together, these findings highlight SynCav1 as a unique and promising gene therapy candidate in the treatment of AD.

Link: https://doi.org/10.1038/s41392-025-02258-z

Repair Biotechnologies, the company I co-founded, develops therapies based on the ability to selectively clear only excess cholesterol inside cells. This is normally an undruggable target. Cholesterol is essential to cell function, but expensive to manufacture. Species evolved a central factory for cholesterol production, the liver, and a complicated system of distribution that delivers cholesterol to and from the liver as needed. The vast majority of cells in the body neither manufacture nor break down cholesterol, but are completely dependent on it. Worse, too much cholesterol is toxic, and cells have little ability to deal with that toxicity when it occurs due to age-related or obesity-related dysregulation of cholesterol transport.

While Repair Biotechnologies focuses on reversal of atherosclerosis, an arguably equally important confirmation to come out of ongoing work at the company is that the presence of excess cholesterol inside cells - and likely other lipids as well - is an important contribution to age-related dysfunction in many tissues throughout the body. Whenever the Repair Biotechnologies scientists branch out to assess a new tissue in mice following treatment to clear intracellular cholesterol and see functional or structural improvement, that is a demonstration of the relevance of intracellular cholesterol to pathology in that tissue.

Thus it is always interesting to see some portions of the research community discussing the excess lipid issue with a focus on their specific tissue or organ of interest. Today's open access paper argues for the importance of excess cholesterol and other lipids in muscle cells. The infiltration of fat into muscle tissue with age and obesity is known to be a bad thing, but here the focus is more on the presence of excess lipids inside muscle cells and how that can be thought to contribute to the cellular dysfunctions that give rise to age-related loss of muscle mass and strength. The Repair Biotechnologies team has not assessed muscle tissue and muscle cells in any great detail to date, as this isn't on the roadmap to treating atherosclerosis, but perhaps they should.

Targeting intramyocellular lipids to improve aging muscle function

Decline of skeletal muscle function in old age is a significant contributor to reduced quality of life, risk of injury, comorbidity, and disability and even mortality. While this loss of muscle function has traditionally been attributed to sarcopenia (loss of muscle mass), it is now generally appreciated that factors other than mass play a significant role in age-related muscle weakness. One such factor gaining increased attention is the ectopic accumulation of lipids in skeletal muscle, in particular, intramyocellular lipids (IMCLs). It has been appreciated for some time that metabolic flexibility of several tissues/organs declines with age and may be related to accumulation of IMCLs in a "vicious cycle" whereby blunted metabolic flexibility promotes accumulation of IMCLs, which leases to lipotoxicity, which can then further impair metabolic flexibility.

The standard interventions for addressing lipid accumulation and muscle weakness remain diet (caloric restriction) and exercise. However, long-term compliance with both interventions in older adults is low, and in the case of caloric restriction, may be inappropriate for many older adults. Accordingly, it is important, from a public health standpoint, to pursue potential pharmacological strategies for improving muscle function. Because of the success of incretin-analog drugs in addressing obesity, these medications may potentially reduce IMCLs in aging muscles and thus improve metabolic flexibility and improve muscle health. A contrasting potential pharmacological strategy for addressing these issues might be to enhance energy provision to stimulate metabolism by increasing NAD + availability, which is known to decline with age and has been linked to reduced metabolic flexibility.

In this narrative review, we present information related to IMCL accumulation and metabolic flexibility in old age and how the two major lifestyle interventions, caloric restriction and exercise, can affect these factors. Finally, we discuss the potential benefits and risks of select pharmacologic interventions in older adults.

Researchers continue to produce a fair number of new aging clocks every year to attempt to measure biological age. One might at this point ask whether the life science community should instead focus on better understanding and utilizing the best of the existing clocks. No new clock can be applied naively to the assessment of potential therapies to slow or reverse aging, as a new clock arrives with no understanding of how exactly the measures making it up relate to specific forms of damage and dysfunction that drive aging. One cannot predict whether the clock will accurately reflect changes in biological age or risk of age-related disease if, for example, senescent cells are cleared, or mitochondrial function improved. Nonetheless, it seems that more effort goes to making new clocks than is put towards the calibration of existing clocks.

In 2015, the World Health Organization (WHO) introduced the concept of intrinsic capacity (IC), defined as the sum of all physical and mental capacities that an individual can draw on at any point in their life. The International Classification of Diseases, 11th Revision, recently added 'aging-associated decline in IC' under code MG2A10, standardizing the clinical use of IC globally as a metric of functional aging. Since the inception of IC, many studies have developed IC scores and demonstrated its association with health-related factors.

Despite the advantages of using IC to assess functional ability, current methods to quantify it require equipment and trained personnel, and the molecular and cellular mechanisms underlying its age-associated decline are still poorly understood. Here we used the INSPIRE-T cohort (1,014 individuals aged 20 to 102 years) to construct the IC clock, a DNA methylation-based predictor of IC, trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities, and vitality. In the Framingham Heart Study, DNA methylation IC outperforms first-generation and second-generation epigenetic clocks in predicting all-cause mortality, and it is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors, and lifestyle choices. These findings establish the IC clock as a validated tool bridging molecular readouts of aging and clinical assessments of IC.

Link: https://doi.org/10.1038/s43587-025-00883-5

Studies of the dose-response curve for exercise have typically shown that little exercise is much better than no exercise, and gains continue at a slowing pace up to a fair way above the recommendation of 150 minutes of moderate to vigorous physical activity per week. See research showing that two to four times that amount further improves outcomes, for example. At some point, however, diminishing returns tip over into harm. There is such as thing as too much physical activity, though few people reach that point. The study here, in which researchers generate a brain aging metric derived from neuroimaging data and correlate its progression with physical activity, is interesting for producing a dose-response curve that looks very similar to those derived from data on physical activity versus incidence of age-related disease or mortality.

A neuroimaging-derived biomarker termed the brain age is considered to capture the degree and diversity in the aging process of the brain, serving as a robust indicator of overall brain health. The impact of different levels of physical activity (PA) intensities on brain age is still not fully understood. A total of 16,972 eligible participants with both valid T1-weighted neuroimaging and accelerometer data from the UK Biobank were studied. Brain age was estimated using an ensemble learning approach called Light Gradient-Boosting Machine (LightGBM).

Over 1,400 image-derived phenotypes (IDPs) were initially chosen to undergo data-driven feature selection for brain age prediction. A measure of accelerated brain aging, the brain age gap (BAG) can be derived by subtracting the chronological age from the estimated brain age. A positive BAG indicates accelerated brain aging. PA was measured over a 7-day period using wrist-worn accelerometers, and time spent on light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), and moderate- to vigorous-intensity PA (MVPA) was extracted. The generalized additive model was applied to examine the nonlinear association between PA and BAG after adjusting for potential confounders.

The brain age estimated by LightGBM achieved an appreciable performance (r = 0.81, mean absolute error [MAE] = 3.65), which was further improved by age bias correction (r = 0.90, MAE = 3.03). We found that LPA (F = 2.47), MPA (F = 6.49), VPA (F = 4.92), and MVPA (F = 6.45) exhibited an approximate U-shaped relationship with BAG, demonstrating that both insufficient and excessive PA levels adversely impact brain aging. Improved brain health may be attainable through engaging in moderate amounts of objectively measured PA irrespectively of intensities.

Link: https://doi.org/10.34133/hds.0257

The present approach to aging in the healthcare community is uncomfortably close to being a matter of Cnut the Great on the beach telling the tide to go back. In clinical practice most of the major diseases of aging remain irreversible for the average individual, a progression that can only be modestly slowed. The only way to achieve the possibility of turning back these conditions is to repair the forms of accumulated cell and tissue damage that maintain the body and brain in a diseased state - to use rejuvenation therapies. The development of these therapies is painfully slow. It has been clear that clearance of senescent cells is very promising for a decade now, but it will be years yet before any large scale human data emerges for senolytic approaches that work well.

The point of today's open access commentary is that the establishment of even crude and limited capabilities for rejuvenation will necessarily require a major upheaval in the way the clinical community engages with aging and age-related disease. The heroic model of coping with the inevitable must be abandoned. Something more useful must take its place. The author here argues that the medical community must shift its primary focus away from end stage disease towards earlier intervention to prevent that disease. This already exists as a major focus of the cardiovascular disease community, even if the preventative technologies used there are not all that great in the grand scheme of things. But for much of the rest of the medical community enacting such a change will be a sizable upheaval.

Rethinking healthcare through aging biology

Modern medicine has revolutionized the way we diagnose and treat diseases, achieving remarkable success in extending life expectancy. Yet, despite these advances, the traditional disease-centric healthcare model has significant limitations. This approach typically kicks in only after pathology has manifested-when patients exhibit symptoms, seek treatment, receive a diagnosis, and begin therapy. While reactive care has its merits, it increasingly falls short in addressing the needs of aging populations. As people age, they often develop a constellation of chronic conditions - multimorbidity - that strains the healthcare system and diminishes quality of life. Conditions such as cardiovascular disease, type 2 diabetes, osteoarthritis, neurodegeneration, and cancer frequently coexist, leading to complex and often ineffective treatments. Polypharmacy - the use of multiple medications to treat co-existing diseases - introduces further complications, including drug interactions, side effects, reduced adherence to treatment regimens, and increased hospitalizations.

Moreover, this disease-specific focus neglects the underlying causes of age-related decline - the very mechanisms that fuel the development of these diseases. However, recent breakthroughs in aging research have unveiled an exciting opportunity: the shared biological roots of many age-related diseases. These mechanisms, known as the hallmarks of aging, often precede the onset of disease by decades. Targeting these aging processes before diseases fully develop offers a bold new approach: not just treating diseases, but preventing them in the first place.

This shift in focus from reactive disease management to proactive healthspan extension is transformative. By intervening early in the aging process, we could delay or even prevent multiple diseases, addressing not just the symptoms, but the biological declines that underlie them. In this context, cutting-edge interventions such as senolytics and rapalogs exemplify the promising potential of targeting aging itself. Senolytics, which selectively eliminate senescent cells that accumulate with age and contribute to chronic inflammation and tissue dysfunction, have shown promise in extending healthspan and alleviating a range of age-related conditions. Likewise, rapalogs - drugs that target the mTOR pathway, a central regulator of cell growth and metabolism - have demonstrated the ability to extend lifespan and improve healthspan by promoting autophagy, enhancing immune function, and reducing inflammation. As clinical trials continue, these interventions are poised to transform aging medicine, but the road to widespread clinical application remains challenging.

The gut microbiome is made up of thousands of microbial species in various proportions. The balance of populations shifts with age to favor harmful, inflammatory microbes over beneficial microbes that manufacture metabolites necessary to normal tissue function. This contributes to degenerative aging to some degree. One of the few ways to permanently alter the gut microbiome is to transplant fecal matter from one animal to another. Fecal microbiota transplantation from a young donor to an old recipient rejuvenates the gut microbiome, restoring youthful population levels. The study here is one of a number to demonstrate that this procedure improves health in old mice, removing much of the contribution of an aged gut microbiome to degenerative aging of the body and brain.

The gut microbiota evolves over a lifetime and significantly impacts the aging process. Targeting the gut microbiota represents a novel avenue to delay aging and aging-related physical and mental decline. However, the underlying mechanism by which the microbiota modulates the aging process, particularly age-related physical and behavioral changes is not completely understood.

We conducted fecal microbiota transplantation (FMT) from young or old male donor mice to the old male recipients. Old recipients with young microbiota had a higher alpha diversity than the old recipients with old microbiota. Compared to FMT with old microbiota, FMT with young microbiota reduced body weight and prevented fat accumulation in the old recipients. FMT with young microbiota also lowered frailty, increased grip strength, and alleviated depression and anxiety-like behavior in the old recipients.

Consistent with observed physical changes, untargeted metabolomic analysis of serum and stools revealed that FMT with young microbiota lowered age-related long-chain fatty acid levels and increased amino acid levels in the old recipients. Bulk RNAseq analysis of the amygdala of the brain showed that FMT with young microbiota downregulated inflammatory pathways and upregulated oxidative phosphorylation in the old recipients. Our results demonstrate that FMT with young microbiota has substantial positive influences on age-related body composition, frailty, and psychological behaviors. These effects are associated with changes in host lipid and amino acid metabolism in the periphery and transcriptional regulation of neuroinflammation and energy utilization in the brain.

Link: https://doi.org/10.1128/msystems.01601-24

With age the immune system becomes (a) ever less capable, but also (b) ever more inflammatory and overactive. Sustained inflammation is disruptive to tissue structure and function, contributing to age-related conditions, while the growing incapacity leads to an inability to sufficiently defend against infectious pathogens, destroy senescent cells, and destroy cancerous cells. The immune system is complex, the regulation of inflammation particularly so, and there are any number of measures that to some degree reflect the aging of the immune system. Not all of them are good, different measures are better or worse in specific contexts, and there is some degree of uncertainty over the quality of any given measure.

Identifying biomarkers of aging is essential for understanding their effects on health, disease, and responses to longevity-promoting interventions. Immunological biomarkers can help differentiate between changes that are driven by aging and those specific to diseases, which is particularly important for conditions that predominantly affect the elderly.

Novel biomarkers, such as the inflammatory aging clock (iAge), leverage deep learning to quantify chronic systemic inflammation and have shown strong correlations with multimorbidity and frailty. Additionally, immune cell proportion changes have been identified as significant biomarkers of aging. Recent studies using single-cell RNA sequencing (scRNA-seq) have revealed novel shifts in immune cell compositions, highlighting the complex and dynamic nature of immune aging. Moreover, lifestyle modifications, including diet and exercise, have shown promise in improving immune aging by positively impacting immunosenescence biomarkers. Additionally, certain drug interventions, such as metformin or mTOR inhibitors, offer targeted therapeutic benefits for conditions associated with immune aging.

This review aims to update the understanding of the clinical significance of immune aging, including its phenotypic and functional changes, and model immune aging in humans. We explore novel biomarkers and their roles, as well as potential strategies for mitigating the adverse effects of immunosenescence through targeted therapies and lifestyle modifications.

Link: https://doi.org/10.1093/jimmun/vkae036

Today's open access paper merges discussion of a number of related topics. Firstly mutation rate in cancer tissue and its relationship to success in immunotherapy, secondly mutation rate in normal tissues as a risk factor for the development of cancer, and thirdly the radically different cancer risks exhibited by different mammalian species. It is well known that long-lived, large species have a much reduced cancer risk relative to short-lived, small species, and as researchers note here, this relationship is better mapped to mutation rates rather than to size or life span. Separately, within a species, cancer is clearly an age-related condition, where risk relates to the accumulated burden of somatic mutations within tissues.

Can the comparative biology of cancer and DNA damage lead to novel approaches to treat cancer or reduce cancer risk in humans? As for all aspects of comparative biology, it is entirely unclear as to whether even the discovery of an influential single genetic difference could give rise to a useful basis for therapy in the near term. On some time scale humanity will engineer itself, create better genomes. We stand a fair way removed from the ability to safely adopt even single gene differences at this time, however. Delivery of gene therapies to desired tissues in adults is a challenge, understanding second order effects is a challenge, and we don't know what we don't know.

Super-high tumor mutational burden predicts complete remission following immunotherapy: from Peto's paradox to druggable cancer hallmark

The somatic mutation theory predicts that cancer risk should scale proportionally with lifetime cell divisions; yet large-bodied and long-lived species exhibit lower-than-expected cancer incidence - a long-standing contradiction termed Peto's paradox. Although Peto's paradox has puzzled scientists for nearly half a century, its underlying mechanisms remain incompletely understood. This study clarifies this enigma by presenting novel evidence: larger-bodied animals generally exhibit a lower-than-expected cancer incidence relative to their body mass, whereas life expectancy only weakly correlates with cancer risk across species. In sharp contrast, cancer incidence in humans is strongly age-dependent, rising exponentially after the age of 40, indicating that chronological aging contributes to the majority (more than 80%) of lifetime cancer risk.

Through comparative analysis of cross-species mutation rates, this study reconciles the conflict between the age-dependent cancer risk in humans and the inter-species variability encapsulated in Peto's paradox. As an iconic example, elephants have evolved enhanced DNA repair mechanisms, notably through expanded copies of the TP53 gene, to curb mutagenesis and preserve genomic integrity, effectively suppressing mutational accumulation within a tolerable amount despite their massive body size and long lifespans. Conversely, smaller and short-lived animals like mice accumulate mutations at a much faster rate, which corresponds to their higher-than-expected cancer incidence.

Notably, this study unifies these observations by identifying a universal pattern: both somatic mutation rate and cumulative lifetime mutation burden correlate strongly with cancer risk across species, positioning mutational burden as a fundamental and evolutionarily conserved hallmark of cancer, transcending species boundaries.

One might view this paper as a companion to a recent discussion of the greater vulnerability of the aged brain to amyloid-β toxicity. Here, researchers point out the dysregulation of RNA splicing in aged neurons, and note its contribution to a greater vulnerability to forms of cell stress. Degenerative aging is formed of many contributions, and every perturbation in normal cell metabolism leaves cells vulnerable to other forms of change and damage. It builds upon itself, degrading function, until some major catastrophe results, both at the level of individual cells and their survival, and at the level of tissues and organs. Addressing the dysregulation of RNA splicing is the subject of a few programs in academia and startup biotech companies such as SENISCA, but these remain at relatively early stages of development.

Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue.

Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins - like the dementia- and ALS-associated protein TDP-43 - mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity, and the failure to respond to new stress events.

Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.

Link: https://doi.org/10.1038/s41593-025-01952-z

Neurodegenerative conditions are clearly associated with the chronic inflammation of aging. Unresolved inflammatory signaling is harmful to tissue structure and function, and a broad range of evidence points to dysregulated immune cell function in the brain as an important contribution to pathology. Inflammatory signaling is complex, however, and finding ways to intervene in unwanted sustained inflammatory reactions that do not also sabotage normal necessary short-term inflammatory reactions has so far proven to be challenging. Here, researchers focused on a well-studied innate immune regulator of inflammation, STING, and show that disabling it can reduce both inflammation in the brain and the progression of Alzheimer's pathology in a mouse model of the condition.

While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches. To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted STING in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition.

Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons. These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD.

Link: https://doi.org/10.1002/alz.70305

An extensive literature of epidemiology demonstrates that being overweight correlates with increased age-related disease, increased medical expenditure, and increased mortality. The greater the excess weight, the worse the outcome. While human studies can largely only uncover correlations between lifestyle choice and health, animals studies convincingly demonstrate that carrying too much visceral fat is disruptive to health and life span. Visceral fat tissue is metabolically active, promoting increased chronic inflammation via a range of mechanisms.

The human evidence leans in the direction of harms being proportional to both the amount of excess visceral fat and the length of time for which that fat is carried. For example, consider the studies in which the highest lifetime waist circumference measure produces better correlations with outcomes in aging than more recent measures of weight and visceral fat burden. In a similar vein, in today's open access paper, researchers show that overweight individuals who achieved sustained weight loss starting in mid-life exhibit a much reduced risk of chronic disease in later life. The point to take away from all of this is that excess visceral fat tissue is very harmful.

Weight Loss in Midlife, Chronic Disease Incidence, and All-Cause Mortality During Extended Follow-Up

Few studies have examined long-term health benefits among individuals with sustained weight loss beyond its association with decreased diabetes risk. This cohort study analyzed data from 3 cohorts that included repeated height and weight measurements: the Whitehall II study (WHII; baseline, 1985-1988), Helsinki Businessmen Study (HBS; baseline, 1964-1973), and Finnish Public Sector study (FPS; baseline, 2000). Participants were categorized into 4 groups based on their first 2 weight assessments and followed up for morbidity and mortality outcomes. Data analyses were conducted between February 11, 2024, and February 20, 2025. Midlife BMI change was categorized as persistent BMI less than 25, BMI change from 25 or greater to less than 25, BMI change from less than 25 to 25 or greater, and persistent BMI of 25 or greater.

There were 23,149 participants, including 4,118 men and women (median age at first visit, 39 years) from WHII, 2,335 men (median age at first visit, 42 years) from HBS, and 16,696 men and women (median age at first visit, 39 years) from FPS. During a median follow-up of 22.8 years, after adjusting for smoking, systolic blood pressure, and serum cholesterol at the first evaluation, WHII participants with weight loss had a decreased risk of developing chronic disease (hazard ratio [HR], 0.52) compared with participants with persistent overweight. This finding was replicated after excluding diabetes from the outcome (HR, 0.58). The corresponding HR in FPS was 0.43 over a median follow-up of 12.2 years. In HBS, weight loss was associated with decreased mortality (HR, 0.81) during an extended follow-up (median 35 years).

Calorie restriction is well known to slow aging in mammals. Short-term improvements in metabolism are fairly similar across mammalian species, but short-lived mammals show a much greater extension of life span in response to calorie restriction than is the case in long-lived mammals such as our own species. Why this is the case remains to be determined, but one might suspect that the answer lies somewhere in the still incompletely cataloged details of autophagy - how exactly autophagy changes with age, and how exactly autophagy differs between species. Researchers have demonstrated that the cellular maintenance processes of autophagy are required to function correctly in order for a slowing of aging to result from calorie restriction, making it the first place to look.

Ovarian aging results in decreased fertility and endocrine function. In mice, caloric restriction (CR) maintains ovarian function. In this study, we determined whether CR also has a beneficial effect on reproductive longevity in the nonhuman primate (NHP). Ovaries were collected from young (10-13 years) and old (19-26 years) rhesus macaques who were either on a diet of moderate caloric restriction or a control diet for three years. To test the effect of CR on follicle number, follicles were analyzed in histological sections from animals across experimental cohorts: Young Control, Young CR, Old Control, Old CR (n = 4-8/group).

In control animals, there was an age-dependent decrease in follicle numbers across all follicle stages. Although there was no effect of diet on total follicle number, the follicle distribution in the Old CR cohort more closely resembled that of young animals. The subset of Old CR animals that were still cycling, albeit irregularly, had more primordial follicles than controls. Assessment of collagen and hyaluronic acid matrices revealed that CR attenuated age-related changes to the ovarian microenvironment. Overall, CR may improve aspects of reproductive longevity in the NHP, but the timing of when it occurs during the reproductive lifespan is likely critical.

Link: https://doi.org/10.18632/aging.206253

Raised blood pressure is damaging in a range of ways, the most obvious of which is pressure damage to sensitive tissues. For example, high blood pressure increases the pace of rupture of capillaries. In the brain these microbleeds leave areas of permanent damage known as hyperintensities for their appearance in imaging of brain tissue. This form of harm adds up over time, and is well demonstrated to correlate with loss of cognitive function and the development of dementia.

Dementia is a leading cause of death and disability worldwide. Here we tested the effectiveness of blood pressure (BP) reduction on the risk of all-cause dementia among 33,995 individuals aged ≥40 years with uncontrolled hypertension in rural China. We randomly assigned 163 villages to a non-physician community healthcare provider-led intervention and 163 villages to usual care. In the intervention group, trained non-physician community healthcare providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic BP goal of <130 mmHg and a diastolic BP goal of <80 mmHg, with supervision from primary care physicians.

Over 48 months, the net reduction in systolic BP was 22.0 mmHg and that in diastolic BP was 9.3 mmHg in the intervention group compared to usual care. The primary outcome of all-cause dementia was significantly lower in the intervention group than in the usual care group (risk ratio: 0.85). Additionally, serious adverse events occurred less frequently in the intervention group (risk ratio: 0.94). This cluster-randomized trial indicates that intensive BP reduction is effective in lowering the risk of all-cause dementia in patients with hypertension.

Link: https://doi.org/10.1038/s41591-025-03616-8

One of the major challenges in aging research is establishing the relative importance of the various well-known different mechanisms, hallmarks, and dysfunctions of aging. This is large part because biological systems and their relationships to one another are not fully mapped and understood at the detail level. Mitochondrial dysfunction is a great example; mitochondria are enormously complex, and even very important processes such as mitophagy are not completely understood in detail. Thus there is considerable debate over the importance of mitochondrial DNA damage to aging.

One of the pillars of supporting evidence for the importance of mitochondrial DNA damage in aging comes from the harmful effects of mutated mitochondrial DNA polymerase gamma (POLG) in mice. This genetic change impairs mitochondrial DNA maintenance machinery in a way that produces a large burden of mutations in mitochondrial DNA, loss of mitochondrial function, and accelerated measures of aging and age-related disease. In today's open access paper, researchers produce a similar burden of mitochondrial DNA in mice without the full presence of the disabling mutation in POLG - and these animals do not exhibit the expected dramatic loss of mitochondrial function. This lets us hypothesize that other functions of POLG are important in mitochondrial function, and undermines the argument for the importance of stochastic mitochondrial DNA damage.

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice

Mitochondrial DNA (mtDNA) mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear.

Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced.

To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal.

These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

The original Pace of Aging that emerged from analysis of Dunedin Study data was a form of epigenetic clock. Here, what the researchers are calling Pace of Aging is instead a form of aging clock derived from clinical chemistry and other simple measures of function such as grip strength. Further, it was generated from data obtained from different study populations. It is not the same at all! There is nothing in common between these assessments. It seems unhelpful to keep the same name. That said, at the present time the use of clinical data as a basis for an aging clock seems more helpful than use of omics data, as one can at least make some attempt to hypothesize regarding the underlying causes for changes in the aging clock output following interventions.

Originally developed using data from the Dunedin Study - a longitudinal study of individuals born in 1972-73 - the initial Pace of Aging tool focused on changes from young adulthood through midlife. A newly refined method for measuring the Pace of Aging in population-based studies provides a powerful tool for predicting risks associated with aging. The team analyzed data from two large-scale, nationally representative studies: the U.S. Health and Retirement Study (HRS) and the English Longitudinal Study of Aging (ELSA). These long-term studies follow adults aged 50 and older - along with their spouses - and collect detailed information on health, cognition, socioeconomic status, and family dynamics. The studies have been ongoing for decades and periodically enroll new participants.

The new approach makes use of data from dried blood spots, physical exams, and performance tests given to participants in their homes at up to three timepoints over eight-year follow-up intervals. Pace of Aging was examined in 19,045 participants who contributed data over 2006-2016, with additional follow-up to determine disease, disability, and mortality through 2022. In the US study, Pace of Aging was measured from C-reactive protein (CRP), Cystatin-C, glycated hemoglobin (HbA1C), diastolic blood pressure, waist circumference, lung capacity (peak flow), balance, grip strength, and gait speed.

"Our findings establish that we can measure important variability in the pace of aging in older people with a relatively limited set of measurements. These metrics consistently predict future health outcomes, including disease onset, disability, and death. And they reveal important differences in aging trajectories across population subgroups. For example, the study reported signs of accelerated aging in people with lower levels of education."

Link: https://www.publichealth.columbia.edu/news/new-pace-aging-measurement-reveals-trajectories-healthspan-lifespan-older-people

Regulation of gene expression is a matter of control over the structure of packaged nuclear DNA, determining which regions are accessible to transcription proteins. This control becomes dysfunctional with age. Evidently there will be sex differences in the outcomes of this dysfunction because males and females have different chromosomes. It remains an open question as to which of these classes of difference are important in male versus female life expectancy and outcomes in aging, and why. Here, researchers discuss the phenomenon of silent X chromosome activation in older females, and whether it might provide a significant contribution to sex differences in aging.

Unlike men, who carry one X chromosome and one Y chromosome, women have two X chromosomes in each cell. However, one of the two X chromosomes is effectively silenced. It folds into a compact structure known as the Barr body and can no longer be read. Without this mechanism, the genes on the X chromosome would be read twice as often in women as in men. Scientists have known for some time that some genes can escape inactivation in the Barr body, resulting in higher gene activity in women. These genes are suspected to influence disease.

Researchers examined the major organs of mice at different stages of life. In the older animals, the proportion of genes that had escaped was on average twice as high as in adult animals - six percent instead of three percent of the genes on the X chromosome. In some organs, the numbers were even higher: in the kidneys, for instance, nearly 9 percent. "With aging, epigenetic processes gradually loosen the tightly packed structure of the inactive X chromosome. This mainly happens at the ends of the chromosome, allowing for genes located in those regions to be read again."

Many of the genes that become active again with age are associated with disease. What effects the reactivated genes may have on disease development will need to be investigated in future studies. This doubled gene activity could have positive effects in some cases and negative effects in others. ACE2, for example - a gene that escapes in the lungs with age - can help limit pulmonary fibrosis. Increased activity of the gene TLR8 in old age, however, may play a role in autoimmune diseases such as late-onset lupus.

Link: https://www.tum.de/en/news-and-events/all-news/press-releases/details/silent-x-chromosome-awakens-with-age

Researchers have been generating aging clocks for going on twenty years now, and as one might expect there are now lot of these clocks. Even just counting the epigenetic clocks one has a great deal of choice. Most studies that make use of clocks choose to assess only a few of the more prominent options, but as today's report on a clinical trial of therapeutic plasma exchange makes clear, the right way to go about this is to assess every single clock one can obtain access to - more than 30 clocks and clock variants in this case. The primary challenge in the use of aging clocks as a means to assess the quality of a potential rejuvenation therapy is that one has no idea how any given clock will react to a specific class of intervention. Is the clock usefully weighing specific parameters that change in response to the intervention? Or weighing too little? Or weighing too much?

The only way to arrive at a comprehensive answer is to calibrate a clock against a given therapy, a lengthy process of assessing aging the old-fashioned way, by waiting to see what happens. No-one is going to run life span studies of interventions in humans for this purpose any time soon, though we might see results emerge from longitudinal studies of exercise and other lifestyle choices over the next decade or two as the use of aging clocks expands. In the absence of those studies, a next best approach is to assess as many clocks as possible for as many interventions as possible, to get a feel for how the results vary. The data in today's paper shows just how much different clocks can vary for one intervention, therapeutic plasma exchange, where it is reasonable to believe that treatment will to some degree reduce some of the dysfunctions of aging. It would be very interesting to see equivalent data for senolytics, mTOR inhibitors, and so forth.

Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange

We conducted a randomized, placebo-controlled trial to assess the safety and biological age (BA) effects of various therapeutic plasma exchange (TPE) regimens in healthy adults over 50. Participants received bi-weekly TPE with or without intravenous immunoglobulin (IVIG), monthly TPE, or placebo. Randomization was based on entry date, and treatments were blinded to maintain objectivity. Primary objectives were to assess long-term TPE safety and changes in biological clocks. Secondary goals included identifying optimal regimens. Exploratory analyses profiled baseline clinical features and longitudinal changes across the epigenome, proteome, metabolome, glycome, immune cytokines, iAge, and immune cell composition.

We demonstrate in 42 individuals randomized to various treatment arms or placebo that long-term TPE was found to be safe, with only two adverse events requiring discontinuation and one related to IVIG. TPE significantly improved biological age markers, with 15 epigenetic clocks showing rejuvenation compared to placebo. Biweekly TPE combined with intravenous immunoglobulin (TPE-IVIG) proved most effective, inducing coordinated cellular and molecular responses, reversing age-related immune decline, and modulating proteins linked to chronic inflammation. Integrative analysis identified baseline biomarkers predictive of positive outcomes, suggesting TPE-IVIG is particularly beneficial for individuals with poorer initial health status. This is the first multi-omics study to examine various TPE modalities to slow epigenetic biologic clocks, which demonstrate biological age rejuvenation and the molecular features associated with this rejuvenation.

The brain is a complex organ. In this era of aging clocks, a number of approaches have been developed to assess the biological age of the brain from neuroimaging and other data. Is one metric for brain age sufficient, however? Here researchers present evidence for different portions of the brain to undergo age-related change at different rates. The researchers correlate their novel imaging-based models of brain aging to measures of cognitive performance in their study population, which gives more weight to the work than would have been the case for modeling alone.

Brain age is a biological clock typically used to describe brain health with one number, but its relationship with established gradients of cortical organization remains unclear. We address this gap by leveraging a data-driven, region-specific brain age approach in 335 neurologically intact adults, using a convolutional neural network (volBrain) to estimate regional brain ages directly from structural MRI without a predefined set of morphometric properties.

Six distinct gradients of brain aging are replicated in two independent cohorts. For example, frontal association cortices exhibited accelerated brain aging relative to sensorimotor cortices in older adults. Spatial patterns of accelerated brain aging in older adults quantitatively align with the archetypal sensorimotor-to-association axis of cortical organization. Other brain aging gradients reflect neurobiological hierarchies such as gene expression and externopyramidization.

Participant-level correspondences to brain age gradients are associated with cognitive and sensorimotor performance and explained behavioral variance more effectively than global brain age. These results suggest that regional brain age patterns reflect fundamental principles of cortical organization and behavior.

Link: https://doi.org/10.1038/s42003-025-08228-z

Immune system function declines with age. Immune cells become more inflammatory, but at the same time less capable. Further, populations of malfunctioning and harmful immune cells grow in number. The immune system is enormously complex, and one might argue that this is the primary reason why researchers have yet to produce a full accounting of the details of immune aging. Producing data is straightforward, but connecting the many different views of cell state that can be produced via omics technologies into a coherent whole is very much more challenging. Here, researchers focus on epigenetic changes, and the summary is illustrative of the present degree to which gene expression data can be readily connected to specific functions.

Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases.

In CD8+ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4+ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism.

Understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations.

Link: https://doi.org/10.1186/s12929-025-01146-6

One of the larger sources of harmful particulate air pollution is the use of solid fuel (wood, coal, and the like) for heating and cooking at home. This is much more prevalent in poor populations and regions than in wealthier parts of the world, but when it comes to risk a coal fireplace is a coal fireplace regardless of how wealthy one is. A large weight of evidence links exposure to particulate matter with an accelerated progression of age-related conditions and increased mortality. The more particulate matter, the worse the outcome. The primary mechanism is thought to be chronic inflammation resulting from the reaction of respiratory system tissues to inhaled particles.

In today's open access paper, researchers process epidemiological data from Chinese populations to quantify the harms done by exposure to solid fuel particulate matter in the home. The effect size is quite large. The fraction of people who age into their 60s without developing a chronic disease or sizable loss of cognitive function is 30% to 40% lower for those who use solid fuel. It is worth noting that fewer than 1 in 10 individuals in this population made it into their late 60s without developing some form of age-related disease or significant loss of function - a reminder that dysfunction and disability lies in all of our futures, if nothing is done to accelerate the development of rejuvenation therapies.

Association between with household solid fuel use and successful aging among older people in China: a cross-sectional and perspective study from CHARLS

A total of 4,047 participants (2,347 men and 1,700 women with the average age of 67.05 ± 6.05 years) from the China Health and Retirement Longitudinal Study 2011 were included in cross-sectional analyses. 2,517 participants at baseline were included in longitudinal analyses and were followed up in 2018. Successful aging was defined according to five components (without major diseases; without disability; high cognitive functioning; without depressive symptoms; active engagement with life).

In cross-sectional analyses, the participants who used solid fuel (coal or crop residue/wood) for cooking and heating had lower prevalence of successful aging than those who used clean fuel (solar energy, natural gas, liquefied petroleum gas or electricity). During the follow-up, 175 (6.95%) participants experienced successful aging. In the longitudinal analysis, after multivariable adjustment of age, sex and other risk factors, individuals who used solid fuel for cooking showed a lower ratio of successful aging, with corresponding odds ratio of 0.66. Consistently, individuals reported solid fuels use for heating were associated with lower odds ratios of successful aging (odds ratio = 0.59). In addition, a self-reported switch from clean to solid fuel or from solid fuel to clean were also significantly associated with successful aging.

Researchers here provide evidence for 5 days of injections with 25-hydroxycholesterol to be senolytic in the vasculature of mice, reducing the harmful burden of senescent cells to reduce age-related aortic stiffness. There may be other mechanisms involved, but the researchers focused on clearance of senescent cells and the potential pathways by which this occurs in response to increased levels of 25-hydroxycholesterol. The comparison with the genetic model of senescent cell clearance is particularly interesting. Whether this treatment also provokes programmed cell death of senescent cells meaningfully in other tissues is an open question left unexamined in this short paper, though earlier work did test the senolytic capacity of 25-hydroxycholesterol in a number of different cell types in vitro.

Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age-related aortic stiffening is driven, in part, by cellular senescence - a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25-hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice.

Old (22-26 months) p16-3MR mice, a transgenic model allowing for genetic clearance of p16-positive senescent cells with ganciclovir (GCV), were administered vehicle, 25HC, or GCV to compare the efficacy of the experimental 25HC senolytic versus genetic clearance of senescent cells. We found that short-term (5 day) treatment with 25HC reduced aortic stiffness in vivo, assessed via aortic pulse wave velocity to a similar extent as GCV. Ex vivo 25HC exposure of aorta rings from the old p16-3MR GCV-treated mice did not further reduce elastic modulus (measure of intrinsic mechanical stiffness), demonstrating that 25HC elicited its beneficial effects on aortic stiffness, in part, through the suppression of excess senescent cells.

Improvements in aortic stiffness with 25HC were accompanied by favorable remodeling of structural components of the vascular wall (e.g., lower collagen-1 abundance and higher α-elastin content) to a similar extent as GCV. Moreover, 25HC suppressed its putative molecular target CRYAB, modulated CRYAB-regulated senescent cell anti-apoptotic pathways, and reduced markers of cellular senescence. The findings from this study identify 25HC as a potential therapy to target vascular cell senescence and reduce age-related aortic stiffness.

Link: https://doi.org/10.1111/acel.70118

A sizable body of epidemiological evidence indicates that particulate air pollution accelerates the onset and progression of age-related disease. The most plausible mechanism is an increase in chronic inflammation via the interaction of these particles with respiratory system tissues. A few very compelling natural experiments exist, in which similar populations happen to have different exposure to particulates, such as in parts of China or the Puget Sound region. Here, researchers take a more model-based approach to estimating future trends for cardiovascular disease resulting from particulate matter exposure. Of note, and as often the case in this sort of studies, individual risk is falling while overall incidence is rising. This is the demographic transition in action. The average age of the population is increasing, and there are more older people to suffer age-related disease.

This study aims to analyze the global trends and projected burden of cardiovascular diseases (CVD) attributable to particulate matter (PM) pollution. The objectives are to assess spatiotemporal trends, sociodemographic variations, and gender differences and to forecast the future burden using data from the Global Burden of Disease (GBD) 2021 study.

We utilized data from GBD 2021 to evaluate age-standardized mortality rates (ASMR) and disability-adjusted life years (DALYs) of CVD attributable to PM from 1990 to 2021. Age-period-cohort models and Joinpoint regression analysis were employed to evaluate temporal trends. The Bayesian age-period-cohort (BAPC) model, which incorporates prior information to improve prediction stability, was selected to project the future burden up to 2045 due to its robustness in handling long-term epidemiological trends.

Between 1990 and 2021, global number of deaths and DALYs for CVD attributed to PM increased by 91.68% and 78.89%, respectively. Despite these increases, ASMR and age-standardized DALYs rates declined significantly, especially among females. The burden disproportionately affected low- and middle- Sociodemographic Index (SDI) regions, with significant gender and age differences. The elderly population and regions with lower SDI will bear the greater burden. Predictions indicate that by 2045, the number of deaths and DALYs will increase by approximately three times, with females experiencing a more pronounced rise.

Link: https://doi.org/10.1186/s12872-025-04724-6

Brain-derived neurotrophic factor (BDNF) is a circulating signal molecule know to produce neuroprotective effects, aiding neurons to resist stress. It may be involved in supporting some of the functions of neurons. Further, it encourages neurogenesis, the production of new neurons from neural stem cell populations and their integration into existing neural circuits. This is essential for memory, learning, and what little capacity for regeneration exists in the central nervous system. More circulating BDNF produces more neuroprotection, more neurogenesis, better defense against the aging of the brain. Today's open access paper provides one example from the many lines of evidence to support this assertion.

From what is presently known, BDNF appears to be one of a short list of circulating signal proteins for which increased levels (presumably up to some safe upper bound) produce effects that are near all beneficial. Others include α-klotho, follistatin, and VEGF. Circulating proteins with this characteristic are good targets for long-lasting gene therapies that can make use of proven, low-cost technologies. One can use a single fat pad injection of a small amount of even an inefficient gene therapy vector, such as off-patent AAV serotypes or PEI conjugated plasmids, to transduce enough cells to make a difference. The transduced cells become factories for the production of the desired signal molecule, and that production can last for years to decades.

Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study

Brain derived neurotrophic factor (BDNF) is the most abundant and extensively researched neurotrophin in the mammalian brain. It protects neurons from stress and neurotoxicity, and supports neurogenesis, development, and differentiation of neurons. Furthermore, BDNF production and signaling are associated with neurophysiological processes such as long-term potentiation (LTP). During the aging process, BDNF levels increase in response to oxidative stress, providing partial antioxidant defense.

In humans, directly measuring BDNF levels in the brain is challenging. Instead, BDNF levels in blood are used as a proxy, as supported by animal studies demonstrating that BDNF can cross the blood-brain barrier bidirectionally and that peripheral and central BDNF levels are closely associated. Regarding human studies, higher blood BDNF levels have been associated with a slower rate of cognitive decline in Alzheimer's disease, and a reduced risk of conversion to dementia. However, it remains uncertain whether blood BDNF levels are associated with the risk of progression to mild cognitive impairment (MCI), which is considered as a pre-dementia state or a high risk stage of dementia, in cognitively normal (CN) individuals. Given that various modifiable lifestyle factors, including physical and cognitive activities, and dietary habits, can increase blood BDNF levels, elucidating the association between BDNF levels and progression to MCI is very meaningful in terms of the prevention of late-life cognitive decline.

In this study, we aimed to investigate whether higher serum BDNF levels are associated with a reduced likelihood of progressing to MCI over a four-year follow-up period in CN older adults. Longitudinal analyses were conducted using follow-up data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study. Among the 274 participants, 26 developed MCI during follow-up. The high BDNF group had a significantly lower incidence of MCI compared to the low BDNF group (hazard ratio [HR], 0.27. This association persisted even after adjusting for BDNF Val66Met polymorphism, amyloid PET positivity, vascular risk factors, cholesterol levels, triglycerides, homocysteine, BMI, smoking, alcohol, TBI history, CES-D, and MMSE scores (HR, 0.14). Subgroup analyses further revealed that the association was significant only in women, individuals younger than 75 years, those with less than a college degree, and amyloid PET-negative individuals.

These findings suggest a protective role of BDNF against clinical progression to MCI in cognitively healthy older individuals. This effect appears to be more prominent in women, as well as in relatively younger, less educated, and amyloid PET-negative individuals.

The nature of small molecule drugs and human metabolic variability is that effect sizes are usually modest and responses usually vary widely across the population. Some patients see little benefit, some patients have side-effects that limit use, and there is always the opportunity to find an alternative path to a new drug that can be used by those people. Separately, investors don't like risk, and tend to favor investment into development focused on proven markets and proven mechanisms of action. Thus wherever there is a sizable market for small molecule drugs for a specific outcome, such as control of blood pressure, there will be continued development to produce ever more small molecule drugs aimed at that outcome. Whether this is good or bad is a matter of perspective, but a large fraction of investment and activity in the pharmaceutical industry is focused on producing "me too" drugs and incremental improvements.

The data from the Launch-HTN trial show that lorundrostat, an aldosterone synthase inhibitor, is a safe and effective treatment for people with uncontrolled or resistant hypertension, demonstrating consistent blood pressure reductions across a large and diverse patient population. It is the largest phase three trial of an aldosterone synthase inhibitor for the treatment of hypertension. The results are a major milestone toward delivering the first targeted aldosterone synthase inhibitor treatment for uncontrolled or resistant hypertension, which could benefit millions of people affected by the conditions.

"Despite available treatments, more than 40% of adults with hypertension worldwide are not reaching their blood pressure goal. There's a major need to explore novel therapies for hypertension and the Launch-HTN trial addressed this need. The aldosterone pathway plays important role in blood pressure regulation, and leads to blood pressure related complications such as heart failure and kidney problems." 30% of people with hypertension have dysregulated aldosterone, meaning that the body's natural mechanism for controlling aldosterone is disrupted. Lorundrostat was designed to reduce aldosterone levels by inhibiting CYP11B2, the enzyme responsible for its production.

The Launch-HTN trial was a global, randomized, double-blinded, placebo-controlled Phase 3 trial, which enrolled eligible adult participants who failed to achieve their blood pressure goal despite being on two to five antihypertensive medications. Lorundrostat 50 mg dosed once daily demonstrated clinically meaningful and sustained reductions in systolic blood pressure, with a 16.9 mmHg reduction at Week 6 (-9.1 mmHg placebo adjusted) and a 19 mmHg reduction at Week 12 (-11.7mm placebo adjusted).

Link: https://www.eurekalert.org/news-releases/1085086

It is well established that exercise improves long-term health in animal studies and correlates with improved health in human studies. Here, researchers show a correlation between sedentary behavior and accelerated brain aging. This is one of many, many similar studies that demonstrate a link between level of exercise and functional outcomes in older individuals. It remains the case that maintaining physical fitness into later life has by far the greatest weight of supporting evidence of all the approaches known to modestly slow aging.

Evidence suggests that midlife physical activity may reduce Alzheimer's disease (AD) risk. In at-risk individuals, we investigated midlife physical activity changes in relation to AD-related pathologies. We included 337 cognitively unimpaired adults with baseline and follow-up physical activity evaluations within 4.07 ± 0.84 years. We performed multiple regressions considering follow-up amyloid-PET burden and MRI-based medial temporal lobe cortical thickness as outcomes.

Remaining sedentary was associated with lower cortical thickness compared to doing limited physical activity, maintaining adherence, or becoming adherent to WHO recommendations on physical activity. Becoming adherent to recommendations was linked to lower amyloid burden compared to becoming non-adherent. Increased activity amounts showed a dose-dependent association with lower amyloid burden.

Link: https://doi.org/10.1002/alz.70007