Aging & Longevity

Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPR^(ER)) and the cytosolic UPR (UPR^(cyto)) in C. elegans that influences lifespan. We find that wild-type animals...

DNA methylation-based epigenetic clocks have been highlighted as promising biomarkers of ageing, and they have been shown to robustly predict morbidity and mortality. However, current literature is lacking a formal analysis of the increased prediction accuracy, or the added value, of the epigenetic clocks over traditional risk factors, such as body composition, smoking, or alcohol consumption, in predicting common chronic diseases. Here, we have compared the most commonly used epigenetic clocks...

Aging is accompanied by widespread remodeling of DNA methylation (DNAm), which can be leveraged to build epigenetic clocks. In mice, most DNAm clocks rely on internal organs or terminal tissues, limiting longitudinal studies. Here, we compared age-associated DNAm patterns in matched blood and tail-an easily accessible but underexplored tissue-and evaluated both as substrates for tissue-specific DNAm age prediction. Matched blood and tail were collected from male C57BL/6N Per2::Luc mice aged...

CONCLUSIONS: The UMNs of the older adults and the potential threat to inequalities require the attention of policymakers. Interventions should focus on improving access to medical services, with a particular emphasis on addressing the needs of vulnerable populations.

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The incidence of neurodegenerative diseases, including Alzheimer's disease (AD), continues to increase with the extension of human lifespan. However, their pathogenesis remains incompletely understood. Altered energy metabolism, particularly glucose metabolism involving glycolysis and oxidative phosphorylation, is widely recognized as an early pathological feature of neurodegenerative diseases. Astrocytes, the most numerous and widely distributed functional cells in the central nervous system...

Age-related macular degeneration (AMD) is a degenerative retinal disease initiated by dysfunction of the retinal pigment epithelium (RPE), in which age-related mitochondrial impairment, oxidative stress, chronic inflammation, and complement activation collectively drive outer retinal dysfunction and RPE atrophy, ultimately leading to progressive central vision loss. Accumulating evidence indicates that mitochondrial abnormalities, including excessive reactive oxygen species (ROS) production,...

Alzheimer's disease (AD) is characterized by neuroinflammation, yet the impact of concurrent systemic infections on the AD brain remains poorly understood. We investigated the molecular mechanisms underlying the central nervous system response to systemic infections in AD by analyzing RNA sequencing data generated in the prefrontal cortex from 202 post-mortem donors (113 AD, 89 controls), where we stratified by the presence of a respiratory infection at the time of death. We identified 763...

CONCLUSION: Based on our data, GrimAgeAcc is associated with ARHL and systemic age-related diseases (dementia, CVD, diabetes), potentially through shared biological pathways (e.g., endocytosis, lysosomal, inflammatory). Chronological age explains 28-50% of these associations, yet ARHL remains independently associated with all three outcomes after age adjustment. The cochlea may be vulnerable, but causal evidence is lacking. All findings are hypothesis-generating and require experimental...

Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease...

Frailty is a multifactorial geriatric condition linked to increased mortality and adverse health outcomes and is associated with gut microbiome features that differ from those observed in healthy ageing. We analyze gut metagenomic profiles in relation to estimated frailty severity and frailty-related clinical outcomes assessed with an internally developed and validated Frailty Mortality Index (FMI) in the SUPERB cohort, comprising 2,081 Swedish women aged 75-80 years. The FMI is a composite...

We examined the associations of reproductive behaviors and genetic susceptibility with aging indicators among female participants in the UK Biobank. Reproductive behaviors included the number of children ever born (NEB), age at first birth (AFB), age at last birth (ALB), and span of years of births (SYB). Aging indicators included frailty, PhenoAge acceleration, KDM-BA acceleration, and brain age difference (BrainAGE-diff). In multivariable analyses, reproductive behaviors showed nonlinear...

Neural circuits must remain functionally stable while adapting to changing demands and levels of stress. While this balance is thought to rely on plasticity programs integrating molecular and activity-dependent signals, mechanistic models of how such adaptations are orchestrated remain limited. Here, we show that impairment of autophagy in the Drosophila mushroom body (MB) induces brain-wide, post-transcriptional remodeling of presynaptic active zones, characterized by increased expression...

Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the...

An established vascular network is a prerequisite to ensuring an optimal supply of oxygen and nutrients for sustaining developmental events and systemic function. Herein, we construct a time-resolved proteolipidomic atlas of the aorta across the human life cycle. trans-omics integration reveals that postnatal ganglioside GM3 accumulation is functionally coregulated with calcium homeostasis mediated by plasma membrane calcium-transporting ATPases (PMCAs). We then verify mechanistically in...

Extracellular matrix degradation is a fundamental pathological feature of osteoarthritis, while the roles of degraded matrix remain largely unknown. We previously showed that serum elastin fragments were a systemic aging driver. Here, we found that elastin fragments were upregulated in synovial fluid in dual-center osteoarthritis patients. Elastin fragments actively impaired joint tissue in mice and human explants. Mechanistically, a specific elastin motif containing...

Sleep deprivation (SD), together with inevitable stress inherent to conventional SD protocols, can induce oxidative stress and inflammation, thereby increasing the risk of premature death. However, the source and signaling pathways underlying reactive oxygen species (ROS) generation remain unclear. Here, we demonstrate that both mechanical and thermogenetic SD, along with possible stress induced by both protocols, lead to initial ROS accumulation in Drosophila gut subregions, including the...

Roman concrete structures have remained serviceable for nearly two millennia and are widely regarded as outstanding examples of durable ancient engineering. Existing literature attributes Roman concrete longevity to the pozzolanic reaction that occurs between reactive volcanic ashes and lime. While the pozzolanic reaction is of fundamental importance, we argue that carbonation over a long period of time also substantially enhances the durability and potential self-healing properties of concrete....

Cellular senescence has emerged as a central mechanism driving cutaneous aging, impaired regeneration, and numerous dermatologic pathologies. Initially evolved as a protective mechanism to prevent malignant transformation and facilitate wound repair, senescence becomes maladaptive when senescent cells persist. Senescent keratinocytes, fibroblasts, and melanocytes can secrete pro-inflammatory mediators and other factors, collectively termed the senescence-associated secretory phenotype (SASP),...

Sirtuin 6 (SIRT6) is a protein deacetylase and ribosyltransferase that is a vital hub for maintaining epigenetic homeostasis, regulating the transcriptome, and repairing DNA double stranded breaks (DSBs). Comprehensive proteomic profiling of the SIRT6 posttranslational landscape, however, remains elusive. The SIRT6 C-terminal domain contains multiple phosphorylation sites. We find that the presence and the use of these sites are strongly correlated with maximum lifespan across mammals....