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Longevity & Mitochondria

NAD+, MOTS-c and Epitalon: Three Angles on Cellular Ageing Research

Beligas Research Team·Oct 24, 2026· 8 min read

A coenzyme, a mitochondrial-encoded peptide and a synthetic tetrapeptide — what each is, what the evidence actually shows, and how to measure their effects in culture.

Ageing research increasingly focuses on mitochondrial function, energy sensing and genome maintenance. NAD+, MOTS-c and Epitalon each map onto one of those themes, but the depth of evidence behind them differs considerably — a distinction worth keeping in mind when designing experiments.

NAD+: the redox coenzyme

Nicotinamide adenine dinucleotide is a coenzyme in hundreds of redox reactions and a consumed substrate for sirtuins, PARPs and the NAD-glycohydrolase CD38. Tissue NAD+ declines with age in multiple rodent models, and CD38 activity has been identified as a major driver of that decline (Camacho-Pereira et al., 2016).

  • Measurement: enzymatic cycling assays give NAD+/NADH ratios; LC-MS quantifies the full NAD metabolome.
  • Handling: NAD+ is sensitive to heat and alkaline pH — prepare fresh solutions in neutral buffer and keep them cold.
  • Context: precursor molecules (NMN, NR) are often studied alongside NAD+ itself, since cellular uptake routes differ.

MOTS-c: a peptide encoded by mitochondrial DNA

MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene. Its discovery showed that mitochondria encode signalling peptides, not only respiratory-chain proteins (Lee et al., 2015).

  • Mechanism: MOTS-c inhibits the folate cycle, raising AICAR levels and activating AMPK in cultured cells.
  • Mouse studies: it improved insulin sensitivity in diet-induced obesity models (Lee et al., 2015) and is induced by exercise, with treatment improving physical performance in aged mice (Reynolds et al., 2021).
  • Assays: phospho-AMPK and phospho-ACC western blots, glucose uptake, and Seahorse oxygen-consumption profiling.

Epitalon: a synthetic tetrapeptide

Epitalon (Ala-Glu-Asp-Gly) was developed by Khavinson and colleagues based on epithalamin, a pineal-gland extract. In human fibroblast cultures the group reported telomerase activation and telomere elongation (Khavinson et al., 2003).

Most published Epitalon data come from a single research group, and independent replication is limited. Studies should therefore include positive and negative controls for telomerase activity and report raw data in full.

  • Telomerase activity: TRAP (telomeric repeat amplification protocol) assay.
  • Telomere length: qPCR (T/S ratio) or flow-FISH across passages.
  • Senescence markers: SA-β-galactosidase staining, p16/p21 expression, population-doubling counts.

Selected literature

  1. Camacho-Pereira J, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016.
  2. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015.
  3. Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021.
  4. Khavinson VKh, et al. Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bull Exp Biol Med. 2003.

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This article summarises published laboratory and preclinical research for educational purposes. It is not medical advice and does not describe use in humans or animals.