Considering Proteostasis and Aging
Proteostasis is the normal maintenance of protein levels and protein structure in a cell. This is disrupted with age, the result of failing quality control, epigenetic change, and other issues. Loss of proteostasis is a hallmark of aging, but has the look of a consequence of aging, not a cause to be addressed. It is also highly complex, and thus progress towards practical therapies is probably better served by a focus on causes of aging rather than the fine details of age-related changes in the cell. Fix the causes, see how well those repair efforts improve long-term health, and then worry about the fine details of the biochemistry of aging.
Proteostasis is the sum of reactions and signalling pathways related to the synthesis, folding, trafficking, disaggregation, and degradation of proteins. One of the hallmarks of aging is a decline in proteostasis. Unsurprisingly, defects in all major steps of proteostasis are related to the accumulation of toxic aggregates and misfolded proteins, a key feature of neurodegenerative diseases. Throughout evolution, a range of protein quality-control mechanisms have emerged, some of which are specialised in monitoring the proteome within specific subcellular compartments. Examples are the cytosolic heat-shock response (HSR), the mitochondrial unfolded protein response (UPRmt), and the unfolded protein response of the endoplasmic reticulum (UPRER). The mechanisms underlying age-related proteostasis collapse are still not completely understood, but studies using Caenorhabditis elegans and mice suggest that it initiates during early adulthood preceding the emergence of age-related diseases.
A fundamental question in biogerontology is why animals lose the ability to maintain proteostasis with aging. A new study observed that an age-related increase in ribosome pausing occurs driven by a reduced activity of the ribosome quality control (RQC) pathway. Another provocative study, in mice, argued that error-prone translation caused by ribosomal ambiguity mutations induces phenotypes that more closely match the progression of Alzheimer's disease than amyloid-β overexpression models do. Their findings suggest that the accumulation of random mutations in DNA over time may induce increased protein misfolding, sequestering away key components of the proteostasis maintenance machinery, such as chaperones, ultimately causing a collapse in proteostasis.