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