Aging Cell最新文献

There is a growing contradiction between the rising demand for mechanical ventilation among the elderly and their heightened sensitivity to ventilator-induced lung injury (VILI). This discrepancy compels us to explore therapeutic targets for VILI in elderly patients. Our research revealed that aging increases the sensitivity of pulmonary endothelial cells to low-magnitude mechanical stretch. By analyzing transcriptome sequencing data from lung tissues of humans and mice at different ages, as well as published transcriptome sequencing data from senescent endothelial cells, we identified tissue kallikrein-related peptidase 8 (KLK8) as an age-dependent upregulated gene in lung tissues. Using KLK8 knockout mice, intra-pulmonary KLK8-overexpressing mice, and mouse lung vascular endothelial cells (MLVECs) with KLK8 overexpression or knockdown, we demonstrated that age-dependent KLK8 upregulation contributes to pulmonary endothelial senescence and increased susceptibility of aged mice to VILI. Mechanistically, KLK8 promotes pulmonary endothelial senescence by inactivating the fibronectin/focal adhesion kinase (FAK) pathway. Through transcriptional profiling, we identified the poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor olaparib as a potential agent that rescues KLK8-induced pulmonary endothelial cell senescence and alleviates VILI in aged mice. Our findings underscore the critical role of KLK8 in pulmonary endothelial senescence and provide preclinical evidence for PARP1/2 inhibitors as a therapeutic target for VILI in elderly individuals.

Studies in laboratory organisms typically minimize all environmental and genetic variation other than the intervention of interest. In aging studies, these highly controlled conditions have yielded profound insights into aging. But even within isogenic cohorts of lab animals in controlled environments, we observe substantial variation in lifespan. Here we exploited the climbing behavior of Drosophila to study variation in mortality among isogenic populations in a controlled environment. We show that fractionating large cohorts of relatively young isogenic flies by climbing behavior predicts future mortality risk and stress sensitivity. Using metabolomics to dissect this variation, we found metabolites whose abundances differ among the fractions. We also took advantage of the large number of individuals in each fraction, and the ease with which they can be collected, to explore the covariance structure of metabolites in flies that are genetically identical, but divisible into short-lived and long-lived fractions. In doing so, we identified metabolites and metabolic pathways as candidate biomarkers of intrinsic mortality risk.

Human umbilical cord blood (HUCB) exhibits distinct characteristics compared to adult blood, offering significant potential for medical applications, particularly in antiaging therapies. However, the metabolic profile of HUCB relative to adult blood remains poorly understood. Moreover, the specific metabolites within HUCB that confer antiaging properties have yet to be identified. Here, we conducted an untargeted metabolomic analysis comparing cord plasma and adult plasma. Our results reveal a unique metabolic landscape in cord plasma, characterized by significant differences in 662 out of 1092 total compounds and 43 out of 59 total human metabolic pathways. Notably, 211 abundant cord metabolites decline with age, involving key aging-related processes, including inflammation, oxidative stress, energy and nutrition metabolism, proteostasis and DNA damage responses, implicating their potential role in counteracting aging. Importantly, a proof-of-concept experiment demonstrates that a formula containing five of these metabolites (carnosine, taurocholic acid, inosine, L-Histidine and N-acetylneuraminic acid) significantly extends both lifespan and healthspan in C. elegans. Collectively, our findings provide novel insights into the distinctive characteristics of the human cord plasma metabolome and identify promising metabolites with therapeutic potential for antiaging and other cord blood-based medical applications.

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.