NAD+, MOTS-c and SS-31: the cellular energy stack

Mitochondria make most of the energy a cell uses, and mitochondrial function declines with age. Those two facts support a large market. The three compounds most often grouped as a "cellular energy stack" are very different things, at very different stages of evidence, and the grouping hides that.

NAD+: a coenzyme, not a peptide

Nicotinamide adenine dinucleotide is a small molecule every cell uses to move electrons in energy metabolism and to fuel enzymes such as the sirtuins and PARPs. It is often sold alongside peptides and injected the same way, but it is not a peptide. Levels fall with age in animal models, and restoring them improves several measures of ageing in mice. That is the case for taking it.

Human trials have mostly tested oral precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), because they are better absorbed than NAD+ itself.

The pattern across these trials: the precursors reliably raise NAD+ in blood and tissue. Whether that translates into better function, let alone longer life, is not established. The Elhassan trial is the cleanest test of the energy claim, and it found that NR raised NAD+ in muscle without changing how the mitochondria performed. Intravenous NAD+ infusions, popular in clinics, have much less controlled data than the oral precursors. See peptides for energy.

MOTS-c: a mitochondrial peptide, mostly in mice

MOTS-c was described in 2015 in Cell Metabolism by Pinchas Cohen's group at the University of Southern California. It is a 16-amino-acid peptide encoded not in the cell's nucleus but in the mitochondria's own DNA, in the 12S rRNA region. In mice, it acted mainly on skeletal muscle, activated the energy sensor AMPK, and prevented insulin resistance with age and with a high-fat diet, and prevented diet-induced obesity. Later work showed it can move into the nucleus under metabolic stress and regulate genes there.

The human data are thin. Observational studies measure MOTS-c in blood: one 2018 study of 10 lean and 10 obese adults found similar levels in both groups (0.48 and 0.52 ng/mL), with a correlation to insulin resistance only in the lean. CohBar, a company developing an analogue called CB4211, reported in a 2021 press release that in a four-week phase 1b study of 20 adults with obesity and fatty liver, liver enzyme ALT fell 21 percent on the drug against a 4 percent rise on placebo, and glucose fell 6 percent. Liver fat fell in both groups. That result was not published in a peer-reviewed journal, and CB4211 is an analogue, not MOTS-c itself.

The FDA says it "has not identified any human exposure data on drug products containing MOTs-C." In July 2026 the PCAC voted 7 to 5, with two abstentions, to recommend it for the 503A bulks list, which is a supply decision, not a finding of benefit. See MOTS-c and the related humanin.

SS-31: the one that became a drug

SS-31, now called elamipretide, is a four-amino-acid peptide that concentrates in the inner mitochondrial membrane and binds cardiolipin, a lipid the energy machinery depends on. It is the only compound on this page with an FDA approval, and the path there was not smooth.

Barth syndrome is a rare inherited disorder of cardiolipin, caused by changes in the TAZ gene. On 19 September 2025 the FDA granted elamipretide (brand name Forzinity, from Stealth BioTherapeutics) accelerated approval for Barth syndrome in patients weighing at least 30 kg. Accelerated approval means the decision rested on a surrogate endpoint, here improved strength of the knee-extending muscle, judged "reasonably likely to predict" real benefit. The FDA requires a confirmatory randomised, placebo-controlled trial. The most common side effects were mild to moderate injection site reactions.

The approval says nothing about elamipretide in healthy people, for ageing or for energy, and the large trial in a broader mitochondrial disease population failed. See SS-31.

Reading the "stack" claim

No trial has tested NAD+ precursors, MOTS-c and SS-31 together, in anyone. The rationale for combining them is mechanistic, not clinical. If you are weighing any of these, the questions worth asking are the ones in our guide to researching a stack and on peptides for longevity.

What to track

Energy is subjective, which is exactly why it needs a fixed scale and a baseline. A daily energy score, sleep, resting heart rate, training performance and fasting glucose or HbA1c give a before and after that means something. In Peptide AI those sit together across the dose log, training log and bloodwork tracking, and supplements like NR and NMN can be logged through the supplement scanner.