The Boost to the Unfolded Protein Response Achieved via Exercise Declines with Age
Exercise achieves benefits to health in large part through upregulation of cellular maintenance processes. In this way it is similar to the practice of calorie restriction, but the outcome is of a lesser degree - exercise does not extend life span in laboratory species, while calorie restriction does. Nonetheless, exercise is certainly beneficial. One of the cellular maintenance processes involved is the unfolded protein response, which, as the name might suggest, clears out proteins that are improperly folded, or have otherwise become stuck at the folding stage of protein manufacture, in the endoplasmic reticulum structure of the cell. Like other maintenance processes, the unfolded protein response becomes less effective with age, for reasons that are far from fully explored. Here, researchers demonstrate this diminished effectiveness in the context of the response to exercise.
Aging is associated with the loss of skeletal muscle mass, quality, and function; decrements that have a negative influence on health span. Resistance exercise improves muscle mass and function, but there is emerging evidence that the molecular and cellular responses to anabolic stimuli (e.g., exercise and nutrition) are attenuated in older adults; a phenomenon termed anabolic resistance. The unfolded protein response (UPR) has emerged as a key regulatory pathway in skeletal muscle protein quality control and adaptations to exercise. Early evidence points to altered UPR as an explanation for age and disease related changes in protein folding and accumulation and aggregation of proteins within the endoplasmic reticulum (ER).
The influence of age on skeletal muscle adaptive UPR in response to exercise, and the relationship to other key exercise-responsive regulatory pathways is not well-understood. We evaluated age-related changes in transcriptional markers of UPR activation following a single bout of resistance exercise in 12 young (27 ± 5yrs) and 12 older (75 ± 5yrs) healthy men and women. At baseline, there were modest differences in expression of UPR-related genes in young and older adults. Following exercise, transcriptional markers of UPR pathway activation were attenuated in older adults compared to young based on specific salient UPR-related genes and gene set enrichment analysis. The coordination of post-exercise transcriptional patterns between the UPR pathway, p53/p21 axis of autophagy, and satellite cell (SC) differentiation were less evident in older compared to young adults.
In conclusion, older adults exhibited decreased markers of UPR activation and reduced coordination with autophagy and SC-associated gene transcripts following a single bout of unaccustomed resistance exercise. In contrast, young adults demonstrated strong coordination between UPR genes and key regulatory gene transcripts associated with autophagy and SC differentiation in skeletal muscle post-exercise. Taken together, the present findings suggest a potential age-related impairment in the post-exercise transcriptional response supporting activation of the UPR and coordination with other exercise responsive pathways (i.e., autophagy, SC differentiation) in skeletal muscle that is likely to contribute to sarcopenia and age-related attenuation of adaptive responses to exercise.