Aging Cell最新文献

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.

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.

Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases.

Epigenetic clocks are machine learning models that predict an organism's chronological age (the time elapsed since birth) or biological age (a proxy for physiological integrity) based on methylation levels from multiple genomic sites. To date, all epigenetic clocks rely exclusively on C5-methylcytosine (5 mC), the predominant DNA methylation mark in vertebrates. However, not all species possess detectable 5 mC levels. Here, we used N6-methyladenine (6 mA), a less-characterized DNA modification type, to develop a series of epigenetic clocks in the buff-tailed bumblebee (Bombus terrestris). Using long-read Nanopore sequencing, we generated genome-wide, base-resolution profiles of 6 mA and 5 mC in males of different ages (n = 15), and developed multiple epigenetic clocks based on distinct features of the aging DNA methylome. All clocks showed strong correlations between predicted epigenetic and chronological age. Moreover, they also detected pharmacologically induced lifespan extension, reflected by a reduction in predicted epigenetic age relative to chronological age, indicating that these clocks capture biological aging. These findings demonstrate that 6 mA can be used to build accurate epigenetic clocks and establish 6 mA as a promising biomarker of aging in animals.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid β (Aβ) deposition, and synaptic dysfunction. However, the mechanisms underlying neurodegeneration remain poorly understood. In this study, we investigated the therapeutic potential of PBX1, a transcriptional regulator implicated in neurodevelopment and neuroprotection, against AD. PBX1 expression was significantly downregulated in postmortem hippocampal tissues from patients with AD and in the APP/PS1 mouse model. In vitro, PBX1a knockdown reduced neurite complexity and increased apoptosis. PBX1a overexpression reversed these effects and reduced soluble Aβ_1-40 and Aβ_1-42 levels. In vivo, hippocampal overexpression of PBX1a restored spatial learning and memory, reduced Aβ burden by 41%, and increased neurite length by 1.5-fold. These behavioral and structural improvements were accompanied by reduced levels of hyperphosphorylated Tau and toxic Aβ oligomers. Mechanistically, PBX1 directly activated the transcription of CRTC2-a coactivator of CREB, thereby increasing CRTC2 expression and its nuclear colocalization with phosphorylated CREB. Restoration of the PBX1-CRTC2-CREB axis enhanced neuronal survival and synaptic integrity. Notably, CRTC2 knockdown blocked PBX1-mediated reductions in Aβ deposition, apoptosis, and hyperphosphorylated Tau expression, confirming the role of the PBX1-CRTC2-CREB axis in conferring neuroprotection. Together, our findings indicate that PBX1 is a key modulator of neuronal resilience in AD and that it functions through transcriptional activation of the CRTC2/CREB pathway. By unraveling a mechanism that links transcriptional regulation to amyloid clearance and cognitive function, this study highlights PBX1 as a promising therapeutic target for AD.

Controlled settings may offer limited insight into the complexities of aging in natural and variable ecosystems. Artwork by Zahida Sultanova.

Major depressive disorder (MDD) is linked to a higher risk of premature aging, but the mechanisms underlying this association remain unclear. Using data from two population cohorts (UK Biobank and Finnish Twin Cohort), we evaluate the relationship between systemic and organ-specific proteomic and epigenetic aging acceleration and MDD. A lifetime history of MDD was associated with accelerated proteomic aging at both systemic and organ-specific levels-including the brain-in both cohorts, with stronger associations than those observed with systemic epigenetic aging. Systemic and brain-specific proteomic aging acceleration were linked to higher risks of incident MDD and a greater risk of Alzheimer's disease, related dementia, and mortality among individuals with MDD in the UK Biobank. Evidence of depressive episode remission attenuated the association between MDD and systemic and brain-specific proteomic aging acceleration. Finally, Mendelian randomization analyses revealed a causal effect of MDD on systemic and brain-specific proteomic aging acceleration. Our results suggest a strong bidirectional association between MDD and biological aging acceleration. Biological aging acceleration, assessed by proteomic systemic and organ-specific clocks, can serve as a novel therapeutic target for treating MDD and for mitigating the long-term risks of adverse health outcomes associated with this condition.

Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.

Caloric (CR) or dietary (DR) restriction improves health and extends lifespan in multiple species. However, the beneficial effects of DR may diminish if introduced late in life, emphasizing the importance of timing for promoting healthspan and avoiding adverse outcomes. Using a metabolomics approach, we investigated the metabolic responses in plasma, liver, and kidney of mice on acute and chronic DR at various ages. Two hundred and five mice including young (2-month-old; n = 72), middle-aged (6-month-old; n = 76), and old (17-month-old; n = 57) mice for DR were involved. No significant metabolic distinctions were observed during acute DR across different ages. Throughout chronic DR, hepatic glucose, glycogen, and glutathione levels-all of which decreased with age-were elevated in all mice, demonstrating an improvement in energy metabolism and enhanced protection against oxidative stress. We also found age-dependent metabolic responses to DR. Specifically, in young mice, amino acids and lactate contributed to gluconeogenesis in the liver during chronic DR. In contrast, in middle-aged and older mice, only fatty acids played a role in the energy supply within the liver. We noted significant hepatic glycogen accumulation in old mice, along with decreased levels of hepatic betaine and sarcosine in young mice, indicating the negative impact of chronic DR on liver function. The findings suggest that the most substantial benefits of DR occur in the middle stage of life, highlighting the need for tailored dietary intervention strategies to promote health span at different life stages.

Aging is associated with a progressive decline in physiological resilience, often linked to impaired stress responses and metabolic dysfunction. In Caenorhabditis elegans (C. elegans), caloric restriction (CR) and pharmacological interventions are widely used to dissect conserved longevity pathways. Here, we identify the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine as a novel modulator of lifespan and stress tolerance in C. elegans. Memantine, but not ketamine, extends median lifespan and reproductive lifespan, suggesting that the observed effects are not shared with ketamine at the tested concentration. Transcriptomic analysis revealed significant overlap between memantine-treated animals and CR models, particularly eat-2 mutants, implicating shared metabolic and longevity-associated pathways. Functionally, memantine was found to reduce mitochondrial and oxidative stress, while enhancing β-oxidation of fatty acids, and modifying behavioral responses to food cues, delaying food-seeking behavior and increasing locomotion under starvation, without affecting lipid storage. In summary, these findings suggest that memantine promotes stress resilience and healthy aging via metabolic changes that overlap with CR-associated pathways, highlighting its potential as a longevity-modulating intervention.