Aging & Longevity

Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant...

Disability and multimorbidity increase with aging and constitute a challenge for the health system. However, different individuals display different aging trajectories, and understanding the underlying relationships between lifespan and disease is fundamental for identifying the different patterns in human lifespan. A previous study explored associations between lifespan and age of onset of diseases of different organ systems, prevalence of escapers, and percentage of life free of disease...

Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain. Systemic injection of...

CONCLUSION: This study suggested that the use of physical restraint in older adults was a more related factor of mortality in men than women. Women were older with lower expectancy life but PR use seemed to be a sign of global health decline in men. Further prospective studies are needed to assess if mortality after PR use is a cause or a consequence of a global health decline.

The growing population of older adults emphasizes the need to develop interventions that prevent or delay some of the cognitive decline that accompanies aging. In particular, as memory impairment is the foremost cognitive deficit affecting older adults, it is vital to develop interventions that improve memory function. This study addressed the problem of false memories in aging by training older adults to use details of past events during memory retrieval to distinguish targets from related...

CONCLUSIONS AND IMPLICATIONS: Our findings underscore the significant impact of multimorbidity on end-of-life experiences and highlight the importance of coordinated care strategies to address the complex needs of patients with multimorbidity and alleviate their symptom burden.

Brain glymphatic activity, as indicated by diffusion-tensor imaging analysis along the perivascular space (ALPS) index, is involved in developmental neuropsychiatric and neurodegenerative diseases, but its genetic architecture is poorly understood. Here, we identified 17 unique genome-wide significant loci and 161 candidate genes linked to the ALPS-indexes in a discovery sample of 31,021 individuals from the UK Biobank. Seven loci were replicated in two independent datasets. Genetic signals...

Immune functions decline with aging, leading to increased susceptibility to various diseases including tumors. Exploring aging-related molecular targets in elderly patients with cancer is thus highly sought after. Here we find that an ER transmembrane enzyme, sterol O-acyltransferase 2 (SOAT2), is overexpressed in regulatory T (Treg) cells from elderly patients with lung squamous cell carcinoma (LSCC), while radiomics analysis of LSCC patients associates increased SOAT2 expression with reduced...

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The blood proteome contains biomarkers of ageing and age-associated diseases, but such markers are rarely validated longitudinally. Here we map the longitudinal proteome in 7,565 serum samples from a cohort of 3,796 middle-aged and elderly adults across three time points over a 9-year follow-up period. We pinpoint 86 ageing-related proteins that exhibit signatures associated with 32 clinical traits and the incidence of 14 major ageing-related chronic diseases. Leveraging a machine-learning...

DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated...

Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and...

Understanding the lifetime risk of dementia can inform public health planning and improve patient engagement in prevention. Using data from a community-based, prospective cohort study (n = 15,043; 26.9% Black race, 55.1% women and 30.8% with at least one apolipoprotein E4 (APOE ε4) allele), we estimated the lifetime risk of dementia (from age 55 years to 95 years), with mortality treated as a competing event. We applied lifetime risk estimates to US Census projections to evaluate the annual...

Analysis of preclinical lifespan studies often assume that outcome data from co-housed animals are independent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result, the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20,000 observations. We show that...

Volcanic provinces are among the most active but least well understood landscapes on Earth. Here, we show that the central Cascade arc, USA, exhibits systematic spatial covariation of topography and hydrology that are linked to aging volcanic bedrock, suggesting systematic controls on landscape evolution. At the Cascade crest, a locus of Quaternary volcanism, water circulates deeply through the upper [Formula: see text]1 km of crust but transitions to shallow and dominantly horizontal flow as...

Aging is a complex process characterized by biological decline and a wide range of molecular alterations to cells, including changes to DNA methylation. In this study, we used a male-specific epigenetic marker of aging to build an epigenetic predictor that measures long-term androgen exposure in sheep and mice (median absolute error of 4.3 and 1.4 mo, respectively). We term this predictor the androgen clock and show its "tick" is mediated by the androgen receptor and can be accelerated beyond...

Cellular senescence is a complex biological response to sublethal damage. The RNA-binding protein HNRNPK was previously found to decrease prominently during senescence in human diploid fibroblasts. Here, analysis of the mechanisms leading to reduced HNRNPK abundance revealed that in cells undergoing senescence, HNRNPK mRNA levels declined transcriptionally and full-length HNRNPK protein was progressively lost, while the abundance of a truncated HNRNPK increased. The ensuing loss of full-length...

A combination of intermittent fasting and administering Wnt3a proteins to a bone injury can rejuvenate bone repair in aged mice.

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CONCLUSION: This study found that nine circulating metabolites and their ratios with significant causal associations to aSAH, while no metabolites and their ratios were causally linked to IAs. These results suggest possible mechanisms and predictive molecular targets for IAs and aSAH.