Development of novel Mitophagy Activating Compounds aiming at disease-free aging
2Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
The most devastating aspect of aging is the debilitating morbidity associated with it. Mitophagy removes damaged mitochondria components from the mitochondrial network, thus facilitating their replacement with new ones, i.e., mitochondrial biogenesis. Therefore, mitophagy is essential for proper mitochondrial function. Unfortunately, however, mitophagy declines progressively with age. Indeed, impaired mitophagy appears to play a crucial role in the pathophysiology of several age-associated diseases, including Alzheimer`s disease, Parkinson`s disease, congestive heart failure, and skeletal muscle weakness. Therefore, mitophagy enhancement through a small molecule drug presents an emerging strategy for treating such maladies.
Previous studies explored the therapeutic potential of the natural polyamine spermidine (Spd). Spd induces mitophagy and autophagy. This way extends the lifespan and health of several animal models, including the nematode Caenorhabditis elegans (C. elegans). However, some Spd metabolic products are toxic, thereby limiting the use of Spd as a drug.
To address this limitation, we have developed synthetic polyamine Mitophagy Activating Compounds (MACs) that overcome these limitations. A prototypic MAC we have explored (VL-004) induces mitophagy in C. elegans and in rodent and human cells. In this way, protect them from oxidative damage in a superior manner to that of Spd. Moreover, VL-004 extends C. elegans life- and healthspan. And provide significant protection from amyloid and polyglutamine proteotoxicity. VL-004 acts through canonical autophagy and mitophagy proteins. Our research aims to take advantage of our initial achievements and conduct further structural optimization to generate a novel drug that can effectively treat degenerative diseases associated with aging.