Understand the source comparison
AICAR versus mitochondrial-derived peptides (MOTS-c)
Perhaps the most conceptually interesting comparison is with MOTS-c, a 16-amino-acid peptide encoded within mitochondrial DNA. Lee and colleagues showed that MOTS-c targets the folate cycle and de novo purine biosynthesis, leading to accumulation of AICAR itse
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- Perhaps the most conceptually interesting comparison is with MOTS-c, a 16-amino-acid peptide encoded within mitochondrial DNA. Lee and colleagues showed that MOTS-c targets the folate cycle and de novo purine biosynthesis, leading to accumulation of AICAR itself and consequent AMPK activation.[9] In other words, one proposed mechanism of a natural mitochondrial peptide is to raise endogenous AICAR — a remarkable convergence. Later work reinforced that MOTS-c and exercise cooperate to regulate PGC-1α and glucose metabolism through AMPK.[10] This shared node is why researchers interested in AICAR often also study these peptides; our overview of what MOTS-c is and how it is classified among mitochondrial-derived peptides situates that relationship.
- AICAR / acadesine
- Converted to ZMP, an AMP-mimetic at the γ subunit
- Human trials only for cardiac surgery & oncology (different endpoints); no endurance/longevity trials
- Metformin
- Indirect (complex I inhibition → ↑AMP/ATP)
- Approved for type-2 diabetes; longevity use investigational
- ADaM-site activators
- Direct allosteric binding
- Preclinical / early clinical; investigational
- MOTS-c
- Raises endogenous AICAR via folate/purine cycle
- Preclinical (animal/cell); no approved use