Aging & Longevity

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Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences...

The EAT-Lancet diet has been recently recommended for its potential health and environmental benefits. Here, leveraging data from the UK Biobank, we performed a comparative analysis to examine the associations of adherence to the EAT-Lancet diet versus traditional plant-based diets with biological aging and further assess the mediating role of metabolomic signatures specific to dietary patterns. Compared with the overall or healthful plant-based diet index, higher adherence to the EAT-Lancet...

Liver-expressed antimicrobial peptide-2 (LEAP-2), the endogenous antagonist of the ghrelin receptor (GHSR1a), counterbalances ghrelin in an energy- and inflammation-dependent manner. Aging is accompanied by endocrine and immunometabolic shifts that may influence this axis. We investigated whether a short course of broad-spectrum antibiotics (vancomycin-metronidazole-neomycin-ampicillin; VMNA) alters LEAP-2 and ghrelin levels in the liver and epididymal white adipose tissue (WAT) of aged male...

CONCLUSION: The present findings emphasize that strengthening individual resilience, along with promoting social and family support and paying attention to emotional relationships, is effective in reducing loneliness in older people.

Growing evidence shows that epigenetic modification and mitochondrial dysfunction are hallmarks of aging and are associated with the development of a wide range of age-related diseases. Mitochondrial biogenesis, which is marked by mitochondrial DNA copy number (mtDNAcn), is one of the major regulations of mitochondrial function by a set of transacting elements, including mitochondrial DNA polymerase gamma (POLG), working on the mtDNA control region. In this study, we investigated the mtDNAcn and...

How do neurophysiological traits that characterize individuals evolve across the lifespan? To address this question, we analyzed task-free magnetoencephalographic recordings from over 1,000 individuals aged 4-89. We found that neurophysiological activity is more similar between individuals in childhood than in adulthood, an effect driven predominantly by arrhythmic brain activity. In contrast, periodic activity-based profiles remain reliable markers of individuality across all ages. The cortical...

INTRODUCTION: Primitive reflexes (PRs) are brainstem-mediated automatic responses that typically disappear in early life, but may reappear in older age, which may be associated with neurodegenerative processes. But the presence of PRs in cognitively healthy adults has not yet been sufficiently explored. The relationship between PRs and cognitive functioning (COG) may be influenced by modifiable factors such as physical activity (PA) and psychological resilience. This cross-sectional...

CONCLUSIONS: In this nationally representative sample of Chinese older adults, social isolation is associated with greater decline of intrinsic capacity, partially mediated through inadequate sleep duration and pain complaints. These findings suggest that interventions aimed at mitigating social isolation, along with integrated management of sleep and pain, may help preserve intrinsic capacity in aging populations.

The TP53 tumor suppressor gene is mutated in a large fraction of human tumors. Close to 11% of TP53 mutations are nonsense mutations, causing premature termination of protein synthesis and expression of truncated inactive p53 protein. The most common TP53 nonsense mutation in human cancer is R213X. To study the impact of TP53 nonsense mutations in vivo, we generated mice harboring the Trp53 nonsense mutation R210X that corresponds to human TP53-R213X. Initially, Trp53^(R210X) mice appear...

Cellular senescence contributes to age-related neurodegeneration, yet its manifestation varies across brain cell types and senescence-inducing stressors. Here, we investigated senescence hallmarks in five human brain cell lines - astrocytes, endothelial cells, microglia, oligodendrocytes, and dopaminergic-like neurons - using chronic 5-Bromodeoxyuridine treatment and validated our findings in primary cells and alternative toxin-induced models. Principal component analysis and transcriptional...

Insulin/insulin-like growth factor signaling inhibits FOXO transcription factors to control development, homeostasis, and aging. Here, we use proximity labeling to identify proteins interacting with the C. elegans FOXO DAF-16. We show that in well-fed, unstressed animals harboring active insulin signaling, DAF-16 forms a complex with the PAR-1/MARK serine/threonine kinase, a key regulator of cell polarity. PAR-1 inhibits DAF-16 accumulation and promotes DAF-16 phosphorylation at S249, at a...

Aberrant innate immune responses contribute significantly to cellular senescence, yet the precise interplay between innate immunity and senescence remains poorly characterized. Here, we elucidate the pivotal role of nuclear respiratory factor 1 (NRF1) in orchestrating innate immune responses that drive senescence and the senescence-associated secretory phenotype (SASP). NRF1 deficiency delayed cellular senescence and ameliorated age-related deterioration in multiple organs. Mechanistically, NRF1...

Organ-specific plasma protein signatures identified via proteomics profiling could be used to quantitatively track organ aging. However, the genetic determinants and molecular mechanisms underlying the organ-specific aging process remain poorly characterized. Here we integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants to uncover the genetic architectures underlying aging across 13 organs. We identified 119 genetic loci associated with organ aging,...

Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day-night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate...

During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of...

The cognitively-intact oldest-old (85 +) may be the most-resilient members of their birth cohort; due to survivorship effects (e.g., depletion of susceptibles), risk factors associated with brain aging biomarkers in younger samples may not generalize to the cognitively-intact oldest-old. We evaluated associations between established aging-related risk factors and brain-predicted age difference (brainPAD) in a cross-sectional cognitively-intact oldest-old sample. Additionally, we evaluated...

Local brain age (LBA) is a regional metric of brain aging that offers a spatially resolved alternative to global brain age, but whose genetic basis is unexplored. This study reports the first genome-wide association study of cortical LBA, as estimated by a deep neural network from the T(1)-weighted magnetic resonance images of 41,708 cognitively normal adults in the UK Biobank. We identified 1,212 single-nucleotide polymorphisms (SNPs) significantly associated with LBA in at least one brain...

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Transcription is regulated in part through histone proteins. Histones can be replaced with variant forms that are particularly critical in the brain and accumulate throughout the lifespan. Recent findings demonstrated that the histone variant H2BE regulates chromatin structure, neuronal transcription, and mouse behavior. However, the role of H2BE in other cell types and throughout the lifespan remains unknown. Here, we discovered that H2BE is enriched in astrocytes and accumulates with age in...