Aging & Longevity

Quantifying biological aging requires biomarkers that capture multisystem physiological decline beyond chronological age. We aimed to compare the prognostic performance of plasma proteomics, metabolomics, and conventional clinical risk factors for all-cause mortality, and to characterize molecular pathways associated with mortality risk and age-related physiological decline. Untargeted plasma proteomics and metabolomics were profiled in 848 community-dwelling adults from the I-Lan Longitudinal...

The extremely short life span of neutrophils is critical for immune homeostasis and immune defense against pathogens, but the molecular mechanisms underlying this phenomenon are not fully understood. Here we report that TNFAIP8 (TNF-α-induced protein 8) family of polarity proteins regulates neutrophil homeostasis by propagating phosphoinositide signaling. Genetic deletion of two members of the TNFAIP8 family, i.e., TIPE0 and TIPE1, resulted in spontaneous neutrophilia and hepatitis. TNFAIP8...

Intracortical microstimulation (ICMS) of somatosensory cortex can restore a sense of touch to people with spinal cord injury. In this early feasibility clinical trial (NCT01894802), we evaluated the safety, efficacy, and longevity of ICMS because there is a paucity of such long-term studies in humans. This information is crucial to the development of clinical neuromodulation devices, particularly for restoring touch, hearing, and vision. ICMS was delivered to five participants with spinal cord...

Brain age estimation using machine learning has gained significant attention as a promising approach to assess cognitive health and aging. By analyzing structural and functional MRI data, these models can predict an individual's brain age, providing insights into neurological conditions and potential interventions. The purpose of this study is to compare the performance of different MRI modalities in predicting brain age and to determine the relative importance of specific brain regions. In this...

Microglia maintain neuronal homeostasis through dynamic surveillance strategies that depend on their functional state. In the healthy brain, highly ramified microglia monitor neuronal integrity via motile processes and transient soma contacts. Aging is associated with reduced process motility and diminished expression of homeostatic markers, raising the question of how microglial surveillance adapts to these changes. Here, we used ex vivo time-lapse imaging of acute cortical slices from young...

Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been...

Aging and chronic inflammation alter hematopoiesis, impacting the hematopoietic progenitor populations in the bone marrow. In this issue of Immunity, Yao et al. show that the canonical type 2 cytokine interleukin 4 reverses age-related hematopoietic and physiologic effects by rebalancing progenitor fates.

Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease...

Cellular senescence is a hallmark of aging and a contributing factor to many age-related morbidity and decline. A key characteristic of senescent cells is a pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP). When tracked in circulation, SASP factors associate with age-related clinical traits and diseases, raising the captivating possibility that the senescence burden, and concomitant susceptibility to age-related morbidity, can be noninvasively assessed in...

The pursuit of high-energy-density lithium-ion batteries demands high-silicon silicon-graphite composite negative electrodes, yet their commercialization remains hindered by interfacial incompatibility and mechanical instability. While an ideal binder must simultaneously achieve robust adhesion to both silicon and graphite, accommodate substantial silicon volume changes, and maintain high binder bulk stability, existing systems fail to harmonize these requirements. Here, we present a molecularly...

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...

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...