Biology subjects

Anderton, E.

Publications and source records attributed to Anderton, E..

3 recordsLinked to original sources

bioRxiv2026

Shifts in protein aggregate stability define proteostasis decline in the aging human brain

Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Using detergent-fractionation proteomics, we show that human brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife. Maximum-stability aggregates decline sharply in old age whereas intermediate-stability aggregates accumulate gradually before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched with Alzheimers disease plaque and tangle constituents. Proteasome and cytosolic chaperone abundance predict individual differences in aggregate burden as strongly as age, offering supportive evidence, in humans, for therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position the accumulation of intermediate-stability aggregates as a molecular event on the path to neurodegenerative disease.

neuroscience↗

bioRxiv2023

Chronically disrupted sleep induces senescence in the visceral adipose tissue of C57BL/6J mice

The role of sleep in systemic aging remains poorly understood, despite sleeps essential function in preserving overall health and the prevalence of reduced sleep quality in modern society. Although reduced sleep correlates with an elevated risk of age-related diseases in humans, the mechanisms underlying this are unclear. In this study, we established a link between sleep and aging by demonstrating that disrupting sleep in C57BL/6 mice drives cellular senescence in the visceral adipose tissue. Sleep disruption also led to increased oxidative stress and DNA damage, both recognized triggers for senescence induction. Cellular senescence is implicated in numerous age-related conditions which are associated with insufficient sleep, such as cardiovascular disease, type 2 diabetes, and chronic inflammation. Our findings identify an accumulation of senescent cells in the adipose tissue, which serves as a potential target through which disturbed sleep accelerates the aging process and elevates the risk of age-related diseases.

molecular biology↗

bioRxiv2023

Amyloid β accelerates age-related proteome-wide protein insolubility.

Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases, including Alzheimers Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (A{beta}) in senile plaques. Moreover, proteins that become insoluble during aging in model organisms are capable of accelerating A{beta} aggregation in vitro. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven protein insolubility as a contributory factor. Here, using an unbiased proteomics approach, we questioned the relationship between A{beta} and age-related protein insolubility. We demonstrate that A{beta} expression drives proteome-wide protein insolubility in C. elegans and this insoluble proteome closely resembles the insoluble proteome driven by normal aging, suggesting the possibility of a vicious feedforward cycle of aggregation in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the CIP is enriched with proteins that modulate the toxic effects of A{beta} and that the gut-derived metabolite, Urolithin A, relieves A{beta} toxicity, supporting its use in clinical trials for dementia and other age-related diseases.

systems biology↗