Aging and Disease最新文献

Functional activities of the gut microbiome, particularly those contributing to short-chain fatty acid (SCFA) metabolism, play a central role in host-microbe interactions and are linked to neuroinflammatory mechanisms underlying Alzheimer's disease (AD). How microbial metabolic functions relate to SCFA concentrations and cerebral amyloid-β (Aβ) burden during the preclinical stage of AD remains poorly understood. In this study, faecal metagenomes from 87 cognitively unimpaired adults were profiled using HUMAnN3 to generate MetaCyc pathway abundance data, normalised and filtered to retain pathways present in at least 30% of participants. A keyword-based search identified 362 SCFA-related pathways spanning acetate, propionate, butyrate, isobutyrate, valerate and isovalerate metabolism. Associations between microbial functions, SCFA concentrations and Aβ status were evaluated using Spearman correlations, Kruskal-Wallis tests across SCFA quartiles, and multivariable linear regression with false discovery rate correction, supported by canonical correspondence analysis and network modelling. A total of 38 significant SCFA pathway correlations were identified. Acetate, butyrate and total SCFA levels showed positive associations with biosynthetic pathways, including L-arginine biosynthesis II, peptidoglycan biosynthesis and flavin biosynthesis, whereas fermentative pathways such as pyruvate fermentation to acetone and lysine fermentation to butanoate were negatively correlated. Butyrate quartiles demonstrated dose-dependent increases in biosynthetic functions and declines in fermentative routes. Canonical Correspondence Analysis (CCA) confirmed a significant multivariate association, and network analysis revealed enhanced fermentative and methanogenic connectivity among Aβ High participants. These findings indicate that amyloid burden is associated with a shift from anabolic to fermentative microbial metabolism and may inform future studies examining potential mechanistic links in preclinical AD.

Aging is a major risk factor for a wide range of chronic diseases. Elucidating the molecular mechanisms underlying aging-associated disorders is essential for developing effective preventive and therapeutic strategies. Recent research has unveiled the regulatory roles of non-coding genomic regions. Among these, alternative polyadenylation (APA), a conserved co-transcriptional mechanism, has emerged as a key modulator of gene expression, with an established involvement in various age-related pathologies. APA alters the length of the mRNA 3' untranslated region (3' UTR), thereby affecting mRNA stability, localization, translational efficiency, and ultimately protein expression. Notably, approximately 70% of human genes undergo APA-mediated regulation, underscoring its extensive influence on cellular function. This review summarizes the advances in exploring the role of APA in aging-related diseases, including musculoskeletal disorders, neurodegenerative diseases, cardiovascular and respiratory diseases. These findings can verify the potential of APA as a novel regulatory player in aging biology and a mechanistic contributor to the pathogenesis of age-associated diseases, highlighting its promise as a therapeutic target.

Multimorbidity is common in older adults, and certain combinations of chronic conditions may confer higher mortality risk. Unhealthy lifestyle behaviours are also linked to shorter life expectancy. This study examined whether lifestyle patterns (LPs) modify the association between multimorbidity configurations (MCs) and mortality. We analysed data from 20,853 adults aged 60 and older in the Northern Netherlands Lifelines cohort, followed for a mean of 12 years. Five LPs were previously identified via latent class analysis, based on diet, physical activity, substance use, sleep, social connection, and stress. Multimorbidity was defined both as a disease count (≥2 non-communicable diseases [NCDs]) and as five latent MCs reflecting distinct NCD combinations. All-cause mortality was estimated using Kaplan-Meier plots and Cox models, reporting hazard ratios (HRs) with 95% confidence intervals (CIs), stratified by LPs. Compared to having no NCDs, mortality risk differed across MCs, with associations varying by LPs. Among participants with a 'Healthy in a balanced way' lifestyle, the 'Complex-Treatment' (HR 3.18, 95%CI: 2.24-4.51) and 'CVD-&-Vascular' (HR 2.35, 95%CI: 1.97-2.79) configurations showed the highest risks. In the 'Unhealthy but no substance use' group, mortality risk across MCs was more heterogeneous, with larger effect sizes. In contrast, multimorbidity defined by disease count showed limited variation in effect sizes across other LPs. LPs shape the mortality risk associated with multimorbidity. Risk variability across MCs was more pronounced in healthier lifestyles. These findings support the value of considering specific multimorbidity profiles-beyond disease count-for prognostic assessment and targeted interventions in older adults.

Chronological age is an inadequate proxy for the biological processes that drive disease risk, progression, and treatment response in older adults. This editorial advocates for a minimal standard in age-related disease research: the inclusion of one prespecified biological aging measure and one prespecified immune aging measure when biospecimens are available. Drawing on studies featured in this issue, we illustrate how biological and immune age account for heterogeneity across diverse domains, including cancer, neurodegeneration, vascular disease, immunosenescence, pain, and fibrosis. In the absence of aging readouts, biologically distinct states remain obscured, obscuring biological variation, weakening inference, and limiting translational relevance. We propose a practical framework for incorporating aging metrics into stratification, interpretation, and study design, with the goal of advancing both mechanistic insight and clinical application in aging biology.

Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major contributor to frailty, disability, and mortality in the elderly. Once considered a physiological consequence of aging, sarcopenia is now recognized as a complex multifactorial syndrome driven by intricate interactions between genetic predispositions, epigenetic regulation, environmental exposures, and lifestyle factors. Recent advances in high-throughput genomics and epigenomics have transformed our understanding of its molecular underpinnings, revealing key genes, signaling pathways, and regulatory networks that govern muscle homeostasis, regeneration, and degeneration. Furthermore, epigenetic alterations such as DNA methylation, histone modifications, and non-coding RNA networks act as critical modulators of muscle aging, bridging genetic risk with environmental and metabolic influences. Here, we review current knowledge of the genomic and epigenomic landscapes of sarcopenia, discuss how they intersect with cellular and systemic processes, and explore how these insights are paving the way for precision diagnostics, risk prediction, and targeted therapeutic interventions.

The prevalence of aging-related diseases, including tumors, cardiovascular and cerebrovascular diseases, and fibrotic diseases, has been consistently increasing in the aging population. In these conditions, nucleolar stress response mechanisms, such as defective ribosome biogenesis and dysregulated DNA damage repair, play instrumental roles in disease initiation and progression. Nucleophosmin 1 (NPM1), a multifunctional nucleolar chaperone, helps maintain cellular homeostasis through these stress response pathways. Accumulating evidence reveals that NPM1 exhibits disease-type-specific, and sometimes dual, roles in tumorigenesis, vascular aging, and multi-organ fibrosis, positioning it as a central regulator of age-related pathological processes. This review summarizes the role of NPM1 in the pathogenesis and treatment of multi-system aging-related diseases. We explore NPM1-related signaling pathways that regulate nucleolar stress responses and cellular homeostasis, evaluate its potential as a predictive biomarker for aging-related diseases, and discuss therapeutic strategies targeting NPM1-associated signaling. Although growing evidence highlights the potential of NPM1 inhibitors to modulate signaling cascades and improve clinical outcomes, context-selective inhibition of NPM1 may unexpectedly worsen disease progression in certain settings, underscoring its functionally dual nature depending on the context of the disease. This review delineates NPM1 signaling as a central orchestrator in aging-related pathogenesis and supports its potential as a therapeutic target to enhance treatment efficacy.

Glioma is an aggressive primary brain tumor with high morbidity and mortality, and it requires novel therapeutic targets. Ubiquitination and deubiquitination pathways regulate tumor progression. USP3, a deubiquitinating enzyme, and PLK1, a cell cycle kinase, have been linked to cancer cell proliferation. This study examined whether USP3 modulates PLK1 through deubiquitination to influence glioma progression. USP3 expression in glioma versus normal tissues was analyzed using TCGA datasets. Gain-of-function and loss-of-function models were generated by USP3 overexpression in U-251MG cells and USP3 knockdown in DK-MG cells. Proliferation was assessed by CCK-8, cell cycle distribution was analyzed by flow cytometry, and migration and invasion were evaluated using Transwell assays. Nude mouse xenografts were used to assess tumor growth, and PCNA immunohistochemistry was performed. Co-immunoprecipitation and Western blotting were used to validate the USP3-PLK1 interaction and to assess PLK1 ubiquitination. USP3 was upregulated in glioma tissues. USP3 overexpression enhanced U-251MG proliferation, promoted cell cycle progression, and increased invasion, while USP3 knockdown suppressed these phenotypes in DK-MG cells. Xenografts derived from USP3-overexpressing cells grew faster and showed higher PCNA levels, whereas USP3 knockdown reduced tumor growth and PCNA staining. Mechanistically, USP3 bound to PLK1, reduced K48-linked ubiquitination of PLK1, and stabilized PLK1 protein levels. USP3 knockdown increased PLK1 ubiquitination and reduced PLK1 abundance. Overall, USP3 promoted glioma malignancy by deubiquitinating and stabilizing PLK1, which enhanced proliferation and invasion. Targeting the USP3-PLK1 axis may represent a potential therapeutic strategy for glioma.

The decline in ovarian endocrine function represents a pivotal event in female aging, initiating systemic biological deterioration well before the end of reproductive capacity. We propose that Hormone Replacement Therapy (HRT) may constitute an early stage geroprotective intervention with mechanistic relevance across the 12 hallmarks of aging. Despite extensive clinical use, HRT remains underutilized as a geroprotector. Although there is promising data, prospective, biomarker-driven interventional studies are required to test this paradigm. This narrative review outlines the role of HRT as a geroprotective therapy, preferably offered and started within 10 years of menopause onset, in clinically eligible women in perimenopause. We emphasize the need for specific clinical guidelines that reflect and manage the endocrine, inflammatory, and metabolic profiles unique to perimenopause. The development of age- and phase-specific biomarkers will be critical to optimize HRT use and ensure precision delivery of longevity-focused care for women.

Age-related declines in muscle and bone mass increase the risk of sarcopenia and osteoporosis. Both conditions contribute to morbidity and mortality in older adults and frequently coexist as osteosarcopenia. Gut microbiota play a crucial role in maintaining muscle and bone homeostasis, and dysbiosis may accelerate the onset and progression of these conditions. We therefore performed a systematic review and meta-analysis of observational studies published up to May 6, 2025. We identified 45 eligible studies including 6,751 participants. Patients with sarcopenia showed significant reductions in α-diversity indices compared with controls, including Chao1 (SMD=-0.28, 95% CI=-0.44, -0.11), observed species (SMD=-0.52, 95% CI=-0.79, -0.25), and ACE (SMD=-0.24, 95% CI=-0.48, -0.01), whereas patients with osteoporosis exhibited no significant differences. Distinct clustering of β-diversity was observed in twelve of eighteen sarcopenia studies (66.7%) and twelve of twenty-one osteoporosis studies (57.1%). This suggests that microbial community structures are altered in both conditions. Moreover, sarcopenia and osteoporosis shared consistent microbial alterations, with enrichment of the genus Eggerthella and depletion of the family Lachnospiraceae and the genus Blautia. A qualitative summary of functional pathway analyses suggests potential enrichment of purine, pyrimidine, cysteine and methionine metabolism, implying common metabolic disruptions. These findings highlight overlapping microbial signatures in sarcopenia and osteoporosis and support a role for gut dysbiosis in musculoskeletal decline. They also provide mechanistic clues that may help guide future preventive and therapeutic strategies for osteosarcopenia.