2. Academic Validation
  3. A Nucleic Acid Prodrug That Activates Mitochondrial Respiration, Promotes Stress Resilience, and Prolongs Lifespan

A Nucleic Acid Prodrug That Activates Mitochondrial Respiration, Promotes Stress Resilience, and Prolongs Lifespan

  • J Am Chem Soc. 2025 Jun 25;147(25):22161-22175. doi: 10.1021/jacs.5c06772.
Takahisa Anada 1 2,  Michiharu Kawahara 2,  Taisei Shimada 2,  Ryotaro Kuroda 2,  Hidenori Okamura 3 4,  Daiki Setoyama 5,  Fumi Nagatsugi 3 6,  Yuya Kunisaki 5,  Eriko Kage-Nakadai 7 8,  Shingo Kobayashi 1,  Masaru Tanaka 1 2
Affiliations

Affiliations

  • 1 Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
  • 2 Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
  • 3 Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
  • 4 Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
  • 5 Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan.
  • 6 Department of Chemistry, Graduate School of Science, Tohoku University, Miyagi 980-8578, Japan.
  • 7 Laboratory of Environment and Health Science, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
  • 8 Institute for Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
PMID: 40512174 DOI: 10.1021/jacs.5c06772
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. AXP-driven stimulation of cellular energy metabolism proposed herein represents a novel geroprotective strategy and paves the way for the development of bioenergetic-molecule therapeutics.

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