Aging Cell最新文献

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also identify urothelium-specific changes in purine, amino acid, and glycerophospholipid metabolism, which may contribute to age-associated cellular perturbations. Lastly, supplementation with depleted metabolites, nicotinamide and d-mannose, reduces DNA damage and oxidative stress and restores mitochondrial integrity in aged mBEDOs. These findings establish mBEDOs as an effective platform for investigating molecular and cellular underpinnings of urothelial aging and exploring metabolism-based interventions for age-associated bladder dysfunction.

Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function (“age-related bioenergetic decline”), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore, our goal was to characterize bioenergetic capacity in platelets, peripheral blood mononuclear cells (PBMCs), monocytes, and lymphocytes of healthy adults from the San Diego Nathan Shock Center Clinical Cohort representative of the adult life course (20–80+ years of age). In our sample of 72 adults, we found that chronological age was positively associated with PBMC (maximal respiration [Max] β = 0.147, p = 0.028) and lymphocyte respiratory capacity (Max β = 0.135, p = 0.041). Notably, the pattern of age-related differences varied by sex; age showed a weak positive association with platelet respiration (Max β = 0.219, p = 0.037) in men but not in women. Similarly, age showed a strong positive association with PBMC respiration (Max β = 0.206, p = 0.018) in women but not in men. We also explored the relationship between glycolysis and respiration and found strong positive associations in platelets, PBMCs, and monocytes, but not lymphocytes. It is possible that, despite our cohort consisting of healthy, disease-free individuals, the elevated respiratory capacity in older adults may be reflective of compensatory mechanisms that require further investigation. Nonetheless, these findings underscore the importance of considering biological context, such as donor health, sex, and tissue type, in understanding age-related bioenergetic differences.

Aging studies using animal and cellular models have uncovered key proteins and pathways central to organismal aging. However, these models differ genetically and physiologically from human aging, posing challenges in translating discoveries to human contexts. In this study, we present a human normal cell aging model based on the development of cytotrophoblasts (CTBs) to syncytiotrophoblasts (STBs) in the placenta. The in vitro-derived STBs from human trophoblast stem cells (hTSCs) recapitulate the maturation and major cellular aging features of in vivo CTB-STB, including multinucleation, hormone secretion, cell cycle arrest, genome instability, epigenetic changes, activation of endogenous transposable elements, and senescence-associated secretory phenotypes (SASPs). Notably, the progressive senescence in the trophoblast system closely matches the predicted aging trajectory of other human tissue stem cells. Known anti-aging molecules, such as mTOR inhibitors and senolytics, attenuate senescence signals in STBs. The established CGA-EGFP reporter hTSC line enables scalable and quantitative screening and identified candidates with it can be further extended to other context-specific aging processes like that of skin fibroblasts. The hTSC-STB system represents a novel physiologically accelerated cellular aging model, bridges the gap between fundamental aging research and interventions, and prioritizes anti-aging candidates for clinical development.

Aging is associated with profound alterations in immune cell composition and function, yet the impact on peripheral γ/δ T-cell subsets remains incompletely understood. Here, we show that the peripheral γ/δ T-cell compartment is markedly remodeled with age in mice. Specifically, innate-like Ly-6C⁻ CD44^hi γ/δ T cells expand in secondary lymphoid organs (SLOs) of aged mice, while adaptive-like subsets decline. This age-related shift is accompanied by enhanced functionality, with Ly-6C⁻ CD44^hi γ/δ T cells from aged SLOs displaying increased IL-17 production both ex vivo and in vivo following LPS challenge. Mechanistically, this functional remodeling correlates with a significant decrease in the expression of the transcription factor Foxo1 in Ly-6C⁻ CD44^hi γ/δ T cells. Type I interferon signaling contributes to the age-dependent downregulation of Foxo1, as Ly-6C⁻ CD44^hi γ/δ T cells from aged mice lacking the IFN-α receptor maintain Foxo1 expression and exhibit reduced IL-17 production. Collectively, our findings reveal that aging, through type I interferon–driven modulation of Foxo1, promotes the expansion and enhanced pro-inflammatory activity of innate-like γ/δ T cells. These changes may reinforce immune surveillance in secondary lymphoid organs but could also contribute to age-associated immune dysregulation and inflammation.

Cellular senescence is an irreversible state linked to aging that involves molecular and functional alterations. The mammalian hippocampus, a key brain region for learning and memory, is highly vulnerable to damage in age-related neurodegenerative diseases, yet the role of cellular senescence in hippocampal aging remains underexplored. Here, we report an early onset of senescence signatures in hippocampal astrocytes of the accelerated aging and frailty mouse model SAMP8. We examine how astrocyte senescence affects excitatory synapse formation, focusing on soluble signals released by astrocytes. Astrocytes isolated from SAMP8 brain and those differentiated from SAMP8 neural stem cells show senescence hallmarks (SA-β-gal, p16^INK4a, Lamin B1 loss), alongside a significant reduction in synaptogenic function. While astrocyte-conditioned medium (ACM) from control mice promotes excitatory synaptogenesis through thrombospondin-1/α2δ-1 neuronal receptor signaling, ACM from senescent SAMP8 astrocytes lacks this capacity. Supplementing senescent ACM with thrombospondin-1 protein or overexpressing thrombospondin-1 gene in senescent astrocytes reinstates synaptogenesis. At the hippocampal level, thrombospondin-1 and synaptic puncta are reduced in SAMP8 mice. Our findings reveal that senescent astrocytes exhibit reduced synaptogenic capacity due to thrombospondin-1 loss, highlighting their contribution to synaptic dysfunction during aging. Preventing senescence in hippocampal astrocytes may thus restore astrocyte-mediated synaptogenesis in the aged brain.

Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.

Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age-related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity-induced cardiac remodeling and inflammaging by activating the AMPK–ULK1 signaling axis and enhancing mitochondrial quality control. In middle-aged male mice with high-fat diet-induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS–STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro-inflammatory mediators, including IRF3 and IFN-γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK-dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.

The aging of the hematopoietic system is central to physiological aging, with profound consequences for immune competence, tissue regeneration, and systemic health. Age-related changes manifest as altered blood cell composition, functional decline in hematopoietic stem cells (HSCs), and deterioration of the bone marrow niche. Beyond hematologic dysfunction, hematopoietic aging acts as a systemic amplifier of age-related diseases through clonal hematopoiesis and inflammatory remodeling. This review integrates recent insights into the mechanisms and systemic impacts of hematopoietic aging, reframing it as a modifiable axis of systemic aging. We highlight emerging rejuvenation strategies—senolytics, metabolic reprogramming, and microbiota-targeted therapies—that aim to restore hematopoietic and immune function, offering promising avenues to improve healthspan and reduce age-related multimorbidity.

Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established. Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.

Aging is accompanied by profound changes in energy metabolism, yet the underlying drivers and modulators of these shifts remain incompletely understood. Here, we investigated how life-history evolution shapes metabolic aging and pharmacological responsiveness by leveraging Drosophila melanogaster lines divergently selected for reproductive timing. We measured organismal oxygen consumption rate and performed untargeted metabolomics in young and old flies of both sexes from long-lived “O” lines (selected for female late-life reproduction) and unselected “B” control lines. Males and females from the O lines maintained stable metabolic rates and largely preserved metabolite profiles with age, whereas B line flies showed age-related increases in oxygen consumption, citrate accumulation, and elevated levels of medium- and long-chain fatty acids, hallmarks of mitochondrial inefficiency and impaired lipid oxidation. Aged B flies also displayed elevated S-adenosylmethionine, reduced sarcosine, and diminished heme levels, indicating dysregulation of one-carbon metabolism and impaired heme biosynthesis. Furthermore, Vitamin B6 metabolites, pyridoxamine, pyridoxal, and 4-pyridoxate, increased with aging only in B line females. Motivated by evidence implicating the renin-angiotensin system in metabolic aging, we treated flies with the angiotensin-converting enzyme (ACE) inhibitor lisinopril. Lisinopril prevented the age-related rise in metabolic rate in B line females, aligning their metabolic phenotype with that of O line flies. This suggests that ACE inhibition may buffer against age-associated increases in metabolic rate and contribute to enhanced metabolic stability. Our results show that selection for delayed reproduction and increased lifespan modifies age-related metabolic trajectories and modulates physiological responses to pharmacological intervention.