SHLP2

also known as: Small humanin-like peptide 2, MT-RNR2-derived SHLP2

A 26-aa mitochondrial-derived peptide, the most-studied of the SHLP1–SHLP6 family (Cohen lab, USC). Preclinical data report insulin-sensitizing, antiapoptotic, and metabolic-protective effects; lower plasma levels in humans correlate with age and with type 2 diabetes. Research-only; no human clinical trials.

A 26-amino-acid mitochondrial-derived peptide (MDP) encoded by a small alternate open reading frame within the 16S rRNA region of mitochondrial DNA, identified and characterized by Pinchas Cohen's group at USC along with five related peptides (SHLP1, SHLP3, SHLP4, SHLP5, SHLP6). The most-studied member of the family. Reported in preclinical studies to enhance insulin sensitivity, protect against β-cell apoptosis in diabetes models, and improve metabolic phenotype in aged mice. Human plasma levels decline with age and are reduced in type 2 diabetes cohorts, supporting a proposed role as an endogenous longevity-associated signal. Research-only; no clinical trials; not available as a registered medicine.

Mechanism of action

Proposed to be secreted from mitochondria and act in autocrine/paracrine fashion. Reported to enhance insulin signaling (PI3K/Akt), protect pancreatic β-cells from apoptosis, reduce oxidative stress, and modulate adipogenesis. Receptor target is not definitively identified but has been proposed to include the CNTFR-WSX-1-gp130 receptor complex used by humanin. Represents one of the clearest examples of a peptide encoded by the mitochondrial genome in an alternate reading frame with autocrine/endocrine bioactivity.

Primary uses

Metabolic aging research (preclinical)
Type 2 diabetes mechanism research (preclinical)
Mitochondrial-derived peptide biology (aging biomarker research)

Typical dosing

Not established for human use

⚠ No human dosing established. Preclinical rodent studies have used intraperitoneal administration of 1–4 mg/kg. Any human use would be unregulated and unsupported by clinical safety or efficacy data.

Regulatory status

Not FDA-approved. Not in any registered human clinical trial. Available only as a synthesized research peptide from peptide-synthesis vendors; any human use would be unapproved and unsupported.

References

[pubmed] Cobb LJ, et al. "Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers." Aging (Albany NY), 2016;8:796-809 (SHLP1–SHLP6 discovery and characterization).
[pubmed] Yen K, et al. "The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan." Aging (Albany NY), 2020;12:11185-11199 (mitochondrial-derived peptide family review).
[pubmed] Mehta HH, et al. "Mitochondrial-derived peptides as biomarkers of aging and age-related diseases." Aging Cell, 2022;21:e13641.

Related peptides

Humanin

A mitochondrial-derived peptide with neuroprotective, metabolic, and anti-apoptotic activity — one of the first signaling peptides identified as encoded by mitochondrial DNA.

MOTS-c

A mitochondrially encoded peptide studied for its effects on metabolic homeostasis, insulin sensitivity, and exercise capacity.

SHLP6

A SHLP-family member with a notably distinct preclinical profile: where humanin and SHLP2 are antiapoptotic, SHLP6 has been reported as pro-apoptotic, suggesting the mitochondrial-derived peptide family includes members with opposing regulatory roles. Research-only.

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.