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Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson's disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and...

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...

The Agency for Healthcare Research and Quality has grant money, but nobody to hand it out

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...