Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update

Abstract

The endoplasmic reticulum (ER) is a dynamic and multifunctional organelle responsible for protein biosynthesis, folding, assembly and modifications. Loss of protein folding regulation, which leads to unfolded or misfolded proteins accumulation inside the ER lumen, drives ER stress (ERS) and unfolded protein response (UPR) activation. During aging, there is a decline in the ability of the cell to handle protein folding, accumulation and aggregation, and the function of UPR is compromised. There is a progressive failure of the chaperoning systems and a decline in many of its components, so that the UPR activation cannot rescue the ERS. Physical activity has been proposed as a powerful tool against aged-related diseases, which are linked to ERS. Interventional studies have demonstrated that regular exercise is able to decrease oxidative stress and inflammation and reverse mitochondrial and ER dysfunctions. Exercise-induced metabolic stress could activate the UPR since muscle contraction is directly involved in its activation, mediating exercise-induced adaptation responses. In fact, regular moderate-intensity exercise-induced ERS acts as a protective mechanism against current and future stressors. However, biological responses vary according to exercise intensity and therefore induce different degrees of ERS and UPR activation. This article reviews the effects of aging and exercise on ERS and UPR, also analyzing possible changes induced by different types of exercise in elderly subjects.

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…The aging process is associated with a number of conditions known to induce ER stress, e.g., deficiencies in autophagic and mitochondrial functions, disturbances in Ca 2+ homeostasis, increased oxidative stress, and disorders in proteostasis and energy metabolism [40]. However, studies on the expression levels of UPR proteins, both transcription factors and ER chaperones, have revealed contradictory results, as reviewed in detail by Estebanez et al [41]. This is not a surprise since the aging process is a progressive state in tissues with both acute and adaptive changes induced by a variety of endogenous stresses and alterations in the microenvironment, e.g., metabolic, hormonal, and inflammatory changes.…”

Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD

“…Crosstalk between the ER and mitochondria also play an important role in aging. The ER is involved in protein synthesis and folding, and interaction between the ER and mitochondrial associated membranes regulates cellular Ca 2+ [ 120 , 121 ]. ER stress triggers the unfolded protein response (UPR) to alleviate the protein burden and prevent misfolding, and chronic UPR activation by garbage in the inflammaging environment can lead to impaired proteostasis and acceleration of age-related diseases [ 122 ].…”

Type 2 diabetes causes skeletal muscle atrophy but does not impair resistance training‐mediated myonuclear accretion and muscle mass gain in rats

“…Although we could not identify the certain cause of discrepancy with previous observations, experimental modality might influence the result. In fact, a previous study has shown that exercise intensity affects activation of ER stress signalling (Estebanez, de Paz, Cuevas, & Gonzalez-Gallego, 2018). Therefore, the role of the ER stress response during exercise-induced skeletal muscle adaptation should be determined in further studies.…”