Longevity Papers

Modulation of mitochondrial dynamics is a viable strategy for lifespan extension. Reactive oxygen species (ROS) play key roles in aging, acting either as signaling molecules to facilitate longevity-associated processes or as stimulators of oxidative stress, exerting deleterious effects on physiological functions. The hybrid molecule MC1 is designed by integrating melatonin and catechol moieties to reconstruct mitochondrial dynamics and selectively regulate the generation of ROS. MC1 combats cell senescence under oxidative stress and DNA damage, and reprograms the mitochondrial energy metabolism by inhibiting the tricarboxylic acid cycle and glycolysis, while initiating fatty acid oxidation to increase energy production. More importantly, MC1 significantly extends the lifespan of

Why some individuals maintain good level of cognitive performances during aging, others dont or even progress toward Alzheimer disease. We profiled the hippocampal proteome of adult LOU/c/Jall rats, a strain associated with spontaneous cognitive longevity, and compared this proteomic state with a published human hippocampal Alzheimer disease dataset. Because individual protein changes did not survive proteome-wide correction, interpretation was based on convergent pathway-level, cell-type enrichment and cross-species directional analyses. The LOU hippocampus displayed a structured remodeling of mitochondrial, lysosomal, proteostatic and synaptic systems. Oligodendrocyte-associated nuclear-encoded complex I/III components were reduced, whereas neuronal mitochondrial aminoacyl-tRNA synthetases, V-ATPase, SNARE-related proteins and inhibitory-transmission markers were increased. CD200 was markedly reduced, but this occurred without accompanying complement, microglial, astrocytic or inflammatory activation signatures. Cross-species overlay indicated that several LOU-associated axes were directionally opposed to late Alzheimer disease, particularly synaptic vesicle and inhibitory-transmission programs, whereas myelin-associated changes occupied a lower-amplitude and non-inflammatory position along an axis altered in early Alzheimer disease. These findings identify a hippocampal proteomic configuration associated with the LOU resilience phenotype and suggest that successful brain aging and Alzheimer disease may involve opposing states of shared hippocampal molecular systems.

Exercise is fundamental to healthy aging, yet how it mitigates age-related molecular changes and how fitness level shapes exercise responses remain unclear. To address these questions, we performed transcriptomics, lipidomics and metabolomics on skeletal muscle of young and older adults with differing physical function, both before and after an acute bout of submaximal exercise. At baseline, older adults exhibited reduced expression of genes associated with cellular respiration and energy metabolism compared to young adults with comparable activity levels. Here we found that 50% of these age-related differences were absent in trained older adults, resulting in profiles resembling those of young adults. Although all participants displayed transcriptional immune and stress responses upon acute exercise, the magnitude of these responses in older adults was positively correlated with their physical fitness. Integrated multiomic analyses further revealed links among mitochondrial respiration, lipid metabolism, stress responses and NAD

Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes and is synthesized in part via the rate-limiting enzyme PCYT1A. In humans, hypomorphic PCYT1A variants cause diverse disorders. To define how graded reductions in PC synthesis affect organismal physiology, we generated and characterized a series of mutant alleles in the Caenorhabditis elegans homolog pcyt-1, including variants corresponding to disease-causing human mutations, as well as an auxin-inducible degradation (AID) allele. We identify a clear allelic hierarchy. The V146M variant is embryonic lethal, whereas A97T is largely benign. P154A is temperature-sensitive, and C211Y causes growth delay, reduced brood size, sterility, and lengthened lifespan at standard temperature. Phenotypes of C211Y are rescued by choline, CDP-choline, or phosphatidylcholine supplementation, supporting reduced enzymatic function. Lipidomic profiling reveals that decreased PC synthesis consistently increases long-chain polyunsaturated fatty acids (LCPUFAs) in both PCs and PEs at the expense of shorter saturated species, without markedly altering the PC/PE ratio at 20°C. At elevated temperature, the P154A variant exhibits protein instability and a decreased PC/PE ratio. Despite significant lipid remodeling, canonical ER, mitochondrial, and metabolic stress GFP-based reporters are not activated; only the oxidative stress response is elevated, consistent with increased peroxidation-prone LCPUFAs in the pcyt-1 mutant. Acute auxin-induced degradation of PCYT-1 in larvae causes developmental arrest, while acute PCYT-1 degradation in adults disrupts oogenesis, demonstrating a continuous requirement for PC synthesis. Together, these findings establish a functional pcyt-1 allelic series and show that limiting PC synthesis drives compensatory remodeling toward LCPUFA-enriched membranes while rendering the germline particularly vulnerable.

Innate immune memory (trained immunity) is mediated by epigenetic and metabolic reprogramming of innate immune cells and hematopoietic progenitors, enabling altered responses to subsequent challenges. Mechanistically conserved across eukaryotes, trained immunity in mammals operates as a dynamically regulated, life-phase-specific system. The demands and constraints on innate immune memory shift across the life span: from tolerogenic programming and maternal immune transfer in fetal and neonatal life, through establishment of innate set points during early-life microbial colonization, to full integration of central and peripheral training with adaptive immunity in adulthood. Aging disrupts this integration, producing simultaneous immunosenescence and inflammaging, potentially through cumulative maladaptive training at the hematopoietic stem cell level. In this Review, we examine how the exposome continuously shapes innate immune trajectories across life and discuss implications for trained immunity-based strategies to limit maladaptive inflammation.

The intestine is one of the first organs to show signs of aging, including cellular changes, microbiota shifts, and reduced regenerative capacity. The different components of the gut-such as the epithelium (which is directly exposed to a diverse array of host-microbe interactions), the microbiota itself, and the underlying enteric nervous system-likely contribute to aging in distinct ways. Understanding their individual and interactive roles is key to elucidating the mechanisms of intestinal aging. To better understand the contribution of individual components to intestinal aging, we analyzed gut tissue characteristics and compared these parameters with the composition and gene expression levels of colonic organoids by using two mouse strains: the aging-resistant SAMR1 line and the SAMP8 line, which exhibit an accelerated aging phenotype. Here, we demonstrate that colonic organoids derived from these mice retain the age-related characteristics of the colonic tissue, including changes in morphology and cellular composition. Furthermore, introducing the enteric nervous system into organoid culture revealed that the age of the epithelium exerts a more pronounced influence on the aging phenotype than the age of the innervating tissue. Interestingly, successfully delivering fecal extracts to organoids revealed that gut microbiota metabolites from aged animals resulted in an aging phenotype of the gut epithelium in vitro. In summary, our findings indicate the impact of aging on the gut epithelium and its interplay with the nervous system and microbiota. This may in future provide new strategies for slowing the aging process in the gut by manipulating the gut commensals.

Sarcopenia and neuromuscular degeneration are key drivers of functional decline during ageing and arise not solely from muscle loss but also from failure of mitochondrial and metabolic stress adaptation across the neuromuscular system. Mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, defective quality control and redox imbalance, contributes directly to muscle weakness, neuromuscular junction instability and motor unit degeneration. However, the upstream mechanisms governing the transition from adaptive remodelling to degenerative collapse remain incompletely defined. Protein arginine methyltransferases (PRMTs) have emerged as critical modulators of mitochondrial and metabolic stress signalling. Beyond epigenetic regulation, PRMTs influence signalling pathways that intersect with AMP-activated protein kinase (AMPK)-Forkhead box O (FOXO) and mechanistic target of rapamycin (mTOR), thereby regulating mitochondrial biogenesis, selective autophagy and mitophagy, proteostatic balance, and anabolic restraint. Distinct PRMT family members exert non-redundant functions across muscle fibres, satellite cells and motor neurons, collectively shaping neuromuscular stress resilience. We propose that PRMTs act as molecular rheostats that bias cellular responses to mitochondrial stress towards adaptive resolution or progression to neuromuscular degeneration, thereby positioning PRMT-regulated metabolic signalling as a unifying mechanism underlying sarcopenia and compromised healthspan.

Identifying the drivers of cellular senescence that contribute to the decline in vascular function with age and disease is critical for developing restorative interventions. Here, we investigated how increased mechanical stress from extracellular matrix (ECM) stiffening shapes endothelial cell (EC) senescence. We developed a 3D human in vitro model that decouples mechanical stress from inflammatory or biochemical signals, enabling the study of senescence responses to tissue stiffening alone. We found that matrix stiffening induces an EC senescence phenotype with elevated p16/p21 and an immunomodulatory senescence-associated secretory phenotype (SASP), in the absence of inflammatory signals. This mechano-induced senescence activates Notch signaling, and treatment with an FDA-approved γ-secretase inhibitor attenuates stiffness-induced senescence. Analysis of fibrotic capsule tissue from patients with synthetic breast implants, a model of localized, mechanically driven fibrosis, validated an increase in p16

Age-related breakdown of the blood-brain barrier (BBB) is associated with cerebrovascular and neurodegenerative diseases, yet its underlying mechanisms remain unclear. Here, we find that BBB leakage begins in midlife and is driven primarily by increased endothelial caveolar transcytosis rather than tight junction disruption. AAV-mediated knockdown of caveolin-1 or restoration of Mfsd2a expression reduces endothelial vesicle formation and BBB leakage in aged mice. Transforming growth factor (TGF)-β1, originating from both brain and systemic circulation, increases with aging and directly suppresses Mfsd2a transcription via the Tgfbr2-Smad2/4 signaling in brain microvascular endothelial cells, thereby promoting caveolar transcytosis and BBB leakage. Endothelial-specific Tgfbr2 knockout or pharmacological inhibition of TGF-β signaling reduces endothelial caveolar transcytosis and BBB leakage and attenuates neurological dysfunction in aged mice. These findings identify TGF-β1-induced endothelial transcytosis as a central mechanism underlying age-related BBB breakdown and offer potential therapeutic targets for preserving brain health in age-related neurovascular disorders.

Superoxide dismutase 1 (SOD1), a copper-dependent antioxidant, is essential for redox homeostasis, and its decline drives renal senescence and fibrosis. However, the mechanisms linking profibrotic signaling to SOD1 inhibition remain unclear. Here, we identified a pathological copper-COMMD1-SOD1 axis in which intracellular copper overload paradoxically suppressed SOD1 activity. In kidney tissues from chronic kidney disease (CKD) patients and complementary in vivo and in vitro fibrotic models, we consistently observed a reduction in SOD1 activity accompanied by elevated intracellular copper levels. Lowering intracellular copper levels restored SOD1 activity, suppressed reactive oxygen species (ROS) accumulation, and alleviated cell senescence and fibrosis. Mechanistically, pathological copper overload impaired SOD1 homodimerization, the essential final step in its activation. We identified copper metabolism MURR1 domain containing 1 (COMMD1) as a key copper-sensitive mediator of this process. Copper overload acted upstream, simultaneously upregulating COMMD1 expression and enhancing its binding affinity to SOD1. This enhanced COMMD1-SOD1 interaction directly disrupted SOD1 homodimer assembly and enzymatic function. Collectively, these findings redefined the regulatory role of copper in SOD1 activity and uncovered a previously unrecognized mechanism by which pathological copper overload paradoxically suppressed SOD1 activity via COMMD1-dependent disruption of SOD1 homodimerization, providing new insight into the pathophysiology of copper dyshomeostasis-associated diseases.

Mosaic chromosomal alterations (mCAs) are a prevalent but poorly understood form of clonal hematopoiesis (CH). Whether mCAs contribute to disease independently of CHIP, and whether their large-scale genomic effects can be resolved to actionable targets, remain unknown. In 452,594 UK Biobank participants, we show that mCAs confer multimorbidity and mortality risk independent of CHIP. Notably, mCA-CHIP co-occurrence defines a very high-risk clonal state with synergistically elevated mortality, identifying a population not captured by CHIP screening alone. To resolve large mCAs to specific disease mechanisms, a cytoband-level mapping framework was developed that links mCAs to discrete genomic loci and candidate effector genes. Functional validation using single-cell transcriptomics and mouse models prioritized MYC (chr8 gain) and S100A9 (chr1 gain) as key drivers of systemic inflammation and multiorgan pathology. These findings establish mCAs as independent, synergistic, and genetically-resolvable drivers of age-related disease, with immediate implications for screening, risk stratification, and therapeutic development.

Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. We previously showed that telomere dysfunction induces synthesis of telomeric noncoding RNAs required for activation of the telomeric DNA damage response (tDDR), a driver of senescence and inflammation. However, whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Terc

Aging is intimately entangled with the reprogramming of metabolic pathways that coordinate energy production, biosynthesis, and molecular turnover. However, visualizing and understanding these metabolic underpinnings within their spatial and temporal contexts remains a major challenge. Metabolic imaging has emerged as a transformative approach that enables spatially resolved visualization of metabolic dynamics both at the molecular or cellular and organismal levels. In this review, we summarize recent advances and applications of metabolic imaging in probing aging biology, with particular emphasis on multimodal nonlinear optical imaging techniques and their applications across diverse aging models. Optical metabolic imaging provides unique insights into the mechanisms of aging by capturing metabolic alterations that span from organelle-level interactions to tissue-scale remodeling. Optical metabolic imaging enables the label-free detection of early metabolic shifts in vivo, representing an emerging frontier in aging research. Looking ahead, optical metabolic imaging holds great promise as a practical and powerful tool for clinical translation, advancing precision medicine and enhancing the diagnosis, monitoring, and evaluation of aging processes to promote human health span and longevity.

T cell output from the thymus falls throughout life and is associated with profound remodeling of the thymic stroma. To what extent the decline in T cell output is caused by aging of the hematopoietic stem and progenitor cells (HSPCs) has been difficult to define because of HSPC heterogeneity, the multi-stage process of HSPC migration, and the cross-talk between hematopoietic and stromal elements of the thymus. To address the contribution of HSPC aging on T cell development, we interrogated T cell differentiation of phenotypically defined HSPCs from young and aged bone marrow using the Artificial Thymic Organoid (ATO) system, an in vitro model which allows quantification of T cell differentiation from single HSPCs within a controlled microenvironment. Phenotypically, most HSCs from young bone marrow were CD150

Biomarkers of aging, particularly DNA methylation-based clocks, have shown promise as tools to assess whether interventions may impact the rate of biological aging. Among possible interventions physical exercise has shown protective effects against many age-associated diseases, while time-restricted feeding (TRF) has shown metabolic benefits in preclinical models. The combined effect of exercise and TRF on aging biomarkers remains largely unexplored. In this 52-week four-armed, randomized, controlled trial (clinicaltrials.gov: NCT07207044) 240 healthy adults aged 65 and above will be allocated to four groups: combined cardio and strength training (EXE), TRF, combined EXE and TRF, or control. Participants will undergo assessments at baseline, 3, 6, and 12 months, with follow-ups at 2, 5, and 10 years. The primary outcome measure is Dunedin Pace of Aging DNA methylation age with secondary measures including RNA-sequencing, metabolomics, inflammatory markers, microbiome analysis, cognitive and physical measures. By deeply phenotyping participants, the Fasting And eXercise (FAXAge) study will provide novel insights into whether TRF, EXE, or a combination can slow or reverse biological aging in older adults.

Over the past decades, numerous studies aimed to discover the fundamental cause of the aging process. Rather than a single root cause, multiple factors were identified, suggesting that aging manifests itself through a progressive degradation of different molecules, cells and in the end, entire systems, directly affecting an individual's health. To address this rapidly growing challenge, various anti-aging strategies have been proposed, among which partial reprogramming has emerged as a promising approach capable of extending both lifespan and healthspan. In this review, we summarize the historical development of aging theories, the effects of established anti-aging strategies, and the evolution of partial reprogramming using Yamanaka factors. We also highlight recent advances in overcoming the efficacy and safety limitations of partial reprogramming, as well as the remaining challenges that must be addressed to fully realize its therapeutic potential.

Prediabetes and Type 2 Diabetes represent major global health challenges and have escalated to pandemic levels. Adipose tissue functions as a critical endocrine organ, playing a central role in maintaining glucose homeostasis during fasting, feeding, and stress responses. In this study, we demonstrated that prolonged chronic hyperinsulinemic stress increases the burden of senescent adipocytes, accompanied by activation of the cGAS-STING signalling pathway. Chronic hyperinsulinemia-induced insulin-resistant 3T3-L1 and human mesenchymal stem cell-derived adipocytes exhibited elevated senescence-associated phenotypes, mitochondrial dysfunction and impaired cellular energetics. Notably, we found that mitochondrial DNA leakage triggered the cGAS-STING pathway in insulin-resistant adipocytes and mouse models. Temporal analysis revealed that mitochondrial dysfunction was detectable at earlier stages of chronic insulin exposure, preceding activation of the cGAS-STING pathway and senescence-associated markers, supporting a progressive model of cellular dysfunction. This phenomenon was also observed in adipose depots of individuals with Type 2 diabetes, underscoring the translational relevance of our findings. Targeting cGAS or STING, either pharmacologically or through genetic silencing, significantly reduced inflammatory and senescence-related features in hyperinsulinemia-induced insulin-resistant 3T3-L1 adipocytes. Furthermore, attenuation of senescence treatment with the combination of Dasatinib and Quercetin alleviated mitochondrial stress and associated adipose dysfunction. Collectively, our findings support a model in which prolonged hyperinsulinemic stress induces early mitochondrial dysfunction, followed by activation of cGAS-STING signalling and the subsequent emergence of adipocyte senescence-associated phenotypes, contributing to adipose tissue dysfunction in insulin resistance and Type 2 Diabetes.

Anti-aging pharmacology has transitioned from early exploratory lifespan-extension studies to a hallmark-informed, multi-level framework that integrates mechanistic, preclinical, and translational evidence. Using a bibliometric-guided, strategy-oriented approach, this review maps the explicit anti-aging drug literature from 2005 to 2025, identifies historically influential compounds, and evaluates their translational readiness. The field converges on three partially overlapping intervention axes: senotherapeutics targeting cellular senescence and SASP signaling, nutrient-sensing and metabolic gerotherapeutics modulating mTOR, AMPK, autophagy, and mitochondrial adaptation, and homeostasis-restoring agents reinforcing redox, inflammatory, and circadian resilience. The Top 10 anchors, prioritized by bibliometric prominence rather than clinical ranking, illustrate both potential and limitations in human translation, while emerging candidates and platform innovations highlight ongoing progress toward precision geromedicine. This synthesis provides a structured framework for interpreting historical and contemporary literature, clarifies the relationship between multi-hallmark engagement and functional outcomes, and guides rational prioritization of candidate gerotherapeutics for future research.