Aging Cell最新文献

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this study integrates machine learning algorithms to explore the potential of MR and LDSC methods for biomarker screening. Gut microbiota is found to be a potential risk factor for 14 age-related diseases. The causal effects of gut microbiota on chronic kidney disease, cirrhosis, and heart failure are partially mediated by aging indicators. Additionally, gut microbiota identified through MR and LDSC methods exhibit biomarker properties for disease prediction (average AUC = 0.731). These methods can serve as auxiliary tools for conventional biomarker screening, effectively enhancing the performance of disease models (average AUC increased from 0.808 to 0.832). This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery. These findings may help to develop new approaches for healthy aging detection and intervention.

Dietary restriction (DR) is a well-established method for extending lifespan across various species, including C. elegans. Among the different DR regimens, axenic dietary restriction (ADR), in which worms are grown in a nutrient-rich sterile liquid medium, yields the most powerful lifespan extension. However, the molecular mechanisms underlying this longevity phenotype remain largely unexplored. Through a pilot screen of candidate genes, we identified the proprotein convertase BLI-4 as a crucial factor in neurons for modulating lifespan under ADR conditions. BLI-4's role appears to be specific to ADR, as it does not significantly impact longevity under other DR regimens. We further explored the involvement of different bli-4 isoforms and found that isoforms b, f, i and j redundantly contribute to the ADR-mediated lifespan extension, while the bli-4d isoform is mainly involved in development. Proteomics analysis revealed that the loss of BLI-4 function under ADR conditions specifically downregulates GOLG-2, involved in Golgi complex organization. This gene also partially mediates the longevity effects of BLI-4 under ADR conditions. Our findings highlight the importance of neuronal BLI-4 and its downstream targets in regulating lifespan extension induced by ADR in C. elegans.

Aging is an inevitable biological process, driven in part by increased oxidative stress, which accelerates cellular damage and contributes to immune system dysfunction. Therefore, targeting oxidative stress has emerged as a potential strategy. Pyrroloquinoline quinone (PQQ), a potent antioxidant, has demonstrated significant efficacy in reducing oxidative stress and modulating immune responses, making it a promising therapeutic candidate. In this study, we investigated the effects of aging on the hematopoietic immune system (HIS) through single-cell RNA sequencing (scRNA-seq) of spleen and bone marrow cells in murine models. Our results revealed widespread age-related inflammation and oxidative stress within immune cell populations. Notably, long-term PQQ supplementation improved physiological parameters and reduced blood inflammatory factors levels in aged mice. Subsequent scRNA-seq analysis demonstrated that PQQ supplementation effectively reduced oxidative stress levels across various HIS cell types and reversed aging-related phenotypes, such as inflammatory responses and immunosenescence. Additionally, PQQ reversed aging-induced disrupted signaling and restored immune homeostasis, particularly in B cells and hematopoietic stem cells (HSCs). Importantly, we identified critical molecular targets, including ASPP1, which mediates PQQ's anti-apoptotic effects in B cells, and Yy1 and CD62L, which were upregulated by PQQ to restore HSCs self-renewal and differentiation potential. Furthermore, the machine learning program and experimental validation demonstrated the senolytic and senomorphic effects of PQQ in vivo and vitro. These findings underscore PQQ's potential not only in mitigating oxidative stress but also in restoring immune homeostasis and promoting cellular regeneration, highlighting its therapeutic potential in addressing immune aging and improving physiological function.

Persistent microglial inflammation is a detrimental contributor to the progression of Parkinson disease (PD) pathology and related issues such as impaired adult hippocampal neurogenesis (AHN) and cognition. We conducted a 10-week exercise program with MPTP-treated mice to determine whether neuroinflammation can be addressed by aerobic exercise and elucidate its underlying regulatory mechanisms. Ten weeks of exercise significantly reduced PD-related pathology and enhanced AHN and memory. These changes were linked to a reduction in neuronal apoptosis, microglial inflammation, and NLRP3 inflammasome activation. In cultured microglia, fibril α-synuclein reduced FNDC5/irisin protein levels and induced NLRP3 inflammasome formation and IL-1β production, which could be diminished by recombinant irisin treatment. Interestingly, "runner serum" isolated from exercising rodents enhanced FNDC5/irisin expression and reduced NLRP3 inflammasome components and IL-1β secretion in α-synuclein-treated microglia. These effects could be diminished by blocking irisin signaling with cyclo RGDyk or NLRP3 agonist, nigericin sodium salt. Exercise-induced neuroprotective effects were weakened by treatment of MPTP-treated mice with cyclo RGDyk. In contrast, systematic administration of irisin partially replicated the beneficial effects of exercise on PD pathology, AHN, and memory function. As a nonpharmacological strategy, aerobic exercise effectively addresses PD pathology and preserves adult neurogenesis and cognition by mitigating microglial inflammation via mediating irisin/NLRP3 inflammasome pathways.

Immunotherapy has transformed the landscape of cancer treatment, with T cell-based strategies at the forefront of this revolution. However, the durability of these responses is frequently undermined by two intertwined phenomena: T cell exhaustion and senescence. While exhaustion is driven by chronic antigen exposure in the immunosuppressive tumor microenvironment, leading to a reversible state of diminished functionality, senescence reflects a more permanent, age- or stress-induced arrest in cellular proliferation and effector capacity. Together, these processes represent formidable barriers to sustained anti-tumor immunity. In this review, we dissect the molecular underpinnings of T cell exhaustion and senescence, revealing how these dysfunctions synergistically contribute to immune evasion and resistance across a range of solid tumors. We explore cutting-edge therapeutic approaches aimed at rewiring the exhausted and senescent T cell phenotypes. These include advances in immune checkpoint blockade, the engineering of "armored" CAR-T cells, senolytic therapies that selectively eliminate senescent cells, and novel interventions that reinvigorate the immune system's capacity for tumor eradication. By spotlighting emerging strategies that target both exhaustion and senescence, we provide a forward-looking perspective on the potential to harness immune rejuvenation. This comprehensive review outlines the next frontier in cancer immunotherapy: unlocking durable responses by overcoming the immune system's intrinsic aging and exhaustion, ultimately paving the way for transformative therapeutic breakthroughs.

With advancing age, the decline in intestinal stem cell (ISC) function can lead to a series of degenerative changes in the intestinal epithelium, a critical factor that increases the risk of intestinal diseases in the elderly. Consequently, there is an urgent imperative to devise effective dietary intervention strategies that target the alterations in senescent ISCs to alleviate senescence-related intestinal dysfunction. The 28-month-old naturally aging mouse model was utilized to discover that the primary factor contributing to the compromised barrier function and digestive absorption of the small intestine was a decrease in both the number and regenerative capacity of ISCs. The underlying mechanism involves the degeneration of mitochondrial function in ISCs, resulting in insufficient energy supply and decreased metabolic capacity. Additionally, our findings indicate that fasting-refeeding can influence the mitochondrial metabolism of ISCs, and that alternate day fasting (ADF) can facilitate the restoration of both the quantity and regenerative capabilities of ISCs, thereby exhibiting a notable antiaging effect on the small intestine. In conclusion, this study provides new insights into the potential beneficial role of ADF in ameliorating intestinal aging, thereby establishing a foundation for future investigations into dietary interventions aimed at addressing age-related intestinal dysfunction.

With advancing age, neurovascular dysfunction manifests as impaired neurovascular coupling (NVC), microvascular rarefaction, and blood-brain barrier (BBB) disruption, contributing to vascular cognitive impairment (VCI). Our previous research established a causal link between vascular senescence induced cerebromicrovascular dysfunction and cognitive decline in accelerated aging models. The present study examines whether chronological aging promotes endothelial senescence, adversely affecting neurovascular health, and whether senolytic therapies can enhance neurovascular function and cognitive performance in aged mice. We used transgenic p16-3MR mice to identify and eliminate senescent cells and employed genetic (ganciclovir) and pharmacological (ABT263/Navitoclax) senolytic approaches. Evaluations included spatial memory performance, NVC responses, cortical microvascular density, BBB permeability, and detection of senescent endothelial cells via flow cytometry. Brain endothelial cells exhibited heightened sensitivity to aging-induced senescence, undergoing senescence at a greater rate and earlier than other brain cell types, particularly during middle age. This microvascular endothelial cell senescence was associated with NVC dysfunction, microvascular rarefaction, BBB disruption, and deteriorating cognitive performance. On the other hand, senolytic treatments in aged mice improved NVC responses, BBB integrity, microvascular density, and learning capabilities. Notably, these findings suggest that the most effective time window for senolytic treatment is in middle-aged mice, where early intervention could better prevent neurovascular dysfunction and mitigate age-related cognitive impairment.

The insulin-like growth factor-1 (IGF-1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF-1 signaling modulates organ aging remain poorly understood. In this study, we assessed age-related changes in IGF-1 expression across multiple organs in mice and identified a more prominent increase in skin IGF-1 levels with aging-a phenomenon also observed in human skin. To explore the consequences of elevated IGF-1, we developed transgenic mice ectopically expressing human IGF-1 in the epidermis, driven by the bovine keratin 5 promoter (IGF-1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single-cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence-associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion. Our findings indicate that excessive IGF-1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF-1 signaling via downstream mechanisms-specifically blocking Ac-p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF-1 through dietary restriction-significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra, leading to motor impairment. A hallmark of PD is the presence of misfolded α-synuclein (α-syn) proteins and their neurotoxic accumulations, contributing to neuronal loss. Additionally, the inflammatory response plays a critical role in modulating the neurodegeneration process in PD. Moreover, peripheral macrophages recognize α-syn, triggering chronic inflammation in both the bloodstream and brain tissue, leading to elevated levels of proinflammatory cytokines, as it was observed in PD patient samples. Insulin-like growth factor 2 (IGF2) is a secreted factor with neuroprotective properties in several neurodegenerative disease models. Moreover, IGF2 signaling has been implicated in the cellular reprogramming of macrophages to an anti-inflammatory phenotype through epigenetic changes. Recently, reduced IGF2 levels in both plasma and peripheral blood mononuclear cells (PBMCs) from PD patient samples were reported, suggesting a potential link between IGF2 levels and inflammation. In this study, we investigated the inflammatory profile of PD patients and the effect of IGF2-reprogrammed macrophages in in vitro and in vivo PD models. Here, we report a significant increase in proinflammatory markers in PBMCs from PD patients. IGF2 treatment prevented α-syn-induced pro-inflammatory profile in murine primary macrophages. Notably, IGF2-reprogrammed macrophage treatment significantly reduced motor impairment, α-syn accumulation, and microglial activation in the Substantia Nigra across different stages of disease progression in the PD preclinical model. These findings highlight the immunomodulatory effect of IGF2 on macrophages and its potential therapeutic impact on PD.