Fight Aging!

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