In turn, this causes an acceleration in the levels of damaged proteins that leads to the decline in multiple biosynthetic and repair activities, which, over time, has deleterious consequences on the health and aging of the organism.Currently, much of our knowledge on protein homeostasis is from studies in yeast and tissue culture cells under normal conditions of cell growth or upon challenge by acute environmental and physiological stress.Continued efforts to study the fundamentals of protein folding in the cell will be essential to understand the complexity of events that occur during proteotoxic stress in diseases of protein conformation.While much of the current attention is at the level of the cell, it will become increasingly important to understand how these events are organized and integrated systemwide at the organismal level.Among the more challenging questions are those associated with cell type specificity and cellnonautonomous interactions.The expression of diseaseassociated aggregationprone proteins causes an imbalance in protein homeostasis with deleterious consequences on the folding of other metastable proteins.This reveals that the cell does not have excess capacity to buffer against protein misfolding, and suggests that the cellular machineries and quality control may be maladapted to certain types of chronic stress.However, beyond folding and clearance mechanisms, the molecular interactions that regulate the functional properties and health of proteins include a much larger proteostasis network with RNA biogenesis, protein synthesis, and translocation having prominent roles. The demonstration that the DAF and HSF stress pathways have essential roles in the regulation of proteostasis and life span provides an important insight.Manipulation of these functional proteostasis networks could therefore restore folding, transport, and clearance machineries and thus prevent the further appearance and accumulation of damaged and misfolded proteins.The arrest of ageassociated decline in proteostasis by restoring the capacity of the quality control machinery could therefore have broadreaching consequences and benefits.Acknowledgments I thank members of my laboratory for their comments, critical discussions, and reading of the manuscript.Science. Science. Science. Science. Science. Science. Science. Science. Science. An effect associated with nuclear factorB inhibition.Science. Science. Science. Nature. Copyright, Cold Spring Harbor Laboratory Press The association between physical activity and risk of neurodegenerative diseases is not well established.We therefore aimed to quantify this association using metaanalytical techniques.We excluded studies of physical activity and cognitive decline without diagnosis of a neurodegenerative disease.Information on study design, participant characteristics, measurement of exposure and outcome variables, adjustment for potential confounding, and estimates of associations was abstracted independently by the two investigators.We calculated pooled relative risk using a random eects model.Despite neurodegenerative diseases presenting a major health problem in ageing communities, modiable risk factors such as diet and exercise have gained relatively little attention.Physical activity is known to prevent a number of chronic diseases including cardiovascular disease, hypertension, type II diabetes, and certain cancers. The association between physical activity and neurodegenerative diseases is, however, less well established.Randomized controlled trials have demonstrated that tness training has a robust eect on improving certain cognitive processes, which may be important for future risk of reasch Chlorophyllin dementia. Various cardiovascular risk factors might also contribute to the development of neurodegenerative disease, thus confounding possible associations with physical activity.