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In the context of population aging, musculoskeletal fitness has emerged as a cornerstone of overall well-being and injury prevention, relying on the coordinated function of cartilage, bone, and muscle. Drawing on the principle of "increasing income and reducing expenditure," we propose a combinatorial formulation consisting of the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide mononucleotide (NMN) and the NAD^(+)-consuming enzyme inhibitor apigenin (API), hereafter referred to as...

This study examined the associations of biological age accelerations (BAAs)-KDM-BA acceleration (via Klemera and Doubal's method) and PhenoAge acceleration (epigenetics-based), defined as residuals from regressing each biological age estimate on chronological age (CA)-with multimorbidity progression (measured by the Charlson Comorbidity Index, CCI), compared to CA. Utilizing UK Biobank data (n = 317,835; median follow-up: 13 years), Cox regression models adjusted for sex, ethnicity, lifestyle,...

The proteinopathy of the RNA-binding protein TDP-43, characterized by nuclear clearance and cytoplasmic inclusion, is a hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). Through CRISPR interference (CRISPRi) screening in human neurons, we identified the decapping scavenger enzyme (DCPS) as a novel genetic modifier of TDP-43 loss-of-function (LOF)-mediated neurotoxicity. Our findings reveal...

CONCLUSIONS: High-load, velocity-intentional resistance training-on land or in water-effectively improves neurocognition, oxidative balance, inflammation, strength, function, and quality of life in older adults. Aquatic training is particularly effective for attenuating oxidative stress and inflammation. Creatine supplementation confers complementary, modality-specific benefits and supports their use in combination to high-speed resistance exercise to promote healthy aging.

Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs....

Aging is a fundamental biological process that influences cancer development in a context-dependent manner; however, how aging-related programs manifest in hepatocellular carcinoma (HCC) remains incompletely understood. Here, we systematically characterized aging-associated features in HCC by establishing a liver cancer-specific aging signature, termed HCCaging, across more than 2,000 tumor samples from 16 independent cohorts. We comprehensively evaluated its heterogeneity and associations with...

Lumbar spinal stenosis (LSS) affects over 100 million people globally, with an increasing incidence due to an ageing population. While LSS is known to be heritable, its genetic basis remains poorly understood. We conduct a genome-wide meta-analysis of LSS in 40,303 cases and 741,469 controls. We identify 73 previously unreported loci in addition to 15 known loci, and highlight spinal degeneration as a key pathogenic mechanism. In 12,784 surgically treated cases, we discover five loci...

Neuronal intranuclear inclusion disease is caused by abnormal GGC repeat expansion in the NOTCH2NLC gene, though its pathogenic mechanism remains incompletely understood. This study shows that the abnormally expanded polyG-uN2C protein, encoded by the repeat sequence, contains intrinsically disordered regions and forms aggregates, leading to mislocalization of nucleophosmin and downregulation of fibrillarin. PolyG aggregates interact with nucleophosmin and rRNA, disrupting ribosomal homeostasis....

The E3 ubiquitin ligase HUWE1 modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and contributes to both oncogenic and tumour suppressor mechanisms in different cancer contexts. Here, by analysing human lung adenocarcinoma (LUAD) patient samples, we reveal that HUWE1 protein expression is commonly upregulated in LUAD tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage....

Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7...

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INTRODUCTION: As the age of the world's population continues to increase it is important to investigate behaviors, such as alcohol consumption, that may negatively impact the health of the older population.

We investigated stressful adversities older adults face, examined whether older men and women experience them differently, assessed the stressfulness of these events and studied their relationship to resilience-the ability to overcome adversity. This cross-sectional study included 1179 respondents from the Helsinki Birth Cohort Study, born between 1934 and 1944. At a mean age of 75 years, respondents reported the most stressful adversity in the past five years, its perceived stressfulness and...

Mobility decline with aging is a major health concern, associated with a higher risk for disability. Despite the prevalence of gait slowing in elderly adults, this issue has not been adequately addressed. The central nervous and skeletal muscle systems are key regulators of gait speed. However, direct molecular communication along the brain-muscle axis and their interactions in mobility resilience remain poorly studied. Extracellular vesicles (EVs) have emerged as a key player in long-distance...