The mitochondrion, often referred to as the powerhouse of the cell, provides a valuable resource through the production of ATP, the cell’s energy, allowing cells to carry out a multitude of critical biological processes. Diminished mitochondrial function leads to inefficient production of ATP and metabolic dysfunction instigating the deterioration of the cellular environment, contributing to systemic failures and organismal degradation. With age, mitochondria become increasingly dysfunctional and are considered to be at least partly responsible for driving age-related pathologies. Research conducted at the Hebrew University of Jerusalem explores a novel class of compounds designed to help sustain mitochondrial function in an effort to improve both lifespan and healthspan.
In order to maintain a highly functional cellular environment, cells undergo autophagy, which removes and recycles aberrant molecules. Autophagy can be either selective, targeting specific organelles, or “bulk”, a non-selective degradation of molecules. A form of selective autophagy, mitophagy specifically targets dysfunctional mitochondria for removal while simultaneously replacing them with newly formed mitochondria—a process known as mitochondrial biogenesis—thus maintaining a healthy mitochondrial population. Both mitophagy and mitochondrial biogenesis have been shown to decline in aging animals, and the prevention of dysfunctional mitochondria has been shown to sustain a healthier organism throughout life.
Prior research has provided evidence that the polyamine spermidine could be key to mediating the activation of mitophagy. Spermidine, a small molecule found in living tissues and, interestingly, found at relatively high levels in many foods comprising the metabolically beneficial Mediterranean diet, is implicated in a variety of biological processes. When supplemented at the appropriate concentration, spermidine has been found to extend the lifespan of multiple organisms through the activation of mitophagy. However, excess spermidine results in the accumulation of toxic metabolic by-products such as acrolein, making it problematic as a pharmaceutical therapy. Current research has sought to provide the health benefits of spermidine without the production of toxic metabolites by engineering a class of structurally similar polyamines, referred to as mitophagy activating compounds (MACs).
C. elegans treated with spermidine are known to have increased mitophagy and an extended lifespan. The synthetically engineered molecule VL-004, a polyamine structurally similar to spermidine, has shown promise as a robust MAC. C. elegans given VL-004 show an extension of lifespan similar to that resulting from spermidine supplementation. As a result of the preservation of both muscle mass and motility and an improved stress response, VL-004-treated animals demonstrate an improvement in general health, in addition to increased lifespan. These benefits were shown to be entirely dependent on mitophagy, as subsequent experiments involving the deletion of critical mitophagy genes completely abrogated the effects of VL-004 treatment. VL-004 was demonstrated to be even more potent than spermidine regarding the activation of mitophagy and, importantly, has shown no evidence of generating toxic by-products such as acrolein. Subsequently, VL-850 was engineered based on VL-004’s structural properties; it has shown to be an even greater MAC, increasing mitophagy in both C. elegans and cultured human cells.
Research is increasingly producing novel pharmaceutical interventions to improve the quality and duration of human lifespan. The hope is to one day incorporate such compounds into a clinical standard of care targeting mitochondria to help stave off the ill effects of aging but also to aid in non-geriatric diseases wherein mitochondrial dysfunction results in deleterious health outcomes.