Mitochondrial Health Stack

SS-31 is a four-amino-acid peptide (a tetrapeptide) that gets inside cells and goes to the inner membrane of mitochondria. There it binds cardiolipin, a fat molecule that holds the energy-making machinery in place^[1]. When cardiolipin is damaged or lost, as happens in many diseases in which cells can't make enough energy, mitochondria make ATP less efficiently^[1]. SS-31 protects cardiolipin and helps keep the inner membrane's folds in shape^[1].

In September 2025, FDA granted accelerated approval to elamipretide as the first treatment for Barth syndrome, a rare inherited mitochondrial disease^[6][7]. The approval was based on improved strength in a leg muscle. Accelerated approval means more trials must confirm that this helps patients^[6].

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, not in the main DNA inside the cell's nucleus^[3]. That makes it unusual. In mouse and cell studies, it acts mainly in muscle and switches on AMPK, the cell's energy sensor, which helps cells take up glucose^[3]. Under stress, such as low glucose, MOTS-c moves into the nucleus and changes the activity of many genes, including antioxidant genes^[12]. In mice, it prevented insulin resistance linked to aging and high-fat diets and prevented diet-related weight gain^[3]. In mice of young, middle, and old ages, it improved physical performance^[13].

In mice, MOTS-c levels in muscle and blood fall with age^[3], and researchers report lower levels with age in some tissues^[13]. In young men, exercise raised MOTS-c in muscle and blood^[13]. One research group has proposed that a MOTS-c gene variant common in Northeast Asian people might be one factor in Japanese longevity, but this is a hypothesis^[14]. FDA reports it has not found any human exposure data for MOTS-c products^[15].

NAD+ is not a peptide. It is a coenzyme, a helper molecule that enzymes need to work. It is included here because mitochondria need it to make energy^[4]. NAD+ helps carry electrons in the chain that makes ATP. It is also needed by two groups of enzymes, called sirtuins and PARPs, that are involved in DNA repair and cell aging^[4][5].

NAD+ levels drop with age in rodents and in human tissues^[4]. In one study of human skin, NAD+ fell steadily with age in both men and women^[5]. You may see the claim that people lose about half their NAD+ by age 50. We could not find a solid source for that figure, and the size of the drop varies by tissue and by study.

Research mostly focuses on precursors, compounds the body turns into NAD+, such as NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside)^[4][16]. In human trials, NR taken by mouth raised blood NAD+ levels^[16][17], and NMN raised blood NAD+ at all three doses tested, most at the two higher doses^[18]. In one trial, NMN improved muscle insulin sensitivity in women with prediabetes^[19]. In a small pilot study of NAD+ given by IV over 6 hours, blood NAD+ did not rise for the first 2 hours, because the body cleared it quickly^[20]. By the end of the 6-hour infusion, blood NAD+ was 398% higher than at the start^[20].