SIRT3 Upregulation as a Basis for Improving Mitochondrial Function in the Aging Brain

SIRT3 beneficially affects mitochondrial function, and its upregulation is a calorie restriction mimetic strategy, since it mediates some of the benefits resulting from a lowered calorie intake. Given this, there is some interest in this as a basis for treatments for neurodegenerative conditions, in which loss of mitochondrial function in the brain is thought to be an important contribution to pathology. Mitochondria are the power plants of the cell, and the brain requires a great deal of energy to operate. So far, efforts to improve mitochondrial function in aged tissues by targeting the expressed levels of specific proteins or metabolites important to mitochondrial metabolism have yet to surpass the effects of exercise or the practice of calorie restriction itself. It seems unlikely that manipulating SIRT3 expression will prove to be any different.

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3's functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise.

SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. Alzheimer's disease (AD) has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3's roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.