Aging Cell最新文献

On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving “the right treatment for the right person and the right time” through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level “omic” modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%–70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become “senolytic-resistant”. Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30%–70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16^INK4a, p21^CIP1, senescence-associated β-galactosidase (SAβgal), γH2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus-resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of proapoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as “senosensitizers”), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.

There is increasing evidence that nutrient composition, even without lowering total calorie intake, can shape lifespan through mechanisms independent of mitochondrial regulation. Brandon and colleagues recently reported that a low-protein, high-carbohydrate (LPHC) diet enriched with non-digestible cellulose, extends lifespan in mice by shifting the liver proteome through altered RNA splicing, a response different from the mitochondrial improvements typically seen with caloric restriction. The authors' findings support the “energy-splicing resilience axis,” which proposes that changes in splicing help cells adapt to energetic and nutritional stress. We discuss how diet influences spliceosomal components such as SRSF1, linking nutrient sensing, AMPK signaling, and tissue-specific resilience pathways. We also consider the splicing paradox in aging, where beneficial isoforms increase despite a concomitant increase in splicing errors. Understanding how dietary and pharmacologic interventions modulate splicing may shed light on strategies to maintain homeostatic proteomes and support healthy longevity.

Against the backdrop of the global trend toward delayed childbearing, elucidating the mechanisms underlying uterine aging has emerged as a critical biomedical priority for addressing age-related implantation failure. Through unbiased global metabolomic profiling of peri-implantation uteri across different ages in mice, we identified nicotinamide adenine dinucleotide (NAD⁺) depletion as a hallmark metabolic feature of endometrial aging. Single-cell RNA sequencing further revealed an expansion of senescent stromal cell populations, which was accompanied by a decline in NAD⁺ levels. Supplementation with NAD⁺ precursors alleviated age-related stromal senescence and endometrial dysfunction, thereby restoring the uterus' implantation competence. Mechanically, we demonstrate that CD38 derived from myeloid serves as a principal driver of uterine NAD⁺ depletion; this process accelerates stromal senescence and impairs uterine receptivity. These findings establish CD38 as a central physiological integrator that links NAD⁺ metabolism to uterine function and highlight it as a promising target for rejuvenation strategies aimed at improving reproductive outcomes in women of advanced maternal age.

Telomerase RNA (TERC) is subject to various modifications, yet the implications of these modifications for telomerase biology remain largely unexplored. In this study, we conducted a comprehensive mapping of N6-Methyladenosine (m6A) modifications within TERC RNA and elucidated their regulatory role in telomerase function. Our findings demonstrate that TERC undergoes methylation at adenosine residues A111 and A435 by METTL3. A deficiency in TERC m6A, which is also linked to various human telomerase disease-related mutations and deletions, significantly reduces telomerase activity and telomere length by disrupting the association between TERC and TERT. Mechanistically, YTHDC1 was identified as a scaffold facilitating the interaction between TERT and TERC, binding to TERT while recognizing m6A sites on TERC. Knockdown of YTHDC1 significantly diminished the interaction between TERT and TERC, thereby reducing telomerase activity and phenocopying the deficiency of METTL3. Furthermore, reconstituting wild-type YTHDC1 rescued telomere attrition, proliferation defects, and senescence in YTHDC1-knockdown alveolar epithelial cells, whereas truncated YTHDC1 (which retains m6A recognition but lacks TERT-binding capacity) failed to restore these phenotypes. Collectively, our work establishes m6A modification of TERC as a central regulator of telomerase function and reveals YTHDC1's scaffolding role in TERT-TERC assembly, shedding new light on the regulation of telomerase and related diseases.

Clinical evidence supports the anti-photoaging efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT), yet its mechanism remains elusive. Paradoxically, ALA-PDT generates reactive oxygen species (ROS), a key mediator of ultraviolet radiation (UVR)-induced photoaging, raising questions about its rejuvenating effects. Here, we employed a multi-omics approach to clarify this paradox. A UVR-induced hairless mouse model of photoaging was treated with ALA-PDT, followed by transcriptomic, proteomic, and metabolomic profiling of skin biopsies. In vitro, fibroblast senescence was induced by UV irradiation to evaluate ALA-PDT's protective effects. Mitochondrial function and citrate (CA) levels were assessed pre- and post-treatment. ALA-PDT significantly ameliorated photoaging phenotypes in mice, with multi-omics data revealing sustained improvements in epidermal structure, extracellular matrix integrity, and immune responses. Key mechanistic findings included ALA-PDT-induced mitohormesis and tricarboxylic acid cycle reprogramming, notably reduced intracellular CA. In vitro, low-dose ALA-PDT downregulated senescence markers and CA content in UV-stressed fibroblasts, concomitant with upregulated mitohormesis markers. These effects were abrogated by inhibiting mitochondrial ROS, suggesting ROS-dependent mitohormetic signaling. Collectively, our data demonstrate that low-dose ALA-PDT alleviates photoaging by mitigating cellular senescence via mitohormesis-mediated CA reduction, offering a novel metabolic intervention strategy for age-related skin disorders.

Aging is an inevitable consequence for all organisms. According to the mitochondrial free radical theory of aging (MFRTA), reactive oxygen species (ROS), which are predominantly generated in mitochondria, are assumed to play a key role. Calorie restriction (CR) delays aging by improving mitochondrial function; however, the molecular mechanisms underlying the effects of ROS and CR on mitochondria remain poorly understood. Oxidative protein modifications in mitochondrial proteins from the heart and cerebrum of young (6.5 months) and old (27 months) rats were quantified and the effects of short-term and lifelong CR interventions were investigated. Mass spectrometry was leveraged to achieve an unbiased and comprehensive analysis of various types of oxidative postranslational modifications (oxPTMs). Contrary to the MFRTA, aging did not cause significant increases in mitochondrial protein oxidation in the heart and cerebrum. CR markedly diminished the overall level of oxPTMs in the heart, particularly in transmembrane proteins. Similarly, the level of oxidative modification of transmembrane proteins in cerebrum was reduced by CR, whereas it perplexingly increased in mitochondrial proteins. The absolute level of oxidized mitochondrial protein was always higher in the heart than in the cerebrum under all conditions. Carbonylation, a prevalent marker of protein oxidation and aging, increased in the heart with age and was notably reduced by CR. However, this trend was not consistent in cerebrum or for some other types of oxPTMs. Therefore, protein oxidation in the heart and cerebrum exhibits distinct responses to chronological aging and dietary interventions, with the latter exerting a stronger influence.

The bidirectional non-linear communication between blood pressure (BP) and heartbeat is critical to cardiovascular homeostasis, which remains poorly understood, especially under hypertensive conditions. We implemented transfer entropy (TE), an information-theoretic measure of directional coupling, to characterize such bidirectional coupling between BP and heartbeat and its relationships to arterial stiffness and walking performance in older adults. A total of 493 older adults (201 normotensive (NTN), 168 controlled-hypertensive (controlled-HTN), and 124 uncontrolled-HTN) completed simultaneous recordings of resting-state beat-to-beat BP and R-R interval for ≥ 10 min. The TE from BP to RR (i.e., BP-RR) and from RR to BP (RR-BP) was quantified. Participants then completed the assessments of arterial stiffness (i.e., brachial–ankle pulse wave velocity, baPWV) and walking speed in single- and dual-task conditions. The validation using surrogate data confirmed the physiological significance of TE (p < 0.0001). Both BP-RR and RR-BP TE were significantly lower in controlled- and uncontrolled-HTN compared to NTN (p < 0.03). In NTN and control-HTN, higher BP-RR and/or RR-BP TEs were associated with slower walking speed (β = −0.25 to −0.16, p < 0.04). Higher BP-RR TE was associated with lower baPWV (β = −0.17 to −0.16, p < 0.04), while higher RR-BP TE was associated with greater baPWV (β = 0.17–0.21, p < 0.03). No such significant associations were observed within uncontrolled-HTN. The observations suggested that TE captures hypertension-related disruption of bidirectional BP-heartbeat information flow, reflecting impaired baroreflex feedback, exaggerated feedforward cardiac influence, and dampening with anti-hypertensive therapy. The distinct associations with vascular stiffness and walking performance suggest TE as a promising marker of cardiovascular integrity and functional reserve in aging.

Individuals with knee osteoarthritis (KOA) have skeletal muscle changes around the knee joint including reduced quadricep muscle mass and increased intermuscular adipose tissue (IMAT). We examined the cellular composition and transcriptional profiles using single-nuclei RNA sequencing in IMAT from 6 older women with KOA and knee pain and 5 older women without KOA or knee pain from the Study of Muscle, Mobility and Aging (SOMMA). From the resulting 21,436 nuclei, we identified 6 major cell types with unique transcriptional profiles, including progenitor cells, adipocytes, macrophages and other immune cells (T/B/NK cells), endothelial cells and smooth muscle cells/pericytes. Sub-clustering of the immune cell population revealed the presence of mast cells and B-cells with greater abundances in the KOA group. The adipocyte population was the most transcriptional diverse population between the KOA group and the group without KOA. Cell–cell communication network analysis highlighted that adipocytes had the most prominent signaling role of all cell types, independent of KOA status; however, signaling of the pro-inflammatory adipokine leptin was enriched in the KOA group. This study provides the first interrogation of the cellular diversity and transcriptional profiles of IMAT in individuals with KOA. Our findings suggest that IMAT may contribute to KOA disease burden potentially through pro-inflammatory signaling.

Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood. Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry–based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization. To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.