Aging Cell最新文献

Age-associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old-aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single-nucleus RNA sequencing before and after sciatic nerve crush from young and old-aged muscles further revealed that sub-synaptic myonuclei in old-aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle-specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10—two nuclear-encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old-aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub-synaptic myonuclei using single-nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain-containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.

Cellular senescence is a fundamental biological process contributing to aging, often accompanied by extensive chromatin remodeling. Dynamic alterations of three-dimensional (3D) genomic spatial structure, driven by chromatin reorganization, play a critical role in cell fate determination, but their relevance in therapy-induced senescence (TIS) remains underexplored. Here, we perform an integrative multi-omics analysis of Hi-C, ATAC-seq, CUT&RUN, and RNA-seq in primary human fibroblasts undergoing TIS induced by ionizing radiation (RAD) or bleomycin (BLEO). We show that TIS leads to global chromatin decompaction, weakened compartmentalization, and destabilization of topologically associated domains (TADs), alongside widespread loss and rewiring of chromatin loops. Notably, RAD and BLEO elicit distinct changes in distance-dependent compartment strength and enhancer–promoter (E-P) loop patterns, reflecting divergent 3D regulatory programs. Importantly, TIS reshapes the chromatin environment around senescence-associated secretory phenotype (SASP) genes, while their adjacent regions exhibit reduced chromatin interactions, allowing transcriptional activation. Our study reveals that 3D genome remodeling in TIS is highly plastic and context-dependent and discloses spatial regulation of gene expression during therapy-induced cellular senescence.

Cell states and biological processes are defined by their epigenetic profiles, distinctive composites of DNA- and histone-based chromatin components. However, the specific histone posttranslational modifications that distinguish cellular senescence and the impact of their distribution on transcription, especially with regard to gene length, have not been fully elucidated. Here, we show that promoter loss of symmetric dimethylated H4R3 (H4R3me^(2s)) and spreading of trimethylated H3K79 (H3K79me³) across gene bodies are functional features of replicative senescence associated with gene upregulation. We report that highly upregulated genes in replicative senescence exhibit enrichment of H3K79me³ and, in contrast to the characteristic trend of aging cells and tissues, are substantially longer than those that are significantly downregulated. Furthermore, by assessing all expressed genes, we demonstrate that gene body accumulation of H3K79me³ during the transition to replicative senescence constitutes a broader phenomenon that is positively correlated with gene length and expression level genome-wide. Consistently, pharmacological inhibition of H3K79me³ deposition attenuates gene upregulation in replicative senescence. We also document a striking increase in the levels of H3K79me³ as well as a robust H4R3me^(2s) to asymmetric dimethylated H4R3 (H4R3me^(2as)) epigenetic switch that manifest globally in late-passage cells, suggesting that these histone modifications might represent novel molecular biomarkers of replicative senescence. Finally, we implicate the associated epigenetic regulators, including DOT1L, PRMT1, PRMT5, and JMJD6, as modifiers of cellular lifespan, potentially disclosing unappreciated therapeutic targets for interventions in normal and pathological aging. Collectively, our findings provide novel insights into the histone code that mediates altered transcriptional regulation in replicative senescence.

Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific GCGR knockout (LKO) mouse model. While male LKO mice exhibited normal lifespan, female LKO mice displayed a significant reduction in survival. Strikingly, and in contrast to prevailing expectations based on metabolic improvements, this shortened lifespan in females occurred despite marked enhancements in metabolic health, including reduced body weight and adiposity, preferential glucose oxidation, elevated metabolic rate, and enhanced glucose tolerance and insulin sensitivity throughout adulthood. Underpinning this detrimental outcome, transcriptomic and biochemical analyses revealed a striking, female-specific activation of pro-inflammatory pathways, notably NF-κB and cGAS-STING signaling, in the liver and kidney of aged LKO mice as well as reduced expression of hepatic xenobiotic metabolism genes. These findings identify a novel, sexually dimorphic role for the hepatic glucagon receptor in regulating lifespan, linking its interruption in females to late-life inflammation and reduced longevity despite an otherwise beneficial metabolic phenotype.

Aging is a heterogeneous process, with organ systems and individuals experiencing variable rates of decline that are not fully reflected by chronological age. This variability contributes to the complexity of system morbidity, which poses increasing challenges for clinical care and biomedical research. In this review, we discuss the heterogeneity of organ and whole-body aging and perspectives on genomics as possible mechanisms that relate to such heterogeneity. We discuss how static genomics, including nuclear genetic variants, and dynamic genetics, such as somatic mutations, epigenetic drifts, and mitochondrial DNA changes might explain the variable rate of aging across organ systems and the whole body. We discuss that the use of metrics that capture heterogeneity in organ and body aging is critical to identify genomic biomarkers of aging, clarifying mechanisms of adaptation versus decline.

Testicular aging, a key feature of late-onset hypogonadism (LOH), is closely associated with Sertoli cells dysfunction. Emerging evidence implicates lipid droplet (LD) accumulation as a hallmark of aging in Sertoli cells, but its role in Sertoli cells senescence and the associated molecular mechanisms are unknown. We found that aging and obesity drove progressive LD accumulation in Sertoli cells, accompanied by mitochondrial dysfunction and ROS overproduction. Palmitic Acid (PA)-induced LD overload in vitro replicated these aging phenotypes, triggering ROS overproduction that provoked ribosome collisions and caused decreased protein synthesis globally. Moreover, LD-driven ROS disrupted mRNA translation, particularly at GA-rich sequences encoding aspartate and glutamate. Collided ribosomes activated the ZAKα-p38 axis in Sertoli cells, causing cellular senescence and impairing the blood-testis barrier. ZAKα inhibitor Nilotinib attenuated testicular atrophy, restored testosterone levels, and mitigated Sertoli cells dysfunction in aged mice. Targeting this pathway with ZAKα inhibitor offers a therapeutic strategy for age-related gonadal decline, bridging lipid metabolism dysfunction, and reproductive aging.

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.