Core Viewpoint - Neurodegenerative diseases, such as Alzheimer's and Parkinson's, affect 1 in every 12 people globally and currently lack curative methods. The core mechanism involves the loss of protein homeostasis and accumulation of protein aggregates in neurons as age increases [3]. Group 1: Research Findings - A study published by Stanford University in Nature reveals that the half-life of neuronal proteins in older brains is on average doubled compared to younger brains, indicating a significant decline in protein homeostasis with age [3]. - The research found that 54% of proteins in aging microglia show reduced degradation and/or accumulation with age, particularly synaptic proteins, which may lead to synaptic loss and cognitive decline [3][6]. Group 2: Protein Homeostasis and Aging - The brain's protein homeostasis, which maintains a balance between protein synthesis and degradation, deteriorates with age, leading to the accumulation of "protein waste" in neurons [6]. - The study highlights that the average half-life of neuronal proteins increases by approximately 100% from young to old age, meaning that older brains clear proteins at about half the rate of younger brains [10]. Group 3: Implications of Protein Accumulation - The research identified 1,726 neuronal proteins in the aging brain, with nearly half showing slowed degradation and/or forming aggregates, including risk gene products associated with neurodegenerative diseases [12]. - Notably, 54% of aggregated proteins exhibit decreased degradation rates with age, indicating that degradation defects directly contribute to protein accumulation, particularly affecting synaptic proteins [12]. Group 4: Role of Microglia - Microglia, the brain's immune cells, are responsible for clearing cellular debris and protein waste. The study found that aging neurons transfer proteins to microglia, which become overwhelmed as the amount of protein to process increases significantly in older mice [14]. - In aged microglia, the quantity of neuronal proteins is over ten times that found in younger mice, with more than half showing degradation defects and/or aggregation tendencies [14]. Group 5: Future Applications - The study not only uncovers new mechanisms of brain aging but also provides a powerful tool for studying protein dynamics. The BONCAT technology can be used to screen for drugs that promote protein degradation, offering new targets for treating age-related brain diseases [18]. - Future interventions may focus on enhancing the degradation capabilities of neurons or improving the clearance abilities of microglia to alleviate protein aggregation [18].