Fight Aging!

A number of approaches that improve mitochondrial function to produce benefits in aging mice, while comparing poorly with exercise as an intervention in humans, appear to work by improving mitophagy. That includes mitochondrially targeted antioxidants such as mitoQ, approaches to NAD+ upregulation such as nicotinamide riboside, and so forth. Mitophagy is the quality control process that identifies worn and damaged mitochondria, and moves them to a lysosome for recycling. Every cell contains hundreds of mitochondria, responsible for generating chemical energy store molecules to power cellular operations. Dysfunctional mitophagy leads to an accumulation of dysfunctional mitochondria. A loss of efficiency in mitophagy occurs with age, and thus there is interest in the scientific community in producing ways to improve this situation. So far, however, the practical outcome of such research has been underwhelming, sirtuins included.

Since sirtuins were found to extend the lifespan of Saccharomyces cerevisiae and Caenorhabditis elegans, the mechanism of sirtuin lifespan extension and whether it can extend the lifespan of other species has been actively studied. With increasing research in the last 5 years, sirtuins are increasingly recognized as being critical for regulating mitophagy and maintaining mitochondrial homeostasis. Taken together, the sirtuin family can activate or inhibit mitophagy through multiple pathways, for instance deacetylation of PGC-1α and FOXO1/FOXO3 and reduction of reactive oxygen species, thereby affecting aging and age-related diseases. By targeting these pathways, it may be possible to delay aging.

A consensus has now emerged from many studies of sirtuin activators that sirtuins mediated aspects of caloric restriction. Sirtuin activators can modulate aging and age-related diseases by activating a variety of sirtuin-induced biological functions, and have demonstrated significant aging delay and disease mitigation in experimental models. Excitingly, some sirtuin activators are already in clinical trials. For example, resveratrol acts in neurological diseases, SRT2104 in inflammation, and nicotinamide riboside in the cardiovascular system. Furthermore, decreased NAD+ levels during aging reduce sirtuin activity, which may contribute to the aging process.

However, there are still many unresolved issues. First, while there is substantial evidence implicating sirtuins in delayed aging and suppression of the aging phenotype through activation of mitophagy, there are few experiments directly demonstrating this pathway. Secondly, the effects of different sirtuin family members on mitophagy and the mechanisms of sirtuin-induced mitophagy in aging remain poorly understood. Sirtuin family members are redundant in regulating lifespan and whether other enzyme activities (excluding acetylation activity) are involved in the aging process. Thirdly, sirtuin in different tissues seems to have different effects. The specificity of sirtuin-induced mitophagy for different aging tissues and age-related diseases also merits further investigation. Fourthly, cancer cells often use mitophagy to maintain their metabolic reprogramming and growth. This is a negative effect of sirtuin-mediated mitophagy. This raises the question that whether activation of mitophagy promotes the growth of cancer cells. Fifthly, it is still unclear about the pharmacokinetics and pharmacodynamics of sirtuin activator NAD+ precursors and the mechanism of their transport through cell membranes into the blood and cells. Hopefully, these questions will be addressed in the future and provide a clearer direction for delaying human aging.

Link: https://doi.org/10.3389/fnagi.2022.845330