Transcriptional Repression of Mitochondrial Function in Aging: A Novel Role for the Silencing Mediator of Retinoid and Thyroid Hormone Receptors Co-Repressor

Significance: Mitochondrial function plays an important role in metabolic homeostasis and has been implicated in aging. Although there is still ongoing debate regarding whether mitochondrion-derived oxidative stress is causative to the aging process, interventions that increase oxidative metabolism and antioxidant pathways in animal models protect against age-related deterioration, such as metabolic diseases and neurodegenerative disorders. Recent Advances: One of the well-characterized transcriptional networks known to improve mitochondrial activity is mediated by transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha), which is activated by AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), two of the major energy sensing molecules that are responsible for the longevity effect of caloric restriction in certain model systems. PGC-1 alpha co-activates several nuclear receptors, notably members of the peroxisome proliferator-activated receptor (PPAR) family, which are key regulators of mitochondrial oxidative metabolism. Critical Issues: Although the AMPK/SIRT1-PGC-1 alpha-PPAR axis plays a prominent role in activating mitochondrial functions, their activities are down-regulated in older animals, suggesting the involvement of dominant negative regulatory mechanisms in the process of aging. Future Directions: In this review, we will discuss the role of a transcriptional co-repressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), whose activity and expression are increased with age, as a negative regulator of mitochondrial function that promotes aging and age-related metabolic diseases.