A nucleic acid prodrug activates mitochondrial respiration and extends lifespan
Abstract
Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of Caenorhabditis elegans. The stimulation of the AXP energy metabolism (AXP stimulation) proposed in this study is expected to offer a new strategy against aging and pave the way for a novel approach in the bioenergetic molecules drug discovery.
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Research summary
The paper addresses mitochondrial dysfunction, a key factor in aging, and presents a prodrug that enhances mitochondrial respiration and ATP levels, which could contribute to lifespan extension. While the findings are solid and provide a potential new strategy for combating aging, the study is conducted in Caenorhabditis elegans, which may limit the immediate applicability to human aging. Thus, while it is a meaningful contribution to the field, its impact is somewhat limited at this stage.
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