Aging Cell最新文献

Menopause is a complex biological transition marked by the decline of ovarian function and estrogen levels, leading to a wide range of physiological and immunological changes in women. Traditional animal models, particularly ovariectomized rodents, have been instrumental in studying menopause; however, they often fail to fully replicate human hormonal and immune responses. Humanized mouse models, which incorporate human immune systems and tissues, represent a promising alternative for bridging this translational gap. This review explores the current applications of humanized mice in disease research and highlights their untapped potential in menopause studies. We discuss the limitations of existing menopause models and propose a novel framework for using humanized mice to investigate estrogen signaling, immune interactions, and functional food interventions. Functional foods such as soy isoflavones, polyphenols, omega-3 fatty acids, and probiotics have shown beneficial effects on menopausal symptoms in clinical and animal studies, yet their immune-modulatory mechanisms remain underexplored in human-relevant models. We advocate for interdisciplinary collaboration to develop and utilize humanized mouse models tailored to menopause research. This integrated approach may offer new insights into the immune-hormonal landscape of menopause and pave the way for personalized, non-invasive therapeutic strategies.

Atherosclerosis, a key pathological basis of cardio-cerebrovascular diseases, is closely associated with aging and endothelial cell senescence. The role of microRNAs (miRNAs) in regulating endothelial cell senescence and atherosclerosis remains incompletely understood. In this study, we discovered that miR-375-3p expression was significantly elevated in the serum of both aged and atherosclerotic mice. Overexpression of miR-375-3p induced endothelial cell senescence, evidenced by increased senescence-associated β-galactosidase (SA-β-gal) staining, upregulation of p15, IL6, and IL8, and inhibited cell colony formation. In vivo inhibition of miR-375-3p in ApoE^−/− mice markedly reduced atherosclerotic plaque formation. We further identified STX6 as a direct target of miR-375-3p, and its overexpression rescued the senescence-related phenotypes induced by miR-375-3p. Mechanistically, the miR-375-3p/STX6 signaling axis promoted endothelial cell senescence via the SMAD2/p15 pathway in a SMAD2-dependent manner, and overexpression of STX6 attenuated atherosclerosis progression in mice. Together, our findings highlight the miR-375-3p/STX6 axis as a critical regulator of endothelial cell senescence and a potential translational use in the prevention of atherosclerosis and related diseases.

Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2, the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.

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.