Longevity Papers

The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function. Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence. Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.

SKN-1, a Cap'n'Collar transcription factor in Caenorhabditis elegans, is a well-established regulator of oxidative stress responses and xenobiotic detoxification. Over the past two decades, the late Dr. T. Keith Blackwell (1957-2025) and colleagues made seminal contributions to defining its biological functions and regulatory mechanisms. Owing to its robust conservation with mammalian Nrf family proteins, SKN-1 research has yielded fundamental insights into how nutrient and stress signals modulate metabolism, proteostasis, and aging. Recently, the discovery that distinct SKN-1 isoforms execute unique physiological roles has further refined this field. In this review, we summarize how SKN-1 regulates longevity, particularly through the mTOR nutrient-sensing pathway, discuss recent advances in isoform-specific regulation, and highlight critical questions for future research.

Cellular senescence is a biological process characterized by stable cell cycle arrest that contributes to tumor suppression and tissue remodeling but can also promote aging-associated dysfunction when senescent cells persist and accumulate. Senescent cells influence neighboring and distant tissues through the senescence-associated secretory phenotype (SASP), of which extracellular vesicles (EVs) are an increasingly recognized component. This review examines how microRNAs (miRNAs) carried by EVs regulate senescence and ageing. miRNAs are key post-transcriptional regulators of senescence, particularly within the p53/p21

Insights into the genetic basis of lifespan evolution can link evolutionary theory with an understanding of health, disease and adaptation. We leverage the power of >200 generations of experimental evolution in a seed beetle to unveil the genomic architecture of lifespan evolution. Replicated populations evolved under regimes favoring either a short or long life, resulting in a near doubling of lifespan. Whole genome re-sequencing revealed that short- and long-lived lines were strongly differentiated (global FST = 0.41) and more than 700 genes showed consistent signs of divergent selection. Remarkably, short- and long-lived lines were consistently divergent in a large number of regions harboring copy-number variants (CNVs), involving >600 genes. The evolution of a long life involved many distinct biological processes, such as DNA fidelity, mitotic integrity, reproduction, metabolism, immunity and stress response. A pedigree-based genome scan for quantitative trait loci (QTLs) uncovered several QTLs with large effects on lifespan, but the genetic basis of a long life was dominated by a very large number of regions with medium and small effects. The genome-wide spatial association with QTL effects was, if anything, stronger for CNVs than for sequence variants. The genetic effects of QTLs on lifespan were positively correlated overall between the sexes, but four regions showed pronounced sex-differences. Our results show that structural variants play a significant role in the evolution of an extended lifespan and the highly polygenic genomic architecture is to some extent sex-specific, consistent with differences in physiology and life history tradeoffs between the sexes.

Cardiomyocyte senescence is a hallmark of cardiac aging and closely associated with diastolic dysfunction and heart failure in older adults. Strategies to effectively delay or reverse cardiomyocyte senescence in the aged heart remain limited. We investigated whether NAD+ replenishment regulates cardiomyocyte senescence and cardiac function in aging.

In this issue of Cell, Grońska-Pęski et al. examine how calorie restriction (CR) affects DNA mutation rates. While CR lowers the accumulation of mutations, this effect does not scale with the degree of lifespan extension. Their work raises important new questions about how CR impacts the causal mechanisms of aging.

Aging alters protein abundance throughout the body, but whether proteomic aging signatures are shared across organs, and how they are represented in RNA, remains unclear. Plasma proteomics does not measure protein abundance directly within individual organs. Here, we developed organ-specific proteomic aging clocks for eight mouse organs. The clocks retained age associations across independent cohorts but transferred poorly between organs of the same mice, indicating predominantly organ-specific aging signatures. This organ specificity extended to RNA. Applied to the transcriptomes of the genes encoding each clock's protein features, with protein-derived weights unchanged, the scores retained age associations in independent transcriptomic cohorts, with stronger associations in the corresponding organs. The strength of age associations across molecular layers also differed by organ: in paired analysis, protein scores tracked age more strongly than RNA scores in brain and skeletal muscle, with no statistically detectable difference in kidney, liver or lung, suggesting a greater post-transcriptional contribution to proteomic aging in brain and muscle. In spatial transcriptomes, protein-derived RNA scores rose with age within tissue niches, usually without detectable changes in relative niche abundance. In the brain, white matter and glia-enriched microdomains showed elevated proteomic scores compared to other regions since young age. Together, these findings support organ-specific regulation of proteomic aging and identify molecular remodeling within persistent tissue compartments.

Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.

Insulin-like signaling modulates aging and lifespan in insects. Here, we discuss a novel view of this control: insulin hormone in the adult regulates the production of the sesquiterpenoid juvenile hormone (JH) that in turn acts as the systemic regulator of aging and lifespan. Work in Drosophila establishes that insulin signaling is allatotropic - it stimulates the production and secretion of JH from the corpora allata. JH then exerts systemic effects on adult survival through its control of specific proteins, translation and proteostasis. The interdependent functions of insulin and JH allow reproduction and longevity to be coupled in many insects or decoupled in social insects with long-lived queens and in some long-lived genetic mutants of Drosophila. Features of these insulin-regulated life history syndromes are also found in the nematode Caenorhabditis elegans. Recognizing the systemic role of JH in aging provides grounds to search for analogous systems in mammals that might modulate human lifespan.

The retinal pigment epithelium (RPE) sustains lifelong proteostasis under chronic stress, yet how post-mitotic cells activate macroautophagy/autophagy when canonical kinase pathways suppress it remains unresolved. Here we demonstrate that AKT1 (protein kinase B alpha), drives autophagy through a non-canonical transcriptional mechanism triggered by isoform imbalance. In RPE and age-related macular degeneration (AMD) models, AKT2 (protein kinase B beta) hyperactivation destabilizes MTORC2 (mechanistic target of rapamycin complex 2) and engages RPS6KB/S6K (ribosomal protein S6 kinase beta) -mediated IRS-1 (insulin Receptor Substrate 1) inhibition, creating a feedforward autophagic arrest. Compensatory AKT1 activation via MTORC2 phosphorylates TERT (telomerase reverse transcriptase) at serine 824, driving nuclear translocation that is independent of telomere maintenance. In the nucleus, TERT assembles with FOXO3 (forkhead Box O3) and MYC (MYC proto-oncogene, bHLH transcription factor) into a tripartite transcriptional complex that occupies the

Food-derived protein hydrolysates frequently contain both collagen-associated hydroxyproline (Hyp) and branched-chain amino acids (BCAAs), but the biological consequences of their combination remain unclear. This study tested whether Hyp changes the effects of leucine (Leu), isoleucine (Ile), and valine (Val) on lifespan and healthspan-related phenotypes in Caenorhabditis elegans and whether these treatment effects are accompanied by coordinated microbial and metabolic remodeling. Amino acid concentrations that did not strongly disrupt bacterial food clearance were selected for lifespan, stress-resistance, motility, muscle-integrity, biochemical, microbiome, metabolomic, and transcriptomic analyses. Hyp+BCAA combinations improved lifespan- and healthspan-related phenotypes in a BCAA- and dose-dependent manner. The strongest combined treatments enhanced resistance to thermal and oxidative stress, preserved age-associated motility and muscle structure, reduced oxidative and lipofuscin-associated markers, and increased ATP-related readouts. Multi-omics profiling showed that these direct treatment effects were accompanied by distinct C. elegans-associated microbiota signatures, altered NAD precursor-related metabolites including nicotinic acid ribonucleoside (NaR), and a Leu+Hyp transcriptional response enriched for energy metabolism, proteostasis, and extracellular-matrix remodeling. Integrated microbiome-metabolome analysis identified a positive association between Rhodococcus abundance and NaR levels. These findings demonstrate that, under the tested culture conditions, Hyp+BCAA exposure improves longevity-related phenotypes and identifies microbial composition, NAD precursor metabolism, and host energy homeostasis as candidate, testable mediators.

Primary sarcopenia, the progressive loss of skeletal muscle mass and function during aging, is partly driven by anabolic resistance, a reduced ability of aged muscle to activate protein synthesis in response to nutrients and hormones. We compared 12-wk time-restricted feeding (TRF) and alternate-day fasting (ADF) interventions initiated at 3, 12, 15, or 18 mo of age in male C57BL/6J mice (analyzed at 6, 15, 18, or 21 mo, respectively). The effects of intermittent fasting on skeletal muscle were strongly age-dependent. Midlife (15 mo of age) TRF preserved lean mass, improved glucose tolerance, and increased insulin-stimulated glucose uptake in isolated muscle, whereas ADF induced broader metabolic remodeling but was associated with lean-tissue loss when initiated later in life. Muscle aging was accompanied by reduced membrane abundance of insulin receptor-plakoglobin-dystrophin glycoprotein complex (DGC) signaling assembly. However, midlife TRF was associated with greater abundance of these protein modules and enhanced postprandial AKT signaling. These findings identify midlife as a responsive window for nutritional timing interventions and link improved muscle insulin responsiveness and maintenance with diet-associated differences in sarcolemmal protein abundance and organization, although targeted perturbation studies are required to establish causality.