npj aging最新文献

Evidence suggests that cancer-related accelerated aging contributes to an earlier onset of chronic diseases; persistent symptoms; and decrements in patients' quality of life. This review presents the Multifactorial Model of Cancer-related Accelerated Aging (MMCRAA), a conceptual framework that is grounded in Life Course Theory and supported by empiric evidence. The model includes six inter-related concepts: person, behavioral, biological, treatment, symptom, and life course factors. The MMCRAA can be used by clinicians and researchers to identify patients at increased risk for cancer-related accelerated aging; guide personalized treatment planning; and inform the development of interventions and research.

Frailty is a common geriatric syndrome associated with increased mortality, yet its underlying biological mechanisms and potential value for early risk stratification remain inadequately understood. In this large prospective cohort of more than 260,000 UK Biobank participants with plasma metabolomic profiling, we identified and validated metabolomic signatures of physical frailty and a 49-item frailty index using 50-times repeated 10-fold cross-validated elastic-net regression. The signatures demonstrated strong internal stability and geographic reproducibility and reflected coordinated alterations across lipid, amino acid, energy, and inflammatory pathways. Higher signature levels were significantly associated with increased risks of all-cause and cause-specific mortality, including cancer, cardiovascular, respiratory, and digestive deaths. Individuals in the highest-risk tertile had more than 2.5-fold higher risks of cardiovascular, respiratory, and digestive mortality. At age 60, individuals above the median signature level were estimated to have 4.1 fewer years of life expectancy. Mediation analyses indicated that the metabolomic signatures statistically explained up to 35% of the observed frailty-mortality association. Associations were stronger among younger individuals and differed by sex and BMI. These findings suggest that frailty-related plasma metabolomic signatures capture systemic metabolic correlates of biological aging and may support early mortality risk prediction and personalized prevention strategies in aging populations.

Tumor necrosis factor α (TNFα) regulates inflammation in metabolic diseases and probably aging-associated inflammation. Here, TNFα´s role in aging-related liver inflammation and fibrosis and underlying mechanisms was assessed in mice. In male C57BL/6J mice, aging increased hepatic inflammation, senescence markers p16 and p21 and Tnfa mRNA expression in liver tissue. In a second study, 4 and 24-month-old TNFα^-/- and wild-type (WT) mice were compared for senescence, liver damage, intestinal barrier function, and microbiota composition. 24-month-old TNFα^-/- mice were significantly protected from the aging-associated increase in hepatic senescence, inflammation and fibrosis found in WT mice. This protection was related with preserved stem cell marker expression, maintained small intestinal barrier function and lower bacterial endotoxin in portal blood. While differing from young mice, intestinal microbiota composition of old TNFα^-/- mice differed markedly from age-matched WT mice. Also, TNFα was found to alter permeability and tight junction protein levels being reversed by the presence of an JNK inhibitor in an ex vivo intestinal tissue model. Taken together, our results suggest that TNFα plays a key role in the development of aging-related liver decline in male mice.

Pharmacological modulation of monoaminergic signaling, a process targeted by many therapeutic and recreational drugs via receptors, transporters, degradation enzymes, or reuptake mechanisms, is emerging as a promising aging intervention and as a strategy to treat various maladies. Monoamines (including dopamine, serotonin, and norepinephrine) are central to the regulation of mood, movement, sleep, memory, and systemic physiology. Here, we demonstrate that Reserpine, chronic inhibitor of the vesicular monoamine transporter (VMAT), robustly extends lifespan in Drosophila melanogaster in a dose-dependent manner. However, reserpine-treated flies also exhibit reduced locomotor activity and impaired survival under acute heat-stress, indicating a context-dependent trade-off between lifespan extension and stress resilience. Transcriptomic profiling revealed that reserpine induces a transcriptionally repressed, low-energy state characterized by downregulation of metabolic, immune, and stress-response genes in treated aged animals. Notably, under heat-stress, reserpine blunts the induction of canonical protective genes, including heat shock proteins and antioxidant genes, resulting in increased proteotoxic vulnerability. These findings highlight the potential trade-offs of monoaminergic modulation and support further investigation of VMAT inhibitors, monoamine modulators and other hypertension drugs as geroprotective agents.

Age-related declines in skeletal muscle health are a major contributor to reduced mobility and development of sarcopenia in the elderly, yet effective interventions to prevent or reverse these declines are not fully optimized. Nutritional strategies to support muscle health in aging populations may be beneficial for improving muscle strength and function. In this study, we explored the effects of astaxanthin (AX), a naturally occurring antioxidant, on aged human muscle progenitor cells (hMPCs). Our findings reveal that AX enhanced proliferation and myogenic commitment of aged hMPCs, with a more pronounced effect in male hMPCs compared to female hMPCs. This dimorphism may be linked to differences in reactive oxygen species (ROS)-scavenging and effects on mitochondrial function. Other hallmarks of aging including DNA damage and cellular senescence showed differing effects of AX treatment. However, NRF2 and SIRT3 increased with AX treatment in both male and female hMPCs. This was accompanied by increased SIRT3 mitochondrial expression in males but not females, suggesting the NRF2-SIRT3 axis as a key driver of myogenicity and potential source of sexual dimorphism in response to AX. These results suggest sex-specific effects of AX in modulating aged hMPC behavior and pose a potential therapeutic strategy for combating age-related muscle decline.

Cerebrospinal fluid (CSF), partly driven by sensory stimulation, is crucial for maintaining homeostasis and clearing metabolic waste. Whether such stimulus-driven CSF flow is disrupted in age-related neurodegenerative diseases of the visual system remains unclear. This study examined the CSF flow during visual stimulation in glaucoma patients and healthy older adults using functional magnetic resonance imaging. In glaucoma, CSF inflow becomes progressively decoupled from the visually evoked blood-oxygenation-level-dependent (BOLD) response. Specifically, the characteristic stimulus-locked CSF patterns, which decrease after stimulus onset and increase after offset, diminish with disease severity. Mediation analysis suggests this flattened CSF pattern is driven by a flatter ascending BOLD slope, leading to a shallower CSF trough and a reduced post-stimulus surge. These results indicate that glaucoma-related functional impairments contribute to downstream alterations in CSF dynamics. Overall, this study provides insight into how glaucoma disrupts visually driven CSF inflow and highlights in vivo biomarkers for monitoring CSF dynamics.

Menopause-related metabolic remodeling may contribute to the excess cardiovascular disease (CVD) burden in aging women, yet the longitudinal metabolic correlates of time since menopause (TSM) and their prognostic value are unclear. In this prospective analysis of 67,582 postmenopausal women without baseline CVD from the UK Biobank, we profiled 251 plasma metabolites by nuclear magnetic resonance and followed participants for a median 13.7 years (8313 incident CVD events). Elastic net regression identified a 95‑metabolite TSM-associated metabolomic signature (Spearman r with TSM = 0.29). In multivariable Cox models, each 5-year increment in TSM (HR 1.14, 95% CI 1.11-1.16) and each 1-standard deviation increases in the metabolomic signature (HR 1.18, 95% CI 1.15-1.21) were independently associated with higher composite CVD risk, with consistent associations across myocardial infarction, ischemic heart disease, atrial fibrillation, heart failure and stroke. Mendelian randomization supported potential causal roles for 29 of the signature metabolites in CVD. Adding TSM or the metabolomic signature to SCORE2 improved 10‑year risk discrimination (area under the curve 0.584 to 0.657 and 0.660, respectively) and reclassification (net reclassification improvement +0.027 and +1.043). These findings implicate cumulative postmenopausal metabolic alterations in vascular risk and support metabolomic enhancement of risk stratification in postmenopausal women.

Genotoxic drugs used to treat cancer can trigger senescence, which contributes to chemotherapy resistance and tumor heterogeneity. However, the resulting cellular and molecular alterations following senescence remain poorly characterized. In this study, chemotherapy-induced senescence was triggered by etoposide in MDA-MB-231 breast cancer cells, and their fibrogenic potential, epithelial-to-mesenchymal transition (EMT), and stemness features were examined. In these cells, key mediators of fibrosis were significantly upregulated, suggesting a profibrotic potential involving TGF-β signaling. Etoposide also accentuated the mesenchymal phenotype of MDA-MB-231 cells and increased their motility. Additionally, nuclear β-catenin accumulation and upregulation of its EMT target genes were observed in senescent cells, alongside increased stemness markers, indicating a plastic cellular state involving Wnt/β-catenin signaling. Interestingly, pharmacological inhibition of the TGF-β/Wnt/β-catenin pathways reduced fibrosis, EMT, stemness marker expression, and cell migration, suggesting that these pathways are key regulators of these processes in senescent cells. These findings provide new insights into the molecular mechanisms driving chemotherapy-induced senescence and highlight these pathways as potential targets to alleviate resistance and aggressiveness in breast cancer.

Periodontitis and smoking are major contributors to oral and systemic health deterioration in aging adults. This study investigated the combined effects of smoking status and periodontitis severity on the subgingival microbiome in 1107 individuals aged 69-72 using shotgun metagenomic sequencing. Smoking was linked to reduced microbial diversity, enrichment of periodontal pathogens, and depletion of health-associated commensals, while increasing periodontitis severity was associated with broader dysbiotic shifts, including enrichment of canonical pathogens. The presence of overlapping taxa suggests shared dysbiotic pathways that may accelerate disease progression in older adults. Notably, the combination of smoking and severe periodontitis was characterized by enrichment of key pathogens, such as Tannerella forsythia, Fusobacterium nucleatum, Actinomyces israelii, and Mogibacterium timidum. Although former smokers showed fewer opportunistic pathogens than current smokers, their microbiomes remained altered compared to never smokers, suggesting persistent differences potentially related to past smoking. Functional profiling revealed largely additive effects of smoking and periodontitis, with enrichment of lipopolysaccharide biosynthesis, proteolysis, and sulfur metabolism, alongside depletion of commensal biosynthetic functions. Overall, the findings highlight the persistent and additive impacts of smoking and periodontitis on the subgingival microbiome, underscoring the importance of addressing both exposures jointly in long-term oral health strategies for older adults.

Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu) in 26 men, ProtAgeGap decreased by the equivalent of 10 months. While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk. Clinical trial number: clinicaltrials.gov: NCT01803568 registered 2013-02-26.