The mitochondrial peptidome — larger than anyone knew
The human mitochondrial genome is a compact 16,569 base pair circular DNA — once thought to encode only 13 proteins plus the RNA machinery needed to make them. The discovery of Humanin in 2001 (encoded within the 16S rRNA gene) established that the mitochondrial genome also encodes biologically active peptides outside its conventional reading frames. MOTS-c (2015) revealed a second mitochondria-encoded peptide with profound metabolic effects.
The SHLP family — Small Humanin-Like Peptides — were systematically identified by Pinchas Cohen's laboratory at USC between 2016 and 2024 by scanning the 16S rRNA gene for additional open reading frames. SHLPs 1–6 were characterised, each encoded by adjacent or overlapping reading frames within the same 16S rRNA region as Humanin. Each has a distinct amino acid sequence, distinct tissue distribution, and distinct biological activity — despite sharing the same mitochondrial genomic origin.
The most studied are SHLP-2 and SHLP-6. SHLP-2 has shown lifespan extension in C. elegans and mouse models and — crucially — is measurably elevated in the blood of human centenarians compared to age-matched controls in their 70s-80s. SHLP-6 regulates glucose metabolism and has effects on reactive oxygen species. Both are endogenous peptides — your mitochondria produce them continuously, with levels declining with age.
Why this matters: Every cell in your body contains mitochondria. Every mitochondrion carries its own genome. For decades, we thought that genome did only 13 things (encode respiratory chain proteins). We now know it also encodes at least 8 biologically active peptides (Humanin, MOTS-c, SHLPs 1–6) — with almost certainly more to be discovered. The mitochondrial peptidome is an entirely new category of endocrine signalling that science barely understood a decade ago.
SHLP-2 protects, SHLP-6 metabolises
SHLP Biology — Current Understanding
The centenarian finding with SHLP-2 is the most clinically intriguing data point. If high SHLP-2 levels are causally associated with exceptional longevity rather than merely correlated, then exogenous SHLP-2 administration becomes a genuinely interesting longevity hypothesis. However, the same caveat applies as to Humanin's IGF-1 binding and MOTS-c's AMPK activation — association with longevity biomarkers does not establish that supplementation extends lifespan in otherwise healthy adults. No human intervention trials with any SHLP peptide have been conducted.
The honest unknowns
The SHLP family is at the earliest stage of characterisation. Key open questions: What are the specific receptors for each SHLP? (Only partially identified.) What are the pharmacokinetics of exogenous SHLP administration? Do the in vitro and animal findings translate to human biology? Would supplementation affect endogenous production? Are there tissue-specific effects that differ from the systemic circulation data? What is the relationship between centenarian SHLP-2 levels and the genetics/epigenetics of exceptional longevity vs the peptide itself?
The community use of SHLP peptides is very limited compared to Humanin or MOTS-c — partly because the science is newer, partly because the human evidence base is essentially non-existent, and partly because synthesis and sourcing of verified SHLP peptides from research chemical suppliers is more difficult to verify than for more established compounds.
The Cohen laboratory at USC continues publishing on the mitochondrial peptidome. Human intervention trials with SHLP-2 are likely within 3–5 years as the basic science matures. Companion diagnostics (SHLP blood level testing) may become available as longevity biomarker panels expand. The discovery of additional members of the mitochondrial peptidome beyond SHLP 1–6 is probable — this is a rapidly evolving area.