Aging Cell最新文献

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.

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.

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.

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.

Shadfar, S., Farzana, F., Saravanabavan, S., et al. (2025), The Redox Activity of Protein Disulphide Isomerase Functions in Non-Homologous End-Joining Repair to Prevent DNA Damage. Aging Cell, 24: e70079. https://doi.org/10.1111/acel.70079.

In the published version of the above article, we would like to make the following corrections:

1. Comet assay—Figure 3C was labelled incorrectly.

The third column of Figure 3C was incorrectly labelled as ‘PDI + NU7441’; this should be corrected to ‘Etoposide + NU7441’.

2. Comet assay—Figure 3D was labelled incorrectly.

We apologize for these errors.

Stem cell-derived extracellular vesicles (EVs) show promise as a therapeutic approach for neurodegenerative diseases, particularly Alzheimer's Disease (AD), where traditional regenerative interventions have achieved limited success. Our previous research demonstrated the neuroprotective benefits of human neural stem cell (hNSC)-derived EVs in 2- and 6-month-old AD mice (5xFAD) that exibited improved cognitive function and reduced AD-related neuropathology. This study aimed to compare the neuroprotective efficacy of EVs derived from two human cell lines: hNSCs from H9 embryonic stem cells and human iPSC-derived microglia (iMGLs). Additionally, we investigated the efficacy of an expanded EV treatment paradigm at subsequently longer time points. Three-month-old 5xFAD mice received weekly retro-orbital vein injections of either hNSC- or iMGL-derived EVs for 4 weeks. Cognitive function testing revealed comparable cognitive improvements in both EV treatment groups compared to vehicle-injected AD mice. Both iMGL- and hNSC-derived EVs significantly reduced amyloid beta plaques, astrogliosis, and microglial activation, while restoring synaptophysin and postsynaptic density protein PSD-95 to control levels in AD brains. Gene expression analysis revealed significantly reduced neuroinflammation and elevated neuroprotective signatures following both EV treatments. MicroRNA analysis of the EV-derived cargo revealed unique and shared miRNA signatures associated with differentially expressed genes in both cell lines. These findings demonstrate the feasibility and neuroprotective benefits of recurrent systemic injections of EVs derived from human NSCs and differentiated human microglia lines in alleviating cognitive dysfunction and neuropathology in Alzheimer's disease.

Nicotinamide adenine dinucleotide (NAD) has garnered significant attention in recent years due to its central role in cellular metabolism and its potential as a supplement to promote health and longevity. While numerous human studies indicate that NAD supplementation offers benefits with minimal or no side effects, some studies show no observable advantages. This discrepancy highlights the importance of identifying individuals who are most likely to benefit from NAD-based interventions. One critical factor in the efficacy of NAD supplementation relates to its declining levels in certain individuals, driven by various causes of NAD depletion. NAD is a vital substrate for numerous enzymatic processes, notably those involving poly-ADP-ribose polymerase (PARP) enzymes. PARP enzymes, especially PARP1, play a pivotal role in DNA repair by detecting and signaling DNA damage. Excessive activation of PARP, hyperparylation, is frequently observed in DNA repair disorders where DNA damage accumulates due to defective repair mechanisms. This hyperparylation has been implicated in the pathogenesis of several premature aging diseases. Such conditions often involve defective DNA repair pathways, elevated parylation levels, and associated mitochondrial dysfunction, factors that contribute to accelerated cellular aging. In model systems that mimic these disorders, as well as in emerging human studies, NAD supplementation has demonstrated promising benefits, including improved DNA repair capacity and improved mitochondrial function. These findings suggest that NAD supplementation could serve as an effective intervention for rare genetic diseases characterized by premature aging and DNA repair deficiencies. More broadly, these insights open new avenues for general aging research.