Aging Cell最新文献

As individuals age, there is a gradual increase in the levels of inflammation in the body, with macrophages, essential immune cell types, assuming a critical role in modulating inflammatory responses and eliminating senescent cells. Prolonged inflammatory reactions can result in tissue damage, the advancement of diseases, and the acceleration of aging processes. Hevin (also known as SPARCL1, secreted protein acidic and rich in cysteine-like protein 1) is involved in regulating inflammatory responses and the polarization of macrophages. The current study seeks to elucidate the role of Hevin in the context of cardiac aging. Aging or young C57 BL/6 male mice were intravenously injected with Hevin or knocked down Hevin with adeno-associated virus serotype 9 (AAV9) vectors. To screen the underlying mechanisms, RNA-seq was used. Meanwhile, RAW264.7 cells were employed to investigate the role of Hevin in macrophage polarization. Aging mice displayed elevated Hevin serum levels compared to their younger counterparts, along with increased Hevin expression associated with poor cardiac function. Administration of Hevin enhanced aging-related cardiac remodeling, whereas Hevin knockout ameliorated such remodeling and dysfunction. RNA-seq analysis unveiled that Hevin triggered CCL5 activation in aging hearts, and blocking CCL5 reversed the adverse effects of Hevin-induced cardiac aging in vivo. Functionally, circulating Hevin released by iWAT stimulated cardiac macrophages via TLR4, prompting their polarization and CCL5 release, exacerbating cardiac dysfunction and attracting more inflammatory cells for the secretion of pro-inflammatory factors. During aging, Hevin expression inversely correlates with cardiac function, and its absence effectively mitigates aging-related cardiac dysfunction by diminishing inflammatory responses. Our study uniquely identifies Hevin as a promising predictive and therapeutic target for cardiac aging.

The gut microbiota changes throughout life, potentially influencing health and triggering physiological disorders. Frailty syndrome (FS) is an age-related condition that reduces quality of life and increases hospitalization and mortality risks, making early detection and prevention essential in older populations. This study analyzed 16S rRNA gene and metagenomics sequencing of fecal samples from 203 older adults (FS: n = 64, non-FS (NFS): n = 139) to assess the role of gut microbiota in FS and related comorbidities, such as sarcopenia and impaired lower extremity function (ILEF) or anthropometric variables. Consistent taxonomic patterns were observed: Eggerthella, Parabacteroides, and Erysipelatoclostridium were significantly abundant in FS, while Christensenellaceae R-7 group, Erysipelotrichaceae UCG-003, and Hungatella were enriched in NFS. Christensenellaceae R-7 group was also associated with better mobility. Metagenomics analysis identified 680 KEGG functions differing between groups, categorized into 28 metabolic pathways. FS individuals had overrepresented biotin metabolism, antimicrobial resistance, and energy production, but underrepresented ribosomal and protein synthesis and sporulation pathways. Resistome analysis found the tetM/tetO (K18220) gene most abundant, alongside tetracycline, β-lactam, and macrolide resistance, primarily mediated by antibiotic efflux and transporters. These findings highlight distinct microbial and functional signatures associated with FS, underscoring the complex interplay between the gut microbiota and host physiology in aging. Adjusting for covariates, age and diabetes acted as confounding factors in FS for both 16S gene and metagenomics sequencing. This study offers new insights into fundamental questions in the biology of aging and opens avenues for microbiota-targeted strategies to improve the quality of life in older adults.

Aging, a major risk factor for numerous diseases, is associated with significant transcriptional changes across organs. However, the age of onset, extent of transcriptomic changes and how they unfold are not fully understood. We performed bulk RNA sequencing on eight organs (brain, heart, kidney, liver, lung, skeletal muscle, spleen, and testis) from male C57BL/6J mice across much of the murine lifespan covering 3-, 5-, 8-, 14-, 20- and 26-month-old animals. Our analysis revealed that age-related transcriptomic shifts vary in both timing and extent, with early shifts in lung, spleen, and testis; mid-life changes in heart, kidney, and skeletal muscle; and later alterations in brain and liver. The extent of age-related transcriptomic changes ranged from very low (testis) to high (kidney, liver, spleen). A linear mixed-effects model identified genes with tissue-specific aging trajectories. By integrating hub gene analysis and functional enrichment, we uncovered aging signatures that are either tissue-specific or shared across multiple organs, including those related to immune response, mitochondrial dysfunction, extracellular matrix remodeling, and cellular senescence. This study provides a systems-level resource for advancing aging research.

Chronic inflammation is a key driver of aging-related diseases, obesity-associated metabolic disorders, and tumor progression. Aging and obesity contribute to the accumulation of senescent cells, which secrete senescence-associated secretory phenotype (SASP) factors that promote tissue remodeling and chronic inflammation. Here, we investigated the pathological roles of angiopoietin-like protein 2 (ANGPTL2), a potential SASP factor, in a mouse model of high-fat diet-induced premature aging. We found that ANGPTL2 deficiency shortened lifespan but attenuated systemic inflammation, indicating a complex role for ANGPTL2 in aging-related processes. ANGPTL2 was required for maintaining intestinal homeostasis under metabolic stress; however, ANGPTL2 also exacerbated adipocyte hypertrophy and cardiac dysfunction. Furthermore, ANGPTL2-mediated inflammation promoted kidney fibrosis but paradoxically protected against perivascular fibrosis in the liver, indicating its organ-specific effects on fibrotic remodeling. In addition, ANGPTL2 influenced immune responses by driving bronchus-associated lymphoid tissue formation. These findings suggest that ANGPTL2 has context-dependent effects, balancing tissue homeostasis and inflammation-driven pathologies. Our study provides novel insights into the dual roles of ANGPTL2 as a SASP factor in regulating inflammation, fibrosis, and tissue remodeling across different organ systems.

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.