Aging & Longevity

Delirium is a common and severe neuropsychiatric syndrome with lasting cognitive consequences, yet its pathophysiology remains poorly understood. We hypothesize that impaired glymphatic flow represents a central mechanism by which delirium evolves. This hypothesis builds on recent evidence showing that major delirium risk factors, such as ageing, dementia, cardiovascular disease and renal failure, are all associated with reduced glymphatic clearance. Similarly, common delirium triggers,...

Sex differences in immune function arise from sex chromosome complement, which drives differential expression and activity of X-linked genes in immune cells, and gonadal steroids that transcriptionally regulate innate and adaptive immune cells through their respective receptors. These fundamental differences shape divergent outcomes between male and female individuals in viral and bacterial infections, post-acute infection syndromes and vaccine responses throughout the lifespan. Understanding...

Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly...

Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural,...

Age-related changes in synaptic function are central to the progression of brain pathologies, including neurodegenerative diseases, underscoring the need for experimental approaches that capture neuronal properties across the lifespan. However, obtaining high-quality tissue preparations from aged animals that permit combined structural and functional analyses of individual neurons is challenging due to increased tissue vulnerability. Here, we present a standardized protocol for acute brain slice...

Parkinson's disease (PD) is a prevalent neurodegenerative disorder that is characterized clinically by a constellation of motoric deficits including resting tremors, bradykinesia, and rigidity. In recent years, there has been increasing interest in the gut-brain axis with several studies examining the relationship between gut microbiome and PD. Although association studies have reported multidimensional microbiome changes in PD, these observed changes may be confounded by various factors,...

Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and...

Despite widespread use in the USA, little is known about the impact of multivitamin-multimineral (MVM) supplementation on metabolomic profiles and how this may translate to biological aging and long-term risk of age-related chronic diseases. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a 2 × 2 factorial, placebo-controlled, double-blinded, randomized clinical trial testing daily MVM (Centrum Silver®) in US older adults. In 399 participants with metabolomics profiles...

Autophagy, a highly conserved cellular degradation process, plays essential roles in various physiological processes including aging. Though autophagy is required for lifespan extension in multiple longevity paradigms, the tissue-specific roles of autophagy-related genes (atgs) in longevity remain incompletely understood. Here, we investigate the tissue-specific requirements of atgs to promote longevity conferred by germline ablation (called gonadal longevity) using C. elegans. Remarkably, we...

Cellular senescence is a stable cell state sustained by specific gene expression programs that are established and maintained through dynamic changes in chromatin organization. Importantly, these programs are highly dependent on the nature of the senescence-inducing stimulus. In recent years, lipid overload has emerged as a relevant metabolic stress capable of inducing senescence across multiple cell types and tissues, particularly in the context of obesity and high-fat diets. Accumulating...

Motor decline is a hallmark of Parkinson's disease (PD) and biological aging, yet the specific relationship between systemic biological aging and neuromotor function remains under-characterized. This study leveraged longitudinal phenotypic and whole-blood DNA methylation data from the Parkinson's Progression Markers Initiative (PPMI) to evaluate associations between seven epigenetic aging measures, spanning first-generation, second-generation (risk-optimized), rate-based, and next-generation...

CONCLUSIONS: This study provides the first Canadian reference data for these lifestyle scales, enabling personalized risk profiling in health promotion. Lifestyle behaviours cluster in ways that highlight the importance of addressing cognitive, social, and mental wellbeing alongside physical activity and brain-healthy eating in older adults.

The incidence of brain diseases increases with aging, but the biological basis of brain aging is still poorly explored. Synaptic dysfunction occurs at the onset of brain diseases and synaptic neuromodulation systems, such as adenosine A(2A) receptors (A(2A)R), are necessary and sufficient to trigger brain dysfunction. Since A(2A)R are upregulated upon aging, we compared wild-type and A(2A)R global knockout mice to test if brain aging involves synaptic senescence linked to A(2A)R overfunction,...

While inflammaging supposedly drives some of the most common diseases affecting the elderly, little is known about the tissue drivers of inflammaging. In this study, we demonstrate that age-dependent activation of nuclear factor κB (NF-κB) in tissue fibroblasts remodeled the immune architecture, promoting the emergence of an exhausted granzyme K (GZMK)^(+)CD8^(+) T cell population recently identified in normal aging as well as autoimmunity and cancer. Fibroblast-specific NF-κB activation...

Disabling hearing impairment is a common human sensory deficit. OTOF is a major deafness gene. It codes for the synaptic protein otoferlin and is essential for transmitter release by inner hair cells (IHCs). Upon genetic loss of otoferlin, cochlear structure and function remain intact up to the IHC synapses, which fail to encode sound. Building on preclinical hearing restoration by AAV-mediated cochlear gene transfer in mice, clinical OTOF-gene-therapy trials are now targeting the pediatric...

Nur77 expression decreases with age in multiple organs, including the liver, brain, heart, and kidney, whereas Sirt2 increases with age in the mouse cerebral cortex and hippocampus. We identified the central role of the Sirt2-P300/Nur77/K310 acetylation axis in regulating muscle homeostasis and regeneration and its age-related alterations. Consistently, we observed reduced Nur77 and elevated Sirt2 expression in aging skeletal muscle, particularly the anterior tibialis, which is enriched in type...

This editorial delineates the conceptual distinctions among lifespan, longevity, and healthspan in biogerontology. Lifespan is defined as the chronological duration from birth to biological death. Longevity refers to the capacity for survival beyond the species-typical average and is best understood probabilistically rather than as a predetermined limit. Healthspan, by contrast, lacks a uniform definition but is most commonly described as the period of life free from major chronic disease and...

CONCLUSION: The between-couple findings support the similarity-attraction theory and highlight gender-specific role transitions that influence cognitive aging, while the absence of within-couple cognitive concordance may be due to the length of assessment intervals or individual differences. These findings emphasize the need for future research with more frequent assessments and better control of trait-like characteristics to clarify these dynamics and support targeted cognitive health...

Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and...

Global population aging intensifies "inflammaging," a bidirectional link between chronic inflammation and aging-related pathology. Among them, S100A8/A9 forms a positive feedback loop of "aging-inflammation". Here, we systematically review the structure and function of S100A8/A9, including extracellularly promoting leukocyte adhesion and myeloid-derived suppressor cell aggregation, and intracellularly regulating NOD-like receptor protein 3 inflammasome, arachidonic acid metabolism, autophagy,...