The endoplasmic reticulum is the site of protein synthesis and lipid synthesis in cells. Damage or other disturbances to cellular processes can lead to an accumulation of unfinished molecules in the endoplasmic reticulum, a condition known as endoplasmic reticulum stress. The cell will respond in various ways when this happens, trying to clear out the unfinished proteins and lipids in order to restore normal function. This all falls under the general heading of cellular housekeeping, and we know that cellular housekeeping mechanisms such as autophagy both decline with age and are influential on the pace of aging. Not influential enough to greatly extend human life spans, probably, but they appear to be a sizable part of the reason why strategies such as calorie restriction can improve long-term health and modestly slow aging in our species.
Under normal circumstances, proteins destined for the secretion are translated directly into the endoplasmic reticulum (ER) via ribosomes embedded in the ER membrane, bound by chaperone proteins, folded, and then packaged into vesicles for secretion. In some cases, however, this pathway can go awry; proteins may become misfolded or unfolded in the ER, and unable to be recovered by the protein quality control machinery. In this instance, the improperly folded protein is targeted for degradation, exported into the cytosol, and degraded by a proteasome. Again, however, this process is imperfect. Some environmental, cellular, or molecular factors can cause disruptions in this pathway, preventing the proper turnover of misfolded or unfolded proteins, potentially leading to their accumulation and aggregation. This generates a cellular condition known as ER stress.
Endoplasmic reticulum stress and the failure to correctly fold proteins are associated with loss of protein function and cell death. To avoid this, the cell resolves misfolded protein stress via two major stress response pathways: the heat shock response (HSR), which handles misfolded proteins in the cytoplasm, and the unfolded protein response (UPR), which takes place in the ER. These protein quality control mechanisms are essential for maintaining the function and integrity of cellular processes. When perturbed, they can lead to whole-cell dysfunction and toxicity. Under normal conditions, both lead to resolution of the cellular stress caused by the presence of misfolded proteins.
The UPR is a complicated signaling pathway which works to resolve ER stress and allow protein synthesis and folding to continue and has been shown to interact with multiple cellular pathways and processes to do so, including (but not limited to) those occurring in the ER. It has also been shown to be impacted by several seemingly unrelated external influences, including aging and lipid metabolism, and dysfunction in this pathway has been linked with shortened cellular lifespan and cell death. Because of this, the study of the molecular mechanisms behind ER stress and the UPR is essential to the understanding of how protein homeostasis impacts the entire cell and its processes, including response to stressors, aging, and cell death.
Aging cells have been shown to have decreased total levels of a number of ER proteins, including protein chaperones which normally supervise and ensure proper protein folding, and assist in targeting misfolded proteins for degradation. This usually prevents the accumulation and aggregation of misfolded proteins and prevents them from having toxic effects on the cell. In addition, the limited chaperones that are still present in the aging ER appear to be impaired. This is possibly due to an increased rate of oxidation of these chaperones in aged cells, leading to structural changes and consequently decreased function.