Aging Cell最新文献

Adipose tissue senescence is increasingly recognized as a key driver of systemic aging and age-related functional decline, yet the endocrine regulators that actively promote this process remain poorly defined. Angiopoietin-like protein 8 (ANGPTL8) is a metabolic factor implicated in lipid metabolism and inflammation and has been associated with multiple aging-related disorders. However, its direct role in adipose tissue senescence and organismal aging remains unclear. Here, we identify ANGPTL8 as a previously unrecognized regulator of adipose tissue aging through integrative analyzes of human cohorts, animal models, transcriptomics, and cellular studies. In a large human cohort, circulating ANGPTL8 levels were strongly associated with biological aging and mortality risk and significantly improved machine learning-based models for age and survival prediction. Consistent with these findings, genetic deletion of Angptl8 in mice extended lifespan, attenuated aging-associated functional decline, and reduced senescence markers in adipose tissue. Transcriptomic analyzes revealed age-dependent upregulation of ANGPTL8 in adipocytes accompanied by activation of pro-senescent transcriptional programs. Mechanistically, ANGPTL8 directly interacted with AKT2 and activated the AKT-mTOR-S6K signaling pathway, thereby promoting cell-autonomous adipocyte senescence. Genetic or pharmacological inhibition of this pathway abolished the pro-senescent effects of ANGPTL8. Collectively, our findings identify ANGPTL8 as an endocrine regulator linking metabolic dysfunction to adipose tissue senescence and systemic aging, highlighting the ANGPTL8-AKT2-mTOR axis as a potential therapeutic target for delaying age-associated functional decline.

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain. Here, we set out to profile the cell-type-specific features of the SASP and characterize the directionality of paracrine senescence-spreading between major brain cell types. Through this analysis, we identified key SASP ligand-receptor pairs involved in this paracrine dissemination. Targeting selected factors with specific inhibitors, we ameliorated some aspects of the paracrine spreading of senescence in a brain cell-type-dependent manner. Taken together, we identified specific SASP targets for therapeutic intervention in the context of human brain cells and thereby informed the SASP-dependent reaction of immune cells and age-related tissue dysfunction across both normal aging and models of neurodegenerative disease.

Cell therapies represent a promising frontier in modern medicine. Mesenchymal stromal cells (MSCs) constitute a valuable source due to their minimal ethical concerns, low immunogenicity, negligible tumorigenicity in vivo, and robust paracrine activity mediated by the secretion of anti-inflammatory and angiogenic factors. Despite these advantages, MSCs undergo rapid replicative senescence accompanied by a progressive loss of stemness markers and functional potency. In this context, cellular rejuvenation has been emerging as a pivotal strategy to restore their original biological features. These approaches aim to modulate the hallmarks of aging; as these processes are highly interconnected, multiple and complementary targets have been proposed. This review aims to discuss and analyze the main rejuvenation strategies reported in the literature for MSCs, with particular attention to approaches that can enhance their functionality and translational potential. In this context, the review focuses on five key categories of interventions: epigenetic modifications, metabolic reprogramming, modulation of cellular senescence, telomere biology, and extracellular vesicles. These strategies represent the fundamental axes through which cellular aging can be counteracted and the efficacy of cell-based therapies improved.

Microglia, the brain's resident immune cells, are transcriptionally diverse and highly dynamic, but during aging and disease they lose their transcriptomic flexibility and adopt a chronically activated state that is associated with neuroinflammation and pathology. An emerging transcriptomic process that is also increasingly implicated in brain aging, neuroinflammation, and disease is the dysregulation of transposable elements (TEs), repetitive genomic sequences with the potential to cause cellular stress/dysfunction. However, there are limited data on microglial TE transcript patterns in these contexts. Here, we analyzed multiple RNA-seq datasets from isolated human and mouse microglia across aging, Alzheimer's disease (AD), and AD-associated pathology. In contrast to previous observations based on whole-brain tissue and other brain cell types, we found that microglial TE transcript levels remained relatively consistent throughout most of the human lifespan before increasing in late life. We also found that TE transcript levels in microglia from AD patients showed minimal changes compared to age-matched controls, and in RNA-seq analyses of transgenic AD mouse models we observed pathology-associated TE transcript decreases. Subsequent analyses identified inverse associations between TE transcript levels and autophagy/lysosome-related gene expression, and in vitro studies suggested that aging- and AD-relevant stimuli, as well as pharmacological autophagy inhibition, modulate TE transcript expression in cultured human microglia. Together, these data provide novel insight into TE transcript dynamics in microglia, highlighting TE transcript patterns that differ from those observed in whole-brain samples and other cell types in aging and AD.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the early development of pathological features associated with aging, ultimately leading to premature death. HGPS primarily affects tissues of mesenchymal origin, as evidenced by the clinical manifestations characteristic of this premature aging disorder, including, but not limited to, osteoporosis, muscle wasting, lipodystrophy, and cardiovascular disease. In this study, we used preclinical mouse models and both genetic and translational approaches to investigate whether an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice. Here we show that osteocyte-derived RANKL deletion in the Zmpste24^-/- mouse model of HGPS reverted bone loss in both long bones and vertebrae. These mice also exhibited increased grip strength and improved endurance capacity. Furthermore, Zmpste24^-/- mice showed increased survival upon osteocyte-specific RANKL deletion. Notably, the use of a translational approach based on the administration of a neutralizing antibody against RANKL also restored bone mass, reduced muscle fibrosis, and extended the lifespan of Zmpste24^-/- mice. Altogether, these findings support that targeting RANKL exerts a beneficial effect on both osseous and extra-osseous phenotypes of HGPS, suggesting the potential of this therapeutic approach to explore in the treatment of this disease.

Vascular aging, not only a victim of vascular cell senescence but also a driving hub of systemic aging, is a complex process in which both anti-aging and pro-aging proteins are involved. Thus, the ideal anti-aging medication should have multiple protein targets; in this case, an lncRNA might be a good choice. AK050834 is a conserved lncRNA, but its roles in vascular biology and vascular aging are currently unknown. Here, we identified that AK050834 was highly expressed in vascular walls and in vascular smooth muscle cells (VSMCs). Notably, AK050834 expression was remarkably increased in aged vessels. By using gain-of-function, loss-of-function, and gene knockout approaches, we identified that AK050834 is a strong regulator of VSMC senescence and vascular aging. In terms of the mechanisms, we found that AK050834 suppressed the expression of the anti-aging protein ATF3 via direct interaction with its promoter, which was further confirmed by a rescue experiment. In addition, AK050834 increased the expression of the pro-aging protein p21 by stabilizing its mRNA. Finally, we found that AK050834 deficiency could effectively prevent vascular aging in mice in vivo. The interesting dual and opposite effects of AK050834 on the anti-aging protein ATF3 and the pro-aging protein p21 suggest that AK050834 might be a novel diagnostic marker as well as an ideal therapeutic and preventive target for vascular aging and many related diseases.

Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.

Aging-related metabolic decline, particularly impaired glucose tolerance, represents a growing challenge in aging populations. Probiotics are promising modulators of host metabolism; however, how sex differences influence their efficacy in mitigating metabolic aging remains poorly understood. Here, we administered Lactiplantibacillus plantarum AS21 to naturally aged male and female mice for 6 months. We observed a pronounced sexual dimorphism in metabolic decline, with aged males exhibiting more severe glucose intolerance than females. Concurrently, circulating citrulline levels were depleted in males but elevated in females. AS21 intervention significantly ameliorated glucose intolerance in aged males, while exerting minimal effects on metabolically stable females. Microbiota analysis revealed that AS21 reshaped the mucosa-associated microbial communities in males, an effect accompanied by increased abundance of microbial citrulline biosynthesis genes (argF, argI) and restoration of circulating citrulline. In contrast, females maintained stable metabolic and citrulline profiles alongside limited microbial alterations. Furthermore, direct citrulline supplementation recapitulated these metabolic benefits, improving glucose tolerance, enhancing glucose-stimulated insulin secretion (GSIS), and stimulating glucagon-like peptide-1 (GLP-1) release. Collectively, these findings demonstrate that AS21 alleviates age-related glucose dysregulation in male mice-a benefit closely associated with the restoration of microbiota-driven citrulline metabolism. This highlights its potential as a sex-specific, microbiota-targeted strategy for managing metabolic aging.

Female reproductive aging is associated with ovarian functional decline, leading to infertility. During aging, biochemical and biophysical changes in the ovarian extracellular matrix (ECM) occur, yet how these properties affect follicle growth and oocyte quality remains poorly understood. Here we describe spatiotemporal changes in the ovarian ECM with age using mass spectrometry, immunohistochemistry, and nanoindentation. While follicle stiffness remains unchanged, stromal matrix remodeling is associated with a ~2.5-fold increase in stiffness. To understand how this increase in stromal stiffness affects age-related follicular dysfunction, isolated young follicles were cultured in soft and stiff hydrogels mimicking young and aged ovarian stromal stiffness, respectively. Higher stiffness lead to a decrease in granulosa cell (GC) proliferation, oocyte quality, and GC-oocyte interactions mediated via transzonal projections (TZPs). RNA-seq revealed TGF-β signaling as a major pathway affected by stiffness, and activation of TGF-β signaling through Smad7 silencing rescued TZP formation and oocyte quality in stiff matrix. These findings provide mechanistic insight into how changes in ECM mechanics contribute to ovarian aging functional decline and reveal potential therapeutic targets to counter fertility loss associated with tissue aging and fibrosis.

With global population aging, sarcopenia and osteoporosis have become critical public health challenges. Muscles and bones are closely interconnected anatomically and functionally, but the biological mechanisms connecting sarcopenia and osteoporosis have not yet been fully elucidated. This study systematically investigated the bidirectional relationship and shared mechanisms between sarcopenia and osteoporosis through multi-omics analysis integrating genomic, proteomic, and metabolomic data from the UK Biobank. Our findings indicated that the two conditions may act as reciprocal risk factors. Higher lean mass index (hazard ratio [HR] = 0.830, 95% confidence interval [CI]: 0.788-0.874), greater hand grip strength (HR = 0.544, 95% CI: 0.531-0.558) and faster usual walking pace (HR = 0.735, 95% CI: 0.723-0.746) were significantly associated with lower osteoporosis incidence, with multiple plasma proteins and metabolites identified as mediators in these associations. Conversely, higher bone mineral density of left heel (HR = 0.613, 95% CI: 0.394-0.946) and right heel (HR = 0.591, 95% CI: 0.380-0.912) were associated with reduced sarcopenia risk. We also observed a positive genetic correlation (r = 0.25, p = 1.6 × 10^-5) between sarcopenia and osteoporosis, as well as substantial overlaps in risk-associated genes and circulating biomarkers between the two conditions with consistent effect directions. Furthermore, modifiable factors including smoking, sleep duration, and physical activity exhibited similar effect patterns between sarcopenia and osteoporosis, with more than 30% overlap in mediating proteins and metabolites. These discoveries highlight common pathophysiological pathways potentially underlying both conditions and are expected to advance the understanding of muscle-bone interdependence.