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The steroid hormone 5-androstene-3β,17β-diol (ADIOL) was discovered nearly a century ago in humans, yet its physiological functions have remained poorly understood. Using C. elegans, we identify ADIOL as essential for several pro-healthspan effects of fasting and caloric restriction (CR). These dietary restriction regimens activate an ADIOL-NHR-91-kynurenic acid signaling axis, partly through transcriptional programs associated with ADIOL biosynthesis. Within this axis, ADIOL acts through...

Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells (ECs) and their role in endothelial dysfunction with aging...

Mental and nervous system disorders often co-occur with cardiovascular diseases in aging populations, yet the biological relationships underlying these associations remain incompletely understood. Using heart and brain imaging data from 33,573 UK Biobank (UKB) participants, we developed a brain age prediction model to estimate the brain age gap (BAG), an imaging-based marker of brain aging. We then examined BAG as a mediator between 82 cardiac imaging-derived phenotypes (IDPs) and 11 disorders....

Aging research has traditionally focused on lifespan and healthspan as primary outcome domains, implicitly treating chronological time as a uniform container of value. The memory-structured reconstruction of extended chronological intervals has not been systematically examined as an aging-related variable. I introduce experienced longevity, defined as the amount of lived time subjectively contained within a fixed chronological interval. Drawing on established distinctions between retrospective...

Genetically diverse groups arrived in three waves, some potentially carrying genes acquired from long-ago Australasian ancestors

Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood,...

The molecular basis underlying muscle atrophy, as it occurs during disuse or aging, and activity-induced hypertrophy remain poorly understood. A major challenge has been defining the diverse cellular and niche environments within skeletal muscle, which is mostly composed of multinucleated myofibers. Here, we present a single-nucleus and single-cell transcriptomic atlas, coupled with spatial profiling, of mouse limb skeletal muscle under resting conditions and during experimentally induced...

Understanding aging and complex diseases requires diverse data, ranging from molecular profiles to imaging and routine clinical tests. However, most multi-omic datasets measure only a subset of modalities and are confounded by batch effects. Here, we present AURORA (AI unification and reconstruction of omics reassembly atlas), a generative deep-learning platform that integrates seven modalities (including transcriptomics, metabolomics, microbiome, 3D and thermal facial imaging, and clinical...

Fatty acids (FAs), as the predominant organic acids, form a major component of the metabolome. We present a multi-tiered method that comprehensively captures FA diversity-including chain lengths (C2-C34), unsaturation, isomers, and endogenous forms-within a single biological specimen. This workflow quantifies the broadest range of free FAs reported to date. Integrated with two complementary tiers profiling the total FA pool from alkaline hydrolysis and esterified acyl compositions across lipid...

Frailty is a complex trait that significantly increases the risk for negative health consequences, including hospitalization and disability. However, the evidence regarding the genetic basis of frailty phenotype (FP) is very limited. We conducted a genome-wide association study (GWAS) on FP using the data from the Canadian Longitudinal Study on Aging (CLSA). We classified the participants as non-frail, pre-frail, and frail, and performed a GWAS utilizing the ordinal logistic regression adjusted...

DNA variants modulate mortality risks across an entire lifespan but their dynamic age-dependent effects have not been resolved in any species for either sex. Here we mapped variants that shape mortality using an actuarial approach, starting with a base population of 6,438 pubescent mice and ending with 559 survivors that lived beyond 1,100 days of age. Twenty-nine Vita loci influence lifespan with strong age- and sex-specific effects. Most act during distinct stages with polarities that often...

Cognitive performance prediction may help identify early cognitive decline. However, the heterogeneity of research findings impedes the identification of key predictors. This study used 21,877 participants (25-74 years) from the German National Cohort (NAKO Gesundheitsstudie, NAKO) to systematically predict cognitive test scores based on brain structure, demographic, health-related, and cognitive data. Importantly, validation analyses were performed across study sites and external samples...

De novo lipogenesis (DNL) is a metabolic process by which carbohydrates are converted into fatty acids and used for immediate energy or stored as triglycerides for later use. Increased DNL in brown adipose tissue (BAT) is believed to be a marker of metabolic health, but indicates poor metabolism if upregulated in hepatic tissue. ChREBP is a primary regulator of whole-body DNL and promotes production of key enzymes including fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA...

High altitude-associated pathophysiological processes may potentially accelerate aging trajectory, while evidence remains limited. We present immune landscape characterization in human populations residing at 3656-meter (Lhasa) and 5070-meter (Tuiwacun) elevations on the Qinghai-Tibet Plateau, complemented by multiorgan single-cell RNA sequencing and spatially enhanced resolution omics sequencing (Stereo-seq) of mice under simulated 5000-meter hypoxic conditions. Comparative analysis revealed...

SRGBHSP is a classic traditional Chinese medicinal. Modern studies found that SRGBHSP had antioxidant, anti-inflammatory and constitution-strengthening pharmacological effects. Oxidative stress is a major factor that can cause an organism to age. Therefore, we proposed that SRGBHSP has an aging modulatory effect by its antioxidant properties. In the present study, we used a C. elegans model to explore the aging modulatory activity of the extract from SRGBHSP. Aging modulatory effects of SRGBHSP...

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic and inflammatory mechanisms, potentially mediated by the gut microbiota, yet the neurobiological impact of comorbid AD+T2DM microbiota from elderly donors remains unexplored. Fecal microbiota from healthy, AD, T2DM, and AD+T2DM postmenopausal female donors (aged 56-89 years) was transplanted into antibiotic-treated male mice. Behavioral testing, blood profiling, hippocampal neurotrophic gene expression, and 16S rRNA...

We propose a computational framework for spatial niche analysis (SpaNiche) in spatial transcriptomics data to uncover colocalization patterns and infer potential ligand-receptor interactions. SpaNiche leverages graph-regularized joint non-negative matrix factorization to integrate information from cell abundance and ligand-receptor expression, identifying spatial colocalization patterns among cell types while providing insights into associated ligand-receptor interactions. Besides, SpaNiche...

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic and inflammatory mechanisms, potentially mediated by the gut microbiota, yet the neurobiological impact of comorbid AD+T2DM microbiota from elderly donors remains unexplored. Fecal microbiota from healthy, AD, T2DM, and AD+T2DM postmenopausal female donors (aged 56-89 years) was transplanted into antibiotic-treated male mice. Behavioral testing, blood profiling, hippocampal neurotrophic gene expression, and 16S rRNA...

Nicotinamide adenine dinucleotide (NAD) is a classical coenzyme regulating cellular energy metabolism. Emerging evidence demonstrates the causal relationship between defective NAD metabolism and various age-associated diseases. The major purpose of the present study was to investigate the role of adipocyte mitochondrial NAD biology in age-associated metabolic diseases. To this end, we focused on solute carrier family 25 member 51 (SLC25A51), a recently identified mitochondrial NAD transporter....