Aging Cell最新文献

Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid β (Aβ) deposition, and synaptic dysfunction. However, the mechanisms underlying neurodegeneration remain poorly understood. In this study, we investigated the therapeutic potential of PBX1, a transcriptional regulator implicated in neurodevelopment and neuroprotection, against AD. PBX1 expression was significantly downregulated in postmortem hippocampal tissues from patients with AD and in the APP/PS1 mouse model. In vitro, PBX1a knockdown reduced neurite complexity and increased apoptosis. PBX1a overexpression reversed these effects and reduced soluble Aβ_1–40 and Aβ_1–42 levels. In vivo, hippocampal overexpression of PBX1a restored spatial learning and memory, reduced Aβ burden by 41%, and increased neurite length by 1.5-fold. These behavioral and structural improvements were accompanied by reduced levels of hyperphosphorylated Tau and toxic Aβ oligomers. Mechanistically, PBX1 directly activated the transcription of CRTC2—a coactivator of CREB, thereby increasing CRTC2 expression and its nuclear colocalization with phosphorylated CREB. Restoration of the PBX1–CRTC2–CREB axis enhanced neuronal survival and synaptic integrity. Notably, CRTC2 knockdown blocked PBX1-mediated reductions in Aβ deposition, apoptosis, and hyperphosphorylated Tau expression, confirming the role of the PBX1–CRTC2–CREB axis in conferring neuroprotection. Together, our findings indicate that PBX1 is a key modulator of neuronal resilience in AD and that it functions through transcriptional activation of the CRTC2/CREB pathway. By unraveling a mechanism that links transcriptional regulation to amyloid clearance and cognitive function, this study highlights PBX1 as a promising therapeutic target for AD.

Controlled settings may offer limited insight into the complexities of aging in natural and variable ecosystems. Artwork by Zahida Sultanova.

Major depressive disorder (MDD) is linked to a higher risk of premature aging, but the mechanisms underlying this association remain unclear. Using data from two population cohorts (UK Biobank and Finnish Twin Cohort), we evaluate the relationship between systemic and organ-specific proteomic and epigenetic aging acceleration and MDD. A lifetime history of MDD was associated with accelerated proteomic aging at both systemic and organ-specific levels—including the brain—in both cohorts, with stronger associations than those observed with systemic epigenetic aging. Systemic and brain-specific proteomic aging acceleration were linked to higher risks of incident MDD and a greater risk of Alzheimer's disease, related dementia, and mortality among individuals with MDD in the UK Biobank. Evidence of depressive episode remission attenuated the association between MDD and systemic and brain-specific proteomic aging acceleration. Finally, Mendelian randomization analyses revealed a causal effect of MDD on systemic and brain-specific proteomic aging acceleration. Our results suggest a strong bidirectional association between MDD and biological aging acceleration. Biological aging acceleration, assessed by proteomic systemic and organ-specific clocks, can serve as a novel therapeutic target for treating MDD and for mitigating the long-term risks of adverse health outcomes associated with this condition.

Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.

Caloric (CR) or dietary (DR) restriction improves health and extends lifespan in multiple species. However, the beneficial effects of DR may diminish if introduced late in life, emphasizing the importance of timing for promoting healthspan and avoiding adverse outcomes. Using a metabolomics approach, we investigated the metabolic responses in plasma, liver, and kidney of mice on acute and chronic DR at various ages. Two hundred and five mice including young (2-month-old; n = 72), middle-aged (6-month-old; n = 76), and old (17-month-old; n = 57) mice for DR were involved. No significant metabolic distinctions were observed during acute DR across different ages. Throughout chronic DR, hepatic glucose, glycogen, and glutathione levels—all of which decreased with age—were elevated in all mice, demonstrating an improvement in energy metabolism and enhanced protection against oxidative stress. We also found age-dependent metabolic responses to DR. Specifically, in young mice, amino acids and lactate contributed to gluconeogenesis in the liver during chronic DR. In contrast, in middle-aged and older mice, only fatty acids played a role in the energy supply within the liver. We noted significant hepatic glycogen accumulation in old mice, along with decreased levels of hepatic betaine and sarcosine in young mice, indicating the negative impact of chronic DR on liver function. The findings suggest that the most substantial benefits of DR occur in the middle stage of life, highlighting the need for tailored dietary intervention strategies to promote health span at different life stages.

Aging is associated with a progressive decline in physiological resilience, often linked to impaired stress responses and metabolic dysfunction. In Caenorhabditis elegans (C. elegans), caloric restriction (CR) and pharmacological interventions are widely used to dissect conserved longevity pathways. Here, we identify the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine as a novel modulator of lifespan and stress tolerance in C. elegans. Memantine, but not ketamine, extends median lifespan and reproductive lifespan, suggesting that the observed effects are not shared with ketamine at the tested concentration. Transcriptomic analysis revealed significant overlap between memantine-treated animals and CR models, particularly eat-2 mutants, implicating shared metabolic and longevity-associated pathways. Functionally, memantine was found to reduce mitochondrial and oxidative stress, while enhancing β-oxidation of fatty acids, and modifying behavioral responses to food cues, delaying food-seeking behavior and increasing locomotion under starvation, without affecting lipid storage. In summary, these findings suggest that memantine promotes stress resilience and healthy aging via metabolic changes that overlap with CR-associated pathways, highlighting its potential as a longevity-modulating intervention.

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.