Aging Cell最新文献

The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis.

Cover legend: The cover image is based on the article A Nuclear Hormone Receptor nhr-76 Induces Age-Dependent Chemotaxis Decline in C. elegans by Rikuou Yokosawa et al., https://doi.org/10.1111/acel.70277.

Aging is commonly attributed to accumulated damage, or evolved antagonistic genetic trade-offs, which lead to an accumulation of damage causing misexpression of genes necessary for longevity. We propose an atavistic dysregulation of gene expression at cellular and tissue levels during aging, framing aging as a gradual regression toward ancestral cellular states. Similarly to the atavistic model of cancer, in which cells revert to unicellular-like behavior, aging may result from the breakdown of coordinated morphogenetic control, leading organs and tissues toward less integrated, ancient unicellular states. We suggest that aging may involve a progressive reversal of the well-known ontogenetic tracing of prior phylogenetic embryonic characteristics. Moreover, aging could involve a loss of large-scale coordination, with tissues reverting to ancient gene expression to different degrees. We tested this hypothesis using a meta-phylostratigraphic analysis, finding: (1) An atavistic over-representation of differential expression in the most ancient genes and under-representation in the evolutionary youngest genes for two multi-tissue aging databases, and tissues covering skin, ovarian, immune, senescent and mesenchymal-senescent cells; (2) No significant atavistic over-representation of the differential gene expression during aging of brain cells and mesenchymal stem cells; (3) overall age-dependent increase of heterogeneity in the direction of the phylogenetic position of tissues' transcriptional profiles; (4) and an overall negative evolutionary age mean shift toward the most ancient genes. Our analyses suggest that aging involves uncoordinated and tissue-specific phylogenetic changes in gene expression. Understanding aging as a structured, heterogeneous atavistic process opens new avenues for rejuvenation, focusing on restoring multicellular coherence in evolutionarily youthful gene expression.

HIV infection induces chronic immune activation, predisposing people living with HIV (PLWH) to early immunosenescence. It is essential to understand the mechanisms behind the senescence-associated secretory phenotype (SASP). This study investigates the role of extracellular vesicles (EVs) in peripheral immunosenescence in HIV infection associated with SASP modulation. Biological and in silico analyses were performed to explore the crosstalk between EVs, miR-21-5p, and SASP. Plasma EVs from PLWH were isolated and used to stimulate peripheral blood mononuclear cells (PBMCs) to evaluate their potential to induce SASP. Mononuclear cells were transfected in vitro to induce the production of EVs carrying specific miR-21-5p and assess their role in SASP induction. Inflammatory and senescence markers were analyzed using an immunoassay, flow cytometry, and RT-qPCR. Biological verifications revealed that plasma EVs from PLWH predominantly induce SASP and drive IL-6 production in HIV-uninfected PBMCs. We confirmed that miR-21-5p expression was increased in plasma EVs from chronically infected PLWH on antiretroviral therapy (ART). Furthermore, we demonstrated that EVs overexpressing miR-21-5p induced SASP, specifically increasing IL-6 levels. SASP-associated cytokines were associated with PLWH with impaired CD4 T cell recovery and a higher prevalence of CD8⁺ and CD4⁺ CD57⁺ T cells. We also corroborate that IP-10, IFN-γ, and IL-6 could be potential biomarkers for identifying PLWH at greater risk of immunosenescence. Our findings provide insights into EVs driving SASP/IL-6 release, and this effect becomes more evident in EVs that carry miR-21-5p. This finding highlights a potential mechanism by which EVs and IL-6 contribute to peripheral immunosenescence in HIV-uninfected cells.

Previous studies have developed proteomic aging clocks to estimate biological age and predict mortality and age-related diseases. However, these earlier clocks were based on cross-sectional data, capturing only the cumulative aging burden at a single time point but were unable to reflect the dynamic trajectory of biological aging over time. We constructed a longitudinal proteomic aging index (LPAI) using data from 4684 plasma proteins measured by the SomaScan 5K Array across three visits in the Atherosclerosis Risk in Communities (ARIC) study (ages 67–90 at last visit). Our two-step approach applied functional principal component analysis (FPCA) to capture protein-level change patterns over time, followed by elastic net penalized Cox regression for protein selection. LPAI was constructed in a randomly selected training set of ARIC participants (N = 2954), tested among the remaining ARIC participants (N = 1267), and validated externally in Multi-Ethnic Study of Atherosclerosis (MESA) participants (N = 3726, ages 53–94 at last exam). Using Cox proportional hazards model, higher LPAI was associated with increased all-cause mortality (HR = 2.50, 95% CI: [2.15, 2.92] per SD), CVD mortality (HR = 1.79, 95% CI: [1.34, 2.39] per SD), and cancer mortality (HR = 1.96, 95% CI: [1.45, 2.64] per SD) risk in ARIC, with statistically significant and directionally consistent associations also observed in MESA. Additionally, higher LPAI was associated with increased multimorbidity and frailty. This study demonstrates the feasibility of developing biological aging measures from longitudinal proteomics data and supports LPAI as a biomarker for aging-related health risks.

Cover legend: The cover image is based on the article Telomerase Depletion Accelerates Ageing of the Zebrafish Brain by Raquel R. Martins et al., https://doi.org/10.1111/acel.70280.

Cover legend: The cover image is based on the article Aged Zebrafish as a Spontaneous Model of Cardiac Valvular Disease by Laura Bevan et al., https://doi.org/10.1111/acel.70266.

Liver aging is characterized by pathological features including lipid deposition, exacerbated chronic inflammation, and increased cell death. Although exercise intervention has been proven effective in delaying liver aging, its fundamental biochemical mechanism remains unclear. This study utilized a naturally aged mouse model and an in vitro cellular senescence system to reveal, for the first time, the cascade mechanism by which β-hydroxybutyrate (β-HB), a core protective mediator induced by aerobic exercise, delays liver aging through regulating the macrophage–hepatocyte crosstalk. Within the aging microenvironment, disturbance of mitochondrial homeostasis results in the cytosolic release of mtDNA, which activates the cGAS-STING signaling pathway and drives macrophage polarization towards the pro-inflammatory M1 phenotype. M1 macrophages subsequently indirectly induce hepatocyte lipid metabolic dysregulation and initiate PANoptosis. Aerobic exercise stimulates the production of endogenous β-HB, which protects mitochondrial function, inhibits the activation of the cGAS-STING pathway in macrophages, facilitates macrophages transformation into the anti-inflammatory M2 phenotype, and ultimately indirectly ameliorates hepatocyte lipid deposition and PANoptosis. Additionally, exogenous β-HB administration efficiently mimics the endogenous ketogenic effect of aerobic exercise, restoring mitochondrial homeostasis, mitigating inflammation, and reducing PANoptosis levels in the liver of aged mice. This study elucidates the molecular mechanisms by which exercise-induced endogenous β-HB confers hepatoprotection. We establish β-HB as an exercise mimetic, exerting its protective effects on the aging liver through targeted inhibition of the innate immune hub STING. These findings provide a robust theoretical and experimental foundation for the translational application of β-HB in clinical nutritional strategies for aging intervention.

Cover legend: The cover image is based on the article Matrix Stiffness Promotes DRP1-Mediated Myofibroblast Senescence to Drive Silica-Induced Pulmonary Fibrosis by Xinying Zeng et al., https://doi.org/10.1111/acel.70275.

Understanding metabolic changes across the human lifespan is essential for addressing age-related health challenges. However, comprehensive metabolomic and lipidomic analyses, particularly in human plasma, remain underexplored. Herein, we performed untargeted metabolomics and lipidomics profiling of plasma collected from 136 individuals aged 0–84 years. This analysis reveals distinct metabolic signatures across life stages, with newborns displaying unique sphingosine (SPH) profiles, while aging was found to be characterized by elevated amino acid levels and lipid imbalances. Notably, we identified linear and nonlinear metabolic trajectories across the lifespan, highlighting critical transition points reflecting the key stages of metabolic reprogramming. By integrating these metabolic patterns, we developed an “aging clock” based on plasma metabolite profiling, thus providing a powerful tool to predict biological age. These findings offer new insights into the dynamic metabolic landscape of aging, paving the way for targeted interventions to improve healthspan and prevent age-related diseases.