Longevity Papers

Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

The hypothalamus is the brain region that regulates systemic body metabolism and multiple brain functions. The adult hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with age-related body changes, the hypothalamic NSC (htNSC) population declines, indicating the potential of htNSC replacement as an anti-aging strategy. Here, we developed protocol to generate htNSCs from human pluripotent stem cells (hPSCs). Implanting the hPSC-derived htNSCs into the hypothalamus of aged mice ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function. Mechanistically, these anti-aging effects were mediated by inter-tissue communication: enhanced neuronal activity in the htNSC-transplanted hypothalamus stimulated adipose tissues to produce and release the anti-aging molecule eNAMPT into systemic circulation via the sympathetic nervous system. Concurrently, the aged inflammatory environment in the hypothalamus was alleviated by peripheral anti-aging signals. Collectively, our findings support the potential of anti- or healthy aging therapies by targeting hypothalamus.

Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.