Aging & Longevity

Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN....

CONCLUSIONS: One year of resistance training in well-functioning older adults at retirement age did not influence volume changes in selected brain regions over a 4-year period.

CONCLUSIONS: This eFI identified older adults at increased risk for adverse health outcomes even when data from routine primary care visits were not available. This tool can be integrated into EHRs for frailty assessment at scale.

Chemotherapy-related cognitive impairment, commonly referred to as "chemobrain," significantly affects cancer survivors' quality of life, yet its underlying mechanisms remain unclear. Most chemotherapeutic agents cannot cross the blood-brain barrier (BBB), yet they cause central nervous system side effects, suggesting alternative pathways of toxicity. Given that these drugs interact with the cerebrovascular endothelium at their highest concentrations, it is logical to hypothesize that...

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Accumulation of cerebral senescent cells may compromise the continuum between vascular and neuronal function, leading to damage and cognitive decline. Elimination of senescent cells might therefore preserve vascular and neuronal functions. To test this hypothesis, we used male and female atherosclerotic LDLr^(-/-);hApoB(100)^(+/+) mice (ATX-mice), a model of vascular cognitive impairment (VCI), treated with the senolytic ABT-263 for 3 months (3- to 6-month or 9- to 12-month old). In young male...

In this review, we explore the mechanisms of the blood-cerebrospinal fluid (CSF) barrier and CSF transport. We briefly review the mathematical framework for CSF transport as described by a set of well-studied partial differential equations. Moreover, we describe the major contributors of CSF flow through both diffusive and convective forces beginning at the molecular level and extending into macroscopic clinical observations. In addition, we review neurosurgical perspectives in understanding CSF...

CONCLUSIONS: This portfolio analysis showed an increase in the number of NIH-funded grants focused on cancer survivors and accelerated aging, but notable gaps are evident. Given the rapidly growing survivor population, many of whom will experience accelerated aging trajectories, there is a critical need to better understand accelerated aging phenotypes and mechanisms, so that those at the highest risk for adverse aging-related effects can be identified and interventions developed.

A microglia subpopulation termed "dark microglia" has been associated with aging and neurodegeneration, although its role has remained elusive. New research from Flury et al. in this issue of Neuron shows that dark microglia drive neurodegeneration via secretion of toxic lipids.¹.

INTRODUCTION: One important aspect of walking aid use is transferring safely to the aid from sitting and transferring back to the chair after walking, since these activities have been associated with falls in older adults. Standard frames require their user to push off the chair or ask for help from a carer, which may over time lead to back pain. This study's aim was to assess whether novel handgrips located above the rear feet of a walking frame would facilitate safe transfer as compared to...

Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related...

Understanding the evolving dynamics of the brain throughout life is pivotal for anticipating and evaluating individual health. While previous research has described age effects on spectral properties of neural signals, it remains unclear which ones are most indicative of age-related processes. This study addresses this gap by analyzing resting-state data obtained from magnetoencephalography (MEG) in 350 adults (18 to 88 y). We employed advanced time-series analysis at the brain region level and...

Longitudinal imaging data are routinely acquired for health studies and patient monitoring. A central goal in longitudinal studies is tracking relevant change over time. Traditional methods remove nuisance variation with custom pipelines to focus on significant changes. In this work, we present a machine learning-based method that automatically ignores irrelevant changes and extracts the time-varying signal of interest. Our method, called Learning-based Inference of Longitudinal imAge Changes...

There is growing evidence that higher intermuscular fat (IMF) is associated with worse processing speed, measured by the digit symbol substitution test (DSST) in older adults. However, the underlying biological mechanisms are not well understood. Considering that both muscle and the brain are metabolically active organs, we sought to identify metabolites that may explain the IMF-DSST association. We assessed 613 plasma metabolites in 2388 participants from the Health, Aging, and Body Composition...

Chemotherapy-induced cognitive impairment (CICI), commonly referred to as "chemobrain," is a frequent and debilitating side effect experienced by cancer survivors treated with paclitaxel (PTX). Preclinical models have shown that PTX promotes cerebromicrovascular endothelial cell senescence, leading to chronic blood-brain barrier (BBB) disruption and neuroinflammation. Conversely, the elimination of senescent cells through senolytic therapies has been shown to restore BBB integrity, reduce...

The increasing number of cancer survivors has brought heightened attention to the side effects of cancer therapies, including chemotherapy-related cognitive impairment (CRCI, commonly referred to as "chemobrain"). Cisplatin and methotrexate, commonly used first-line chemotherapeutics in gynecologic oncology for cancers such as breast, ovarian, and bladder cancer, are clinically associated with long-term cognitive deficits. Building on our previous preclinical studies demonstrating that...

Alzheimer's disease (AD) is predominantly the most recurring and devastating neurological condition among the elderly population, characterized by the accumulation of amyloid-β (Aβ) and phosphorylated tau proteins, and is accompanied by progressive decline of learning and memory. Due to its complex and multifactorial etiology, a wide variety of therapeutic interventions have been developed. Despite constant advancements in the field, effective treatments that ameliorate the severity of...

Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation,...

A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran¹ (individualized neoantigen vaccine with...

Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging,...