Aging & Longevity

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Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the aging population. Although frailty has been recognized as a potential risk factor, previous studies relying on static assessments cannot capture its dynamic nature. This study aims to prospectively evaluate the association between dynamic frailty trajectories and incident AMD. The baseline cohort included 462,573 UK Biobank participants who were free of AMD and had frailty phenotype (FP) data at...

Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific...

Aging is a heterogeneous process, with organ systems and individuals experiencing variable rates of decline that are not fully reflected by chronological age. This variability contributes to the complexity of system morbidity, which poses increasing challenges for clinical care and biomedical research. In this review, we discuss the heterogeneity of organ and whole-body aging and perspectives on genomics as possible mechanisms that relate to such heterogeneity. We discuss how static genomics,...

Cell states and biological processes are defined by their epigenetic profiles, distinctive composites of DNA- and histone-based chromatin components. However, the specific histone posttranslational modifications that distinguish cellular senescence and the impact of their distribution on transcription, especially with regard to gene length, have not been fully elucidated. Here, we show that promoter loss of symmetric dimethylated H4R3 (H4R3me^((2s))) and spreading of trimethylated H3K79...

Age-varying DNA methylation sites reflect increasing interindividual epigenetic divergence during aging, offering insights into health heterogeneity and potential for personalized interventions. Leveraging longitudinal DNA methylation data (3 waves over 5 years) from 135 relatively healthy Chinese older adults in the Rugao Longitudinal Ageing Study, we systematically characterized dynamic DNA methylation changes with age via mixed-effects modeling, identifying 125,353 age-associated (i.e., sites...

Testicular aging, a key feature of late-onset hypogonadism (LOH), is closely associated with Sertoli cells dysfunction. Emerging evidence implicates lipid droplet (LD) accumulation as a hallmark of aging in Sertoli cells, but its role in Sertoli cells senescence and the associated molecular mechanisms are unknown. We found that aging and obesity drove progressive LD accumulation in Sertoli cells, accompanied by mitochondrial dysfunction and ROS overproduction. Palmitic Acid (PA)-induced LD...

CONCLUSIONS: IC, particularly in the domains of cognition and mobility, was prevalently impaired among older adults. We identified both common and domain-specific factors associated with IC, offering insights for developing targeted interventions to enhance IC.

The human gut microbiome (GM) is increasingly recognized as one of the main systems influencing the aging trajectory. Age-related dysbiosis, with imbalance between symbionts and pathobionts, can in fact fuel chronic inflammation (inflammaging) and promote frailty. In older individuals, GM composition is characterized by marked inter-individual variability and consistently influenced by environmental exposures. Studies conducted in animals and closed human communities suggest that social contacts...

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Hematopoietic stem cells (HSCs) reside in the bone marrow in a quiescent state, but can be mobilized into the blood in response to inflammation, cytokine stimulation, nervous activity or hypoxia. Chronic inflammation, a hallmark of aging, accelerates HSC aging by promoting myeloid-biased differentiation and reducing self-renewal capacity, yet the role of mechanical stimulation in regulating these processes remains poorly understood. Here, we found that PIEZO1 senses shear stress in blood flow to...

Aging is accompanied by the progressive accumulation of biological deficits, which increases susceptibility to developing multiple chronic diseases (that is, multimorbidity). The biological underpinnings of multimorbidity remain poorly understood. Here we analyzed 54 blood biomarkers reflecting inflammatory, vascular, metabolic and neurodegenerative processes in 2,247 individuals aged 60 and over from the Swedish National Study on Aging and Care in Kungsholmen. Multimorbidity was assessed using...

Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia-myelin interactions are spatiotemporally regulated remains unexplored. Here, by examining spinal cord white matter tracts in mice, we determined that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of...

The age-related decline in immunity is accompanied by the accumulation of senescent CD8^(+) T cells. Using senescent cell isolation coupled with multi-omics profiling, we reveal the transition to senescence to be controlled by chromatin state-specific transcription factor (TF) networks in younger and older donors independent of age. These TF networks mediate widespread enhancer remodeling, repressing cell identity genes while upregulating inflammatory and secretory pathways. Inhibition or...

Aging is associated with the decline of many bodily functions including motor coordination. Aging-related impairment in motor coordination can result in falls, which reduce independence, health span, and quality of life in the elderly. To study the neural mechanisms that underlie this decline, we studied aged mice and observed a progressive decline in motor coordination on multiple motor coordination assays. The cerebellum is critically involved in motor coordination and balance, and cerebellar...

Big data approaches to discovering nongenetic risk factors have lagged behind genome-wide association studies that routinely uncover novel genetic risk factors for diverse diseases. Instead, epidemiology typically focuses on candidate risk factors. Since modern biobanks contain thousands of potential risk factors, candidate approaches may introduce bias, inadequately control for multiple testing, and overlook important signals. Doublethink, a model-averaged hypothesis testing approach, offers a...

Impaired neural stem cell (NSC) proliferation/activation is associated with brain aging, but the underlying mechanisms remain poorly understood. Here, we unexpectedly find that DMTF1, a transcription factor that regulates the Arf/p53 axis in cancer, is down-regulated in the NSCs of a premature aging model driven by telomerase deficiency. DMTF1 up-regulation was able to rescue the impaired proliferation of telomere dysfunctional NSCs. Mechanistically, DMTF1 regulates the transcription of Arid2...

Aging involves widespread metabolic dysregulation, including a decline in total nicotinamide adenine dinucleotide (NAD) levels. While NAD precursor supplementation elevates total NAD levels, it does not reveal tissue-specific effects of an altered NADH [reduced form of NAD^(+) (oxidized NAD)]/NAD^(+) balance. To address this, we generated transgenic Drosophila expressing the genetically encoded xenotopic enzyme LbNOX, which converts NADH to NAD^(+). LbNOX expression modulated both NAD(H) and...

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Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)-derived long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice. Plasma EV LINE-1 RNA levels markedly increase with age and strongly correlate with...