Can we untie the linkage between life extension and a decline in healthspan via healthy mitophagy?

Removal of damaged mitochondria by a process called mitophagy is essential for animal health.

However, the efficiency of this process gradually decreases with age, resulting in the accumulation of damaged mitochondria that contribute to an increase in redox stress and various disease states such as Alzheimer`s disease, Parkinson`s disease, heart failure, and skeletal muscle weakness. Therefore, increasing mitophagy by pharmacological means is an emerging strategy for treating age-associated conditions.

Studies from recent years show that the natural polyamine spermidine increases autophagy/mitophagy and, in this way, extends life- and healthspan. However, some of its degradation products are harmful, so the use of spermidine as a drug is limited. To address this, we have developed and tested synthetic polyamine derivatives. These compounds induce mitophagy and thus protect against oxidative injury and toxic disease proteins. In addition, these Mitophagy Activating Compounds (MACs) lengthen both life expectancy and health, demonstrating that longevity and healthspan are not mutually exclusive. Finally, we provide insights into the mechanism of action of the MACs. We will leverage this knowledge toward a more rational design of effective MACs to treat age-associated diseases.