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Too much or too less lipid deposition increases mortality, while in contrast, modest lipid deposition during aging is crucial for healthspan. How animals determine the aging state and then promote appropriate lipid deposition for lifespan benefits are largely unknown. In this study, we identified citrulline as a key metabolite driving aging-related lipid deposition for healthspan in Caenorhabditis elegans. Citrulline deficiency reduced aging-related lipid accumulation and shortened lifespan, an...

The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, N^(ε)-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive...

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Understanding the consequences of individual DNA methylation variation is crucial for advancing our knowledge of human biology and disease. Yet, the collective impact of individual traits on DNA methylation and their downstream effects on gene expression across human tissues remain poorly understood. Here, we quantify the contributions of sex, age, genetic ancestry, and BMI on autosomal DNA methylation variation across 9 human tissues and 424 individuals from the Genotype-Tissue Expression...

A significant subset of tumors, including >50% of osteosarcomas-an aggressive bone malignancy affecting children, adolescents, and young adults-relies on alternative lengthening of telomeres (ALT), a telomerase-independent, DNA repair-based mechanism for telomere elongation. The overall 5 year survival rate for osteosarcoma patients is ∼65%, underscoring the need to develop novel targeted therapies. Through the Cancer Dependency Map, we identified SMARCAL1, a DNA translocase previously shown to...

This study applied Ward's hierarchical clustering to detailed neuropsychological data from a community-recruited sample of 180 older adults to identify naturally occurring cognitive subgroups and characterize multidomain cognitive heterogeneity beyond conventional mild cognitive impairment (MCI) criteria. Twenty-two demographically adjusted z-scores spanning memory, language, executive function, and attention/processing speed were submitted to Ward's method, and the resulting four-cluster...

Loss of muscle mass and quality (myopenia and myosteatosis) are hallmarks of aging and predictors of disability, yet their relationship with biological aging in younger adults is unclear. This prospective cohort study included 165,015 adults (mean age 39.9) who underwent low-dose chest computed tomography (CT) between 2010 and 2020. A longitudinal subset of 61,669 participants had repeated scans (median follow-up 4.1 years). We adopted blood-based Phenotypic Age acceleration (PhenoAgeAccel) and...

α-Synucleinopathies are devastating neurodegenerative diseases characterized by pathological accumulation of a neuronal protein, α-synuclein (αSyn). Lowering soluble αSyn levels is a promising therapeutic strategy to limit aggregation and neurotoxicity, but directly targeting this protein is hindered by its intrinsically disordered structure and other factors, such as its conformational heterogeneity and intracellular drug delivery barriers. Consequently, increasing attention has been directed...

Central to Alzheimer's disease pathology are prefibrillar oligomer assemblies of amyloid-β (Aβ) peptide. A widely discussed hypothesis proposes that amyloid-β oligomers insert into neuronal lipid membranes, disrupting their integrity and causing a loss of cellular homeostasis in Alzheimer's disease. This membrane disruption is believed to be a major source of Aβ-induced neurotoxicity. Cryo electron tomography (cryo-ET) has facilitated 3D nanoscale imaging of Aβ-membrane interactions under...

High levels of mitochondrial DNA (mtDNA) deletions have been described in the substantia nigra. However, the mechanisms involved are poorly understood. We found that transient expression of a mitochondrial targeted restriction endonuclease (mitoPstI) in mice leads to an accumulation of mtDNA rearrangements that involve both the PstI cleavage sites and unrelated specific regions of the mtDNA, including the MTERF1 binding site and the edge of the D-loop. This pattern of rearrangements after...

Alzheimer's disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions, and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major...

Introduction Falls are a major public health concern among older adults, leading to injuries, loss of independence, and increased mortality. A Body Shape Index (ABSI), which integrates waist circumference with height and weight, may better capture abdominal adiposity than BMI. To our knowledge, this is the first study to examine the association between ABSI and fall risk in older adults using data from the National Health and Aging Trends Study (NHATS). Methods We analyzed data from NHATS, a...

CONCLUSIONS AND IMPLICATIONS: Social prefrailty and frailty are prevalent and follow a clear educational gradient. Integrating social frailty assessments into routine clinical screenings and directing targeted policy interventions toward less-educated older adults are urgently needed to promote healthy aging.

Exercise is a powerful non-pharmacological strategy for preserving brain health during aging. However, whether intrinsic exercise capacity is associated with a distinct molecular phenotype in the aged brain, independent of training intervention, remains unclear. Aged selectively bred low-capacity runner (LCR) and high-capacity runner (HCR) rats were studied. Hippocampal DNA methylation was profiled by reduced representation bisulfite sequencing (RRBS), and differentially methylated regions...

The buildup of toxic aggregates formed by the amyloid-β peptide 1-42 (Aβ(42)) is a central process in Alzheimer's disease (AD) pathology. The peptide's self-assembly and toxicity are highly dependent on its primary amino acid sequence and can be altered by modifying key residues. Specifically, the single amino acid substitutions A30W, K28A, and M35C can reduce the aggregation and toxicity of the Aβ(42) peptide. In this study, we further evaluated the effects of these mutations in a C6 rat glioma...

Male reproductive ageing is a complex process involving progressive and detrimental histological and physiological alterations to the testis and beyond. Age-related morbidities often confound reproductive function, making it difficult to disentangle systemic from reproductive male ageing. We have previously shown that healthy ageing is associated with full spermatogenesis, normal sperm production and hormonal secretion. However, the molecular mechanisms allowing the human testis to age without...

We present CIT-Lasso, a framework that uses only summary statistics to identify, genome-wide, sets of variants carrying non-redundant information on a phenotype, distinguishing likely causal variants from correlated variants that are merely associated. The open-source implementation completes genome-wide analysis in under 15 min on one CPU. In simulations, it outperforms existing methods in false discovery rate control, power, and fine-mapping resolution. Applied to an Alzheimer's disease...

Age-associated thymic involution leads to a reduction of T-cell production, which constitutes a primary factor in immunosenescence, thereby increasing vulnerability to cancer, infections, and autoimmune disorders. Thymic epithelial cells (TECs), essential for T-cell development, exhibit progressive senescence with aging. The development of strategies to mitigate TECs senescence and delay thymic degeneration has emerged as a significant research focus. Here, aged C57BL/6J mice and immortalized...

Researchers found that semaglutide, the active ingredient in Ozempic and Wegovy, slowed biological aging markers in adults with HIV, marking the first clinical evidence that the drug may influence human aging. Although the findings are encouraging, scientists say larger studies are needed before concluding that the medication can help people age more slowly.