Aging Cell最新文献

During brain aging, terminally differentiated neuroglia exhibit metabolic dysfunction and increased oxidative damage, compromising their function. These cellular and molecular alterations impair their ability to maintain myelin sheath integrity, contributing to age-related white matter degradation. Calorie restriction (CR) is a well-established intervention that can slow biological aging and may reduce age-related metabolic alterations, thereby preserving the molecular function of aging glia. Here we present a single nucleus resolution, transcriptomics dataset evaluating the molecular profile of oligodendrocytes and microglia in the brain of aging rhesus monkeys following lifelong, 30% calorie restriction. Oligodendrocytes from CR subjects exhibited increased expression of myelin-related genes and showed enrichment in glycolytic and fatty acid biosynthetic pathways. In CR subjects, a subpopulation of oligodendrocytes upregulated cell adhesion gene, NLGN1 and were in closer proximity to axons. Microglia from CR subjects upregulated amino acid and peptide metabolism pathways and showed a reduced myelin debris signature. Our findings reveal cell-type specific transcriptional reprogramming in response to long term CR and highlight potential protective mechanisms against myelin pathology in the aging primate brain.

Preovulatory follicle aging is the period between formation and ovulation of a mature follicle. Previous studies had shown that mammalian preovulatory follicle aging is associated with chromosomal abnormalities and developmental defects such as decreased implantation, increased malformation and mortality and lower embryonic weight. Our understanding of the molecular events governing this process has been hampered by the difficulty in accessing them in vivo under natural conditions. We hypothesize that the quality of the mature oocyte is regulated by crosstalk between the oocyte and the somatic microenvironment during extended storage prior to ovulation. By combining temporal profiling and tissue-specific functional analyzes in Drosophila, we characterize a spatiotemporal crosstalk between the oocyte and the granulosa cells that governs preovulatory follicle aging in vivo. Preovulatory follicle aging is characterized by two distinct phases-early oocyte protective and late degenerative phases. The degenerative phase involves a positive feedback loop between oocyte mitochondrial dysfunction mediated by a mitochondrial-localized microprotein PIGBOS, and granulosa cell functional decline through a circular RNA circdlg1. Activation of the feedback loop is suppressed by germline Sestrin during the early phase. Our findings highlight that natural preovulatory follicle aging in vivo is governed by a mechanism that represses an oocyte-degenerative positive feedback loop between oocyte and granulosa cells.

The amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). While the production of Amyloid beta (Aβ) has traditionally been considered the primary cause of AD, the role of the APP intracellular domain (AICD) remains largely elusive. In this study, we established a novel model in the adult fly wing by expressing human APP, recapitulating AD-associated axon degeneration. Using this model, we discovered that ectopic APP expression in Drosophila wing margin neurons led to age-dependent axon degeneration. APP's effect depended on AICD production, and AICD overexpression alone was sufficient to induce axon degeneration in adult wings. Further investigations indicated that APP- or AICD-induced axon degeneration could be alleviated by blocking autophagy, but not apoptosis. Additionally, we identified a FoxO/Snail-Atg1 axis as an essential mediator of APP/AICD-induced autophagy-dependent axon degeneration. Finally, we demonstrated that administration of chloroquine, an autophagy inhibitor, effectively ameliorates APP- or AICD-induced axon degeneration. Our findings provide crucial insights into how APP induces autophagy-dependent axon degeneration through AICD production, laying a foundation for future investigations into AD pathogenesis.

COX7RP is a critical factor that assembles mitochondrial respiratory chain complexes into supercomplexes, which is considered to modulate energy production efficiency. Whether COX7RP contributes to metabolic homeostasis and lifespan remains elusive. We here observed that COX7RP-transgenic (COX7RP-Tg) mice exhibit a phenotype characterized by a significant extension of lifespan. In addition, metabolic alterations were observed in COX7RP-Tg mice, including lower blood glucose levels at 120 min during the glucose tolerance test (GTT) without a significant difference in the area under the curve (AUC), as well as reduced serum triglyceride (TG) and total cholesterol (TC) levels. Moreover, COX7RP-Tg mice exhibited elevated ATP and nicotinamide adenine dinucleotide levels, reduced ROS production, and decreased senescence-associated β-galactosidase levels. Single-nucleus RNA-sequencing (snRNA-seq) revealed that senescence-associated secretory phenotype genes were downregulated in old COX7RP-Tg white adipose tissue (WAT) compared with old WT WAT, particularly in adipocytes. This study provides a clue to the role of mitochondrial respiratory supercomplex assembly factor COX7RP in resistance to aging and longevity extension.

Tendon degeneration is common, and its risk increases with age both in humans and horses. Tendon regeneration and healing is limited due to inherent low cell density and vascularisation, and current treatments are insufficient as indicated by scar tissue formation and a high re-injury rate. The tendon vasculature plays a crucial role in tendon homeostasis, regeneration and healing, making it a potential therapeutic target. However, the effect of ageing on the tendon microvasculature is poorly understood. Here, we provide the first comprehensive characterisation of the tendon microvasculature. We employed high-resolution 3D imaging techniques, using micro-computed tomography (μCT) and confocal microscopy, to investigate age-related alterations in the vasculature within the equine superficial digital flexor tendon (SDFT), a functional equivalent of the human Achilles tendon. μCT analysis revealed a well-developed vascular network within the interfascicular matrix (IFM) and demonstrated significant age-associated reductions in vascular volume (70%), vessel diameter (30%) and density (74%). 3D immunolabelling showed significant reductions in MYH11- (96%) and desmin-positive (78%) volumes; however, there was a pronounced age-associated increase in von Willebrand factor (VWF)-positive volume (220%), which was accompanied by a significantly higher (249%) pericyte density. Taken together, these results indicate a loss of larger blood vessels in the IFM but an increase in small vessel formation, suggesting that neo-angiogenesis is induced in aged tendon alongside a loss of vascular homeostasis. These insights enhance our understanding of tendon ageing and may contribute to developing new therapeutic approaches for improving tendon health and repair in older individuals.

Ovarian aging is a complex process that compromises fertility and elevates the risk of reproductive disorders. To elucidate its spatiotemporal dynamics, we integrated single-nucleus RNA sequencing and spatial transcriptomics to construct a comprehensive aging atlas of 12 human ovarian tissues spanning ages 12-54 (prepubertal, age 12, n = 1; young, ages 23-29, n = 4; middle-aged, ages 32-34, n = 2; and older-aged, ages 42-54, n = 5). Our analysis revealed aging-related transcriptomic shifts, including impaired mitochondrial oxidative phosphorylation and reproductive structure development in aged human ovaries. We identified a novel endothelial cell (EDC) subtype, CLDN5⁺ blood EDCs, which exhibited unique functional specialization as semiprofessional antigen-presenting cells. In contrast to other cell types that lost cell identity during aging, CLDN5⁺ blood EDCs displayed transcriptomic sensitivity to aging, characterized by enhanced antigen-presenting capabilities, and heightened inflammatory activity. Spatial mapping further uncovered immunoglobulin-expressing (IGHG1⁺/IGKC⁺) cell accumulation in the ovarian periphery, correlating with advancing age. Critically, aging disrupted global cellular connectivity while amplifying the DLK1:NOTCH3 axis between theca cells and CLDN5⁺ blood EDCs, which may contribute to the dysregulation of ovarian functions. We also detected the upregulation of DLK1 in granulosa cells from patients with primary ovarian insufficiency. This study significantly enhances our comprehension of the underlying mechanisms of human ovarian aging and concurrently pinpoints potential therapeutic avenues for addressing related disorders.

Mammalian fully grown oocytes are believed to exhibit a weakened DNA damage response, leading to the accumulation of substantial levels of DNA damage and increased frequency of aneuploidies in an age-dependent manner. These hallmarks of reproductive ageing are generally presumed to be irreversible by rendering the oocyte chromosome complement incompatible with development. To test whether this is indeed true, we performed a series of germinal vesicle (GV) transfers between oocytes from females of late breeding/post-breeding age and oocytes from young animals. Our results show that age-associated DNA damage can be effectively suppressed: introducing the GVs of advanced-maternal-age (AMA) oocytes into DNA repair-competent cytoplasts generated by selective enucleation (SE) of young oocytes effectively suppresses the signs of age-dependent DNA damage. This is accompanied by a partial recovery of the chromatin dynamics and, surprisingly, a higher fidelity of chromosome segregation. By dissecting the GV fractions, we show that the ability to sense and repair DNA is linked to the free, non-chromatin-bound nuclear factors but not the oocyte nucleolus. Finally, we show that the overall improved state of the reconstructed oocytes is accompanied by enhanced full-term development. Therefore, contrary to popular belief, our results show that the age-associated decline in oocyte quality can be effectively mitigated, opening new possibilities for cell-based oocyte therapy.

Loss of regeneration is a key feature of aging organs, often linked to stem cell exhaustion. Skeletal muscle stem cells (MuSCs) undergo age-related numerical and functional decline, contributing to reduced regenerative potential. Using low-input multi-omics, we systematically profiled the epigenome, transcriptome, and 3D genome of MuSCs from individual mice across 3 age groups (young, old, and geriatric) and both sexes. At baseline, young male MuSCs showed reduced expression of cell cycle-related mRNAs. In aged mice, particularly males, MuSCs exhibited early alterations (emerging during the transition from young to old age) including enhanced proinflammatory signaling, and loss of cell identity. Late alterations (emerging during the transition from old to geriatric age) included heightened inflammation, widespread enhancer activation, and extensive 3D genome rewiring. Proinflammatory pathways were enriched for interferon signaling and correlated with endogenous retroviral expression and NFκB activity. Late-stage epigenome and 3D genome rewiring reflected downstream degenerative changes in muscle organization, response to cytokines, and loss of myogenic identity. Thus, progressive molecular shifts may explain the aggravated proliferative deficit and functional impairment observed in MuSCs during aging.

In human populations, cognitive performance in early life has been identified as a strong predictor of future dementia risk. If cognitive ability were a stable trait across the adult lifespan of mice, then this species would provide an excellent framework for understanding the biology underlying this modifiable risk factor. To address this issue, longitudinal cognitive testing was performed in female C57BL/6J mice aged between 4 and 18 months of age. By tracking individuals, we were able to demonstrate that the cognitive performance of an animal in specific tasks at 4 months of age was a remarkably reliable indicator of performance at 18 months of age. Variability in the performance of individuals was not associated with differences in macroscopic brain structure, but single-cell recording from neurons of the prefrontal cortex did identify age-related changes in membrane excitability. Most importantly, this study demonstrated that strategies adopted early in life to explore a nine-arm radial maze were maintained across the adult lifespan and learning effects associated with repeated exposure to a test contribute to this stability. Overall, our results demonstrate that, like humans, cognitive ability in mice is a stable trait and the cognitive reserve necessary for healthy brain ageing is established early in life.

Heavy metal ion exposure has become a global public health concern. Among them, lead is an extremely toxic heavy metal that poses serious health hazards to humans, particularly threatening vulnerable groups such as children and the elderly. Currently, the effects of chronic low-dose lead exposure on the auditory system have yet to be reported. In this study, we established a chronic lead exposure mouse model and conducted comprehensive auditory function assessments. The results demonstrated that lead-exposed mice developed high-frequency hearing loss at early stages, which progressively worsened over time. Morphological examination of the inner ear revealed hair cell loss, reduced synaptic ribbon numbers, and disruption of gap junctions in lead-exposed mice. Furthermore, immunofluorescence staining confirmed significantly decreased expression of the mitochondrial protease LONP1, along with markedly increased expression of its substrate HMGCS2, in the stria vascularis, sensory epithelium, and spiral ganglia of lead-exposed mice. These findings indicate that chronic low-level lead exposure causes inner ear damage and irreversible auditory dysfunction, while accelerating age-related hearing loss in C57BL/6J mice. These preclinical results suggest that chronic lead exposure may represent a significant risk factor for age-related hearing loss, deepen our understanding of lead-induced auditory system impairment, and hold profound implications for preventing hearing damage in populations at high risk of lead exposure.