Aging Cell最新文献

Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)-derived long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice. Plasma EV LINE-1 RNA levels markedly increase with age and strongly correlate with established brain aging biomarkers, including neurofilament light chain (NFL). Utilizing mouse models, we demonstrate that EVs from aged individuals penetrate the blood–brain barrier, deliver LINE-1 RNA to microglia, and initiate cGAS-STING signaling, leading to pronounced neuroinflammation, neuronal damage, and impaired cognition. Pharmacological blockade of LINE-1 reverse transcription by 3TC or inhibition of STING signaling with H151 significantly ameliorates these age-associated deficits. Notably, aged peripheral tissues, especially brain and lung, emerge as primary sources of pro-aging EVs enriched with LINE-1 RNA, revealing a novel mechanism of inter-organ communication in aging. Our findings position EV-derived LINE-1 RNA and its downstream cGAS-STING pathway as critical systemic drivers of brain aging, presenting promising therapeutic targets for mitigating cognitive decline and age-related neurodegenerative diseases.

Age-varying DNA methylation sites reflect increasing interindividual epigenetic divergence during aging, offering insights into health heterogeneity and potential for personalized interventions. Leveraging longitudinal DNA methylation data (3 waves over 5 years) from 135 relatively healthy Chinese older adults in the Rugao Longitudinal Ageing Study, we systematically characterized dynamic DNA methylation changes with age via mixed-effects modeling, identifying 125,353 age-associated (i.e., sites showing significant shifts in average methylation levels with age) and 3145 age-varying CpG sites (i.e., sites showing significant interindividual variability in methylation trajectories with age). Functional analysis revealed distinct enrichment profiles: age-associated CpG sites were enriched in nervous system development, cell signaling, and disease-related pathways, whereas age-varying CpG sites were enriched in cell adhesion, synaptic organization, and organ morphogenesis pathways. Notably, both categories showed significant enrichment in nervous system-related pathways, such as regulation of nervous system development and neuronal cell body. Established epigenetic clocks (e.g., HannumAge) were significantly enriched for age-associated CpG sites but not for age-varying sites. Furthermore, we quantified the pace of aging across eight major organ systems and identified 925 significant associations between organ-specific pace of aging and longitudinal methylation change rates at age-varying CpG sites. Pathway enrichment analysis revealed organ system-relevant biological functions—CpG sites associated with a given organ system were often enriched in pathways relevant to that system's function—with additional evidence of cross-system enrichment. Together, our findings elucidate the role of methylation variability in multi-organ systems aging and its potential for revealing mechanisms of aging heterogeneity and guiding precision monitoring and interventions.

Older adults are disproportionately affected by infectious diseases like influenza (flu) due to immune declines and poor vaccine responses. Senolytics have been shown to improve various age-related conditions and positively influence infection outcomes, yet their potential to enhance vaccine responses has not yet been explored. Here, we evaluated the potential of senolytic combination Dasatinib (D) and Quercetin (Q) treatment prior to influenza vaccination to potentiate immune responses in aged mice. D + Q had minimal impact on overall vaccination and flu outcomes in vaccinated mice, including viral load and lung pathology. However, we observed altered CD8 T cell immunodominance and increased serum total PR8 (whole flu) IgG antibodies in D + Q treated vaccinated aged mice during infection. These findings reveal a new aspect of immunomodulation with senolytics.

N6-methyladenosine (m6A) methylation, a dynamic and reversible modification of eukaryotic mRNAs, plays critical roles in diverse cellular processes. Although METTL3-mediated m6A deposition has been implicated in cellular senescence, the mechanisms controlling METTL3 stability and activity during senescence remain poorly defined. Here, we demonstrate that both m6A levels and METTL3 protein abundance are significantly reduced in replication-induced and stress-induced senescence models. METTL3 depletion promotes senescence by inducing telomere dysfunction via diminished expression of shelterin components TRF2 and POT1. Mechanistically, we identify PRKN (Parkin) as a senescence-associated E3 ubiquitin ligase that promotes METTL3 proteasomal degradation through K48-linked polyubiquitination at lysine 164. Genetic PRKN inhibition in pre-senescent cells rescues METTL3 expression, restores TRF2/POT1 levels, reduces telomere dysfunction-induced foci (TIFs), and attenuates senescence-associated β-galactosidase (SA-β-gal) activity. Crucially, PRKN overexpression accelerates telomere dysfunction and senescence in wild-type METTL3-expressing cells but not in cells expressing the ubiquitination-resistant K164R METTL3 mutant. Our findings establish METTL3 ubiquitination as a pivotal regulator of telomere integrity and senescence progression, unveiling a therapeutic target for age-related pathologies.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid-beta plaques and neurofibrillary tau tangles in the brain, neuroinflammation, and cognitive impairment. The 3xTg-AD mouse is a commonly used model in AD studies. 3xTg-AD males display inconsistent pathology; therefore, most studies utilize females. An understanding of why sexual dimorphism exists in this model is lacking. In humans, low circulating choline levels are associated with elevated AD pathology, while higher choline intake reduces pathology in AD mouse models. Here, we sought to understand if blood choline levels are associated with the sex discrepancies observed in 3xTg-AD mice. Body weight and chow consumption were measured, and blood plasma samples were collected at 3, 6, 9, 12 months of age and at end-point in 3xTg-AD and NonTg mice. 3xTg-AD females and NonTg males consumed more chow and gained more body weight than other groups. Longitudinally, 3xTg-AD mice had lower plasma choline levels than NonTg mice, while levels declined with age in NonTg mice. Female 3xTg-AD mice had higher AD-like pathological burden than males, but males had higher mortality rates across the study. IntelliCage automated phenotyping revealed high water-seeking behavior in males. 3xTg-AD mice displayed higher impulsivity compared to NonTg mice. Males were better at spatial and attention tasks but perseverated during avoidance testing compared with females. These findings demonstrate a persistent reduction in circulating choline levels across the lifespan of 3xTg-AD mice despite adequate dietary intake. Given choline's roles in metabolism, inflammatory regulation, and neuronal function, chronically low circulating choline may contribute to the various dysfunctions observed in this model.

A key characteristic of senescent and ageing cells is a reduction in number and increase in size of nucleoli. Although a number of pathways have been suggested, the mechanisms underlying this altered nucleolar phenotype, and the downstream consequences, remain poorly understood. The PolI complex component, TIF-IA, has previously been implicated in regulating this characteristic nucleolar phenotype in response to stress. Here we explored the role of TIF-IA in senescence and ageing. We show that TIF-IA accumulation, particularly in the nucleus and nucleolus, is an early response to oncogene- and therapy-induced senescence (OIS and TIS) in vitro. Using multiple mouse models, we also demonstrate accumulation of TIF-IA in response to senescence induction and ageing in vivo. We demonstrate that TIF-IA accumulation is not required for cell cycle arrest but that in OIS and TIS, it is essential for phenotypic changes to nucleoli, the senescence-associated secretory phenotype (SASP) and establishment of stable senescence. We demonstrate that in proliferating cells, TIF-IA binds the cargo receptor, p62 (SQSTM1), and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts this interaction. Finally, we show that TIF-IA accumulation causes an increase in reactive oxygen species (ROS) levels. Together, these results establish TIF-IA accumulation as a key regulator of the nucleolar phenotype and the SASP in senescence and uncover a novel, p62-dependent mechanism driving this process. These findings offer significant new insights into nucleolar size regulation in senescence and ageing, and suggest a potential relationship with the inflammatory phenotype.

Ovarian somatic cells are essential for reproductive function, but no existing ex vivo models recapitulate the cellular heterogeneity or interactions within this compartment. We engineered an ovarian somatic organoid model by culturing a stroma-enriched fraction of mouse ovaries in scaffold-free agarose micromolds. Self-organized ovarian somatic organoids maintained diverse cell populations, produced extracellular matrix, and secreted hormones. Organoids generated from reproductively old mice exhibited reduced aggregation and growth compared to young counterparts, as well as differences in cellular composition. Interestingly, matrix fibroblasts from old mice demonstrated upregulation of pathways associated with the actin cytoskeleton and downregulation of cell adhesion pathways, indicative of increased cellular stiffness that may impair organoid aggregation. Cellular morphology, which is regulated by the cytoskeleton, significantly changed with age and in response to actin modulation. Moreover, actin modulation altered organoid aggregation efficiency. Overall, ovarian somatic organoids have advanced knowledge of cellular contributions to ovarian aging.

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.