Aging Cell最新文献

The aging of the hematopoietic system is central to physiological aging, with profound consequences for immune competence, tissue regeneration, and systemic health. Age-related changes manifest as altered blood cell composition, functional decline in hematopoietic stem cells (HSCs), and deterioration of the bone marrow niche. Beyond hematologic dysfunction, hematopoietic aging acts as a systemic amplifier of age-related diseases through clonal hematopoiesis and inflammatory remodeling. This review integrates recent insights into the mechanisms and systemic impacts of hematopoietic aging, reframing it as a modifiable axis of systemic aging. We highlight emerging rejuvenation strategies—senolytics, metabolic reprogramming, and microbiota-targeted therapies—that aim to restore hematopoietic and immune function, offering promising avenues to improve healthspan and reduce age-related multimorbidity.

Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established. Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.

Aging is accompanied by profound changes in energy metabolism, yet the underlying drivers and modulators of these shifts remain incompletely understood. Here, we investigated how life-history evolution shapes metabolic aging and pharmacological responsiveness by leveraging Drosophila melanogaster lines divergently selected for reproductive timing. We measured organismal oxygen consumption rate and performed untargeted metabolomics in young and old flies of both sexes from long-lived “O” lines (selected for female late-life reproduction) and unselected “B” control lines. Males and females from the O lines maintained stable metabolic rates and largely preserved metabolite profiles with age, whereas B line flies showed age-related increases in oxygen consumption, citrate accumulation, and elevated levels of medium- and long-chain fatty acids, hallmarks of mitochondrial inefficiency and impaired lipid oxidation. Aged B flies also displayed elevated S-adenosylmethionine, reduced sarcosine, and diminished heme levels, indicating dysregulation of one-carbon metabolism and impaired heme biosynthesis. Furthermore, Vitamin B6 metabolites, pyridoxamine, pyridoxal, and 4-pyridoxate, increased with aging only in B line females. Motivated by evidence implicating the renin-angiotensin system in metabolic aging, we treated flies with the angiotensin-converting enzyme (ACE) inhibitor lisinopril. Lisinopril prevented the age-related rise in metabolic rate in B line females, aligning their metabolic phenotype with that of O line flies. This suggests that ACE inhibition may buffer against age-associated increases in metabolic rate and contribute to enhanced metabolic stability. Our results show that selection for delayed reproduction and increased lifespan modifies age-related metabolic trajectories and modulates physiological responses to pharmacological intervention.

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

Aging is a multifactorial process influenced by genetic, environmental, and metabolic factors. Dysregulated nutrient sensing and metabolic dysfunction are hallmarks of aging, and reduction of insulin/IGF-1 signaling or metabolic interventions such as caloric restriction extend lifespan across species. Endogenous metabolites reflect and mediate these metabolic cues, linking nutrient status to epigenetic and transcriptional programs by serving as cofactors for chromatin-modifying enzymes or as allosteric modulators of transcription factors. Some metabolites have emerged as key regulators of longevity, integrating into networks to concurrently influence multiple aging-related pathways. In this review, we summarize evidence supporting the lifespan-extending effects of key endogenous metabolites across diverse model organisms and discuss their mechanisms of action. These insights underscore the potential of targeting metabolic networks as a multifaceted strategy to delay aging. Finally, we consider the translational promise of metabolite-based interventions to extend healthspan while minimizing adverse effects, and we note remaining challenges such as optimal dosing, context-specific effects, and demonstrating efficacy in humans.

Neovascular age-related macular degeneration (nAMD) is a major cause of irreversible vision impairment in elderly populations, characterized by pathological angiogenesis beneath the macula. Although anti-VEGF therapies have demonstrated clinical effectiveness, significant challenges including drug resistance and the need for frequent intravitreal injections persist. As natural nanovesicles, exosomes derived from mesenchymal stem cell (MSC) can mediate intercellular communication, making them an attractive alternative for modulating cellular processes. This study explored the anti-angiogenic effects of MSC-derived exosomes in nAMD, with particular emphasis on the role of a specific exosomal lncRNA lnc-AGT-3. Our results showed that lnc-AGT-3 expression was reduced in both nAMD patients and choroidal neovascularization (CNV) models, and its overexpression effectively inhibited pathological angiogenesis in vitro and in vivo. Mechanistically, lnc-AGT-3 enhanced the p53 signaling pathway by blocking the ubiquitination and degradation of p53 and ultimately inhibited neovascularization, a process potentially linked to its direct interaction with heterogeneous nuclear ribonucleoprotein K (hnRNP K). Our findings position MSC-derived exosomes enriched with lnc-AGT-3 as an innovative therapeutic paradigm for nAMD, acting through p53 pathway modulation to potentially overcome current treatment limitations.

With the increasing trend of delayed childbearing, the decline in oocyte quality associated with advanced maternal age has emerged as a pressing concern. However, the mechanism remains unclear, and effective strategies for improvement are currently lacking. Previously, we reported that the downregulation of the mevalonate pathway in aged granulosa cells (GCs) contributed to meiotic defects in oocytes, which may implicate farnesyl pyrophosphate-mediated protein farnesylation. Nevertheless, the role of farnesylation in ovarian aging and its impact on oocytes requires further investigation. In this study, using cumulus-oocyte complexes (COCs) from young and aged female mice, we observed impaired cumulus expansion and concurrent meiotic defects during aged oocyte maturation, accompanied by significantly reduced protein farnesylation in aged GCs. Furthermore, inhibiting farnesylation with FTI-277 in young COCs recapitulated the aging phenotype, disrupting cumulus expansion and inducing meiotic defects similar to those in aged COCs. Conversely, restoring farnesylation via farnesol supplementation effectively ameliorated these deficits in both aged COCs (in vitro) and aged mice (in vivo). Proteomic analysis and experimental validation identified prostaglandin E2 synthase 2 (PTGES2) as a farnesylated protein. Mechanistically, age-related decline in PTGES2 farnesylation in GCs reduces its endoplasmic reticulum localization and impairs prostaglandin E2 (PGE2) production, thereby compromising PGE2-dependent cumulus expansion and oocyte maturation. Collectively, our findings highlight the detrimental effects of decreased farnesylation in aged GCs on oocyte quality and propose a potential therapeutic strategy for improving the developmental competence of aged oocytes.

Senescent cells display indefinite growth arrest and a pro-inflammatory, senescence-associated secretory phenotype (SASP). As the accumulation of senescent cells in tissues with age plays detrimental roles in age-related pathologies, there is much interest in finding therapeutic strategies to eliminate them or suppress the SASP. In this study, we investigated the impact of the secretome and extracellular vesicles (EVs) derived from human trophoblast stem cells (hTSCs) on senescent human fibroblasts. We found that the hTSC conditioned medium (hTSC-CM), and in particular the EVs (hTSC-EVs), significantly reduced the levels of mRNAs encoding SASP factors and the secretion of SASP factors including CXCL1, IL8, and GDF15. Proteomic analysis of hTSC-CM and EVs indicated an enrichment in proteins involved in cell adhesion, tissue repair, and remodeling of the extracellular matrix (ECM). Furthermore, incubation of senescent cells with hTSC-EVs attenuated DNA damage and inflammatory signaling, at least in part by suppressing the function of NF-κB, a major transcriptional regulator of the SASP program. Our findings underscore the value of hTSC-CM and EVs therein in therapeutic approaches directed at senescent cells.

Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A-overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A overexpression significantly reduced Aβ plaque deposition in brain tissue of APP/PS1 mice. Mechanistically, SV2A was identified as a novel APP-binding protein that attenuated the amyloidogenic processing of APP by inhibiting its interaction with β-site APP cleaving enzyme 1 (BACE1). Furthermore, SV2A overexpression altered the subcellular distribution of APP, shifting its localization away from the endosomal-lysosomal compartments. Collectively, our findings unveil SV2A as a critical regulator of APP metabolism and propose it as a promising therapeutic target for intervening in the early pathological progression of AD.

With an aging population, the incidence of age-related hearing loss (ARHL) continues to increase. Aging cells exhibit reduced nicotinamide adenine dinucleotide (NAD⁺) levels and impaired autophagy; however, the mechanisms underlying these processes remain largely unclear. In our study, we assessed the role of nicotinamide nucleotide adenylate transferase 1 (NMNAT1) in cochlear hair cell aging using D-galactose (D-gal)-induced aging HEI-OC1 cells and cochlear explants. We observed a significant reduction in NMNAT1 expression in HEI-OC1 cells and cochlear hair cells treated with D-gal. Notably, NMNAT1 overexpression activated autophagy and decelerated hair cell aging. Metabolomic analysis revealed a dysregulated tricarboxylic acid cycle in Nmnat1-knockout cells, indicating that NMNAT1 regulates autophagy and metabolic pathways that affect hair cell aging. These findings offer novel insights into the association between autophagy and metabolism during aging and highlight NMNAT1 as a potential therapeutic target for the prevention and treatment of ARHL.