Aging Cell

Regular physical activity is a cornerstone of healthy aging, offering a wide range of benefits, including the modulation of immune regulation and reduction of chronic inflammation. With aging closely linked to persistent, low-grade inflammation, i.e. inflammaging, the effects of exercise intensity on acute immune responses in older adults remain not fully understood. In this study, we explored how moderate and intense acute continuous exercise impact immune cell activation, cytokine production a...

The decline in mobility with aging is a major health concern, associated with a high risk for disability. Despite the widespread prevalence of gait slowing in elderly adults, this issue has not been adequately addressed. The central nervous system and skeletal muscle system are key regulators of gait speed. However, direct molecular communication along the brain-muscle axis and the role of these interactions in mobility resilience remain poorly studied. Recently, extracellular vesicles (EV), mem...

Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable "trainability" remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation. Plasma proteomics in older a...

Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia include inflammation, muscle stem cell depletion, mitochondrial dysfunction and loss of motor neurons, but whether there are key drivers of sarcopenia is not yet known. To gain deeper insights into age-related sarcopenia, we performed transcriptome profiling on lower limb muscle biopsies from 72...

Advances in mass-spectrometry(MS)-based technologies have leveraged our understanding of skeletal muscle responsiveness to exercise in humans. However, there is a lack of such data in females, particularly pertaining to female athletes and menstrual cycle phase-based sprint interval training(SIT) despite its efficacy and popularity. Here, we present a comprehensive proteomic analysis of skeletal muscle adaptations to high-frequency SIT during different menstrual cycle phases in female athletes. ...

Exercise-driven alterations of the immune system are a key mechanism in the prevention and treatment of various diseases. Here, we performed mass spectrometry-based proteomics analysis on peripheral blood mononuclear cells (PBMCs) at a depth of >6000 proteins. Comparing time- and workload-matched high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (MICE) we discover versatile changes in the proteomic makeup of PBMCs and reveal profound alterations related to effect...

Primary sarcopenia is a progressive, age-related decline of skeletal muscle strength, size, and quality, the socio-economic and health impacts of which are set to increase due to global ageing. Despite differences in the physiology of female and male skeletal muscle being well characterised, their alteration with age is less clear. Here we report a striking sexual dimorphism in arm muscle ageing in 478,438 UK Biobank participants aged 40-82 yr. Although the sex difference in age-related arm musc...

In a randomized, dose-response trial, we used molecular and phenomic profiling to compare responses to traditional (TRAD) moderate intensity endurance and resistance training vs. high-intensity tactical training (HITT) that encompassed explosive whole-body interval training and high-intensity resistance training. Ninety-four participants (18-27 years) completed 12 weeks of TRAD or HITT followed by 4 weeks of detraining. Although similar performance and body composition improvements were observed...

Aging manifests as the progressive declines of homeostatic resilience and repair mechanisms, marked by dysregulations across systems and increasing individual heterogeneity. However, the breadth of measures of homeostatic dysregulation remains underexplored. Here, we introduce DISCO as a novel measure of homeostatic dysregulation, integrating clinical, proteomics, metabolomics, and microbiomes data. DISCO demonstrated moderate correlation with chronological age but robustly predicted mortality, ...

BackgroundBones and muscles are connected anatomically, and functionally. Preliminary evidence has shown the gut microbiome influences the aging process of bone and muscle in animal studies. However, such evidence in humans is still scarce. This study aimed to assess the microbiome-bone and microbiome-muscle associations in two cohorts of community-dwelling older adults. MethodsWe leveraged information from two large population-based cohorts, i.e., the Rotterdam Study (mean age 62.7 {+/-} 5.6 y...

BackgroundThe brain-body energy-conservation model proposes that signals from metabolically active senescent cells, including growth differentiation factor 15 (GDF15), prompt the brain to downregulate systemic energy expenditure, leading to functional decline. However, large-scale human studies testing this hypothesis are lacking. We examined whether circulating GDF15 is associated with physiological and cognitive ageing phenotypes and whether it mediates the relationship between psychological ...

Microsampling techniques, particularly dried blood spots (DBS), offer a minimally invasive alternative to venipuncture for biomarker profiling in endurance exercise. This study leverages NULISAseq, an ultra-sensitive proteomics platform, to analyze inflammatory responses in athletes participating in a half-marathon. A cohort of six individuals--three endurance athletes and three sedentary controls--underwent longitudinal blood collection at five timepoints: pre-run (R-7, R-1), mid-run (R), and p...

Biomarkers of aging, particularly DNA methylation-based clocks, have shown promise as tools to assess whether interventions may impact the rate of biological aging. Among possible interventions physical exercise has shown protective effects against many age-associated diseases, while time-restricted feeding (TRF), has shown metabolic benefits in preclinical models. The combined effect of exercise and TRF on aging biomarkers remains largely unexplored. In this 52-week four-armed, randomized, cont...

Genome-wide association studies of physical activity traits have mapped numerous loci, yet the molecular mechanisms through which exercise influences human biology remain poorly defined. Mechanistic progress has been limited by heritability-dominated signals, siloed single-omic analyses, and the lack of integrative models that connect genetic associations to causal, system-level pathways. We introduce the first deep learning, multi-omic framework for exercise genomics, unifying causal inference,...

The genetic underpinnings of elite sprint performance remain largely elusive. For the first time, we uncovered rs10196189 (GALNT13) in the cross-ancestry, genome-wide analysis of elite sprint and power-oriented athletes and their controls from Jamaica, the USA, and Japan, and replicated this finding in two independent cohorts of elite European athletes (meta-analysis P < 5E-08). We identified statistically significant and borderline associations for cross-ancestry and ancestry specific loci in G...

Epidemiological studies have revealed that the elderly and those with co-morbidities are most susceptible to COVID-19. To understand the genetic link between aging and the risk of COVID-19, we conducted a multi-instrument Mendelian randomization analysis and found that the genetic variation that leads to a longer lifespan is significantly associated with a lower risk of COVID-19 infection. The odds ratio is 0.32 (95% CI: 0.18 to 0.57; P = 1.3 x 10-4) per additional 10 years of life, and 0.62 (95...

Aging manifests as progressive deterioration in cellular and systemic homeostasis, requiring systems-level perspectives to understand the gradual molecular dysregulation of underlying biological processes. Here, we report systems-level changes in the molecular regulation of biological processes under multiple lifespan-extending interventions in mice and across age in humans. In mouse cohorts, Differential Rank Conservation (DIRAC) analyses of liver proteomics and transcriptomics show that mechan...

Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementat...

Autophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy a...

Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Therefore, we performed the first multivariate genome-wide association study of the latent genetic architecture between 30 frailt...