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Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce...

The prevalence of Alzheimer's disease neuropathological changes (ADNCs), the leading cause of cognitive impairment, remains uncertain. Recent blood-based biomarkers enable scalable assessment of ADNCs¹. Here we measured phosphorylated tau at threonine 217 in 11,486 plasma samples from a Norwegian population-based cohort of individuals over 57 years of age as a surrogate marker for ADNCs. The estimated prevalence of ADNCs increased with age, from less than 8% in people 58-69.9 years of age to...

Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic...

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Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer's disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1)...

Aging is a natural physiological process that may be accompanied by pathological changes, particularly in the brain. Iron is an essential trace element supporting various physiological functions and maintaining cellular homeostasis. However, iron levels tend to increase in certain brain regions of older adults and are associated with the development of neurodegenerative diseases. Despite this association, the causal relationship between aging, iron accumulation, and neurodegenerative diseases...

Women's reproductive health plays a pivotal role in both longevity and the aging process. We conduct Mendelian randomization (MR) and observational analyses to investigate these relationships. Univariate MR analyses reveal that older age at first birth, later menarche, higher estradiol, and sex hormone-binding globulin (SHBG) increase longevity, while pre-eclampsia liability decreases longevity. Older ages at first birth and at first sexual intercourse are associated with lower DNAmGrimAgeAccel,...

Despite ample research on cognitive aging, it is still largely unknown whether cognition is organized in a distinct manner, with different cognitive domains and subcomponents interrelating with each other. It is also unknown whether this cognitive organization is stable or changes with increasing age. Following the PRISMA guidelines statement, we conducted a systematic review of multivariate studies of cognitive aging with the aim to identify a potential cognitive organization in healthy aging....

Senescence contributes to the pathology of abdominal aortic aneurysm (AAA); however, the regulation of senescence in AAA remains unclear. Here, we sought to determine the role of gasdermin-E (GSDME)-dependent non-canonical pyroptosis in AAA. GSDME-dependent non-canonical pyroptosis is activated in the lesioned vascular walls of mouse models and patients with AAA. GSDME deficiency inhibits vascular senescence and AAA progression. Combined analyses of single-cell RNA sequencing (scRNA-seq), bulk...

Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant forms of primary liver cancer, with limited therapeutic options and a poor prognosis. Cellular senescence contributes to the progression of chronic liver disease while creating a microenvironment that supports tumor growth. This study aims to identify dual-purpose therapeutic targets for HCC treatment and cellular senescence intervention, potentially leading to more effective therapeutic strategies. Utilizing the AI-driven...

Accelerated biological aging (BA) is linked to adverse cardiovascular events, but its role in heart failure with preserved ejection fraction (HFpEF) remains unclear. We analyzed 1,727 HFpEF patients from RED-CARPET Study (ChiCTR2000039901), assessing BA using Klemera-Doubal and PhenoAge methods. During a median 4.9-year follow-up, 321 all-cause and 180 cardiovascular deaths occurred. After full adjustment, per 1-SD increase in BA acceleration showed significantly higher risk of all-cause...

Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy and vaccine failure^(1-3). Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility^(1,3-5). Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic...

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Frailty is a heightened vulnerability to physiological stressors caused by cumulative physiological decline over a lifespan. Psychological issues (depression and stress) and social problems (such as loneliness and social isolation) serve as potential risk factors for unfavorable comorbidities, including frailty, cardiometabolic disorders, and unexpected mortality. In this study, we aimed to elucidate the relationship between frailty and psychosocial factors in an aging population. The...

This study aimed to assess whether dietary nitrate supplementation with resistance training (RT) augments gait performance and functional mobility in inactive middle-aged and older adults. We hypothesized that combining nitrate-rich beetroot juice (BRJ) with RT would yield improvements in gait and functional mobility compared to RT with nitrate-depleted beetroot juice placebo (PLA) supplementation. In this 12-week, randomized, double-blind, placebo-controlled pilot trial, 28 healthy, inactive...

Multimorbidity of cardiometabolic disease (CMD) and cancer is a growing but understudied global challenge in an aging world. Here, we perform multistate analysis in 429,555 UK Biobank participants to investigate transition patterns, identify multiomics signatures, and construct prediction models from baseline to single and multiple morbidities. During a median follow-up of 15 years, 105,903 participants develop single morbidity and 15,088 develop multimorbidity of CMD and cancer. Participants...

CONCLUSION: The findings suggest that targeted interventions are needed to promote physical activity and rural-urban disparities in healthy lifestyles should be addressed among the oldest-old Chinese.

BACKGROUND: Sarcopenia and cognitive impairment (CI) are major contributors to disability in older people, significantly reducing quality of life and imposing a substantial burden on healthcare systems. Sarcopenia accelerates cognitive decline through mechanisms such as chronic inflammation, mitochondrial dysfunction, and disruption of the muscle-brain axis. Conversely, CI impairs motor planning and daily functioning, further exacerbating muscle loss and physical deterioration. Previous studies...

Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H(2)O(2) selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an...

Sporadic early-onset Alzheimer's disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight...