SHLP-2

SHLP2, small humanin-like peptide 2; family members SHLP1–SHLP6; "mitochondrial-derived peptides" (MDPs) alongside humanin and MOTS-c

Longevity & cellular

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Summary

Class: Naturally occurring mitochondrial-derived peptides; SHLP2 is 26 amino acids, encoded within the mitochondrial 16S rRNA gene. Synthetic copies are used in research and circulate as research chemicals
Mechanism: Cytoprotective and metabolic signalling similar to humanin — reduces apoptosis and oxidative stress, improves mitochondrial function and insulin sensitivity in rodents; recent work points to hypothalamic action and to chaperone-like effects on misfolded proteins
Routes studied: Intraperitoneal, intravenous and intracerebroventricular injection (rodents); cell culture; subcutaneous (community)
Dose range reported: Rodent: SHLP2 ~1–3 mg/kg/day IP in metabolic studies; cell culture low-micromolar. Community-reported: 1–5 mg subcutaneous daily or several times weekly. No human dose exists
Half-life: Not characterised in humans. Circulating SHLP2 is detectable in plasma and declines with age (mouse and human)
Storage: Lyophilised: refrigerate, protect from light. Reconstituted: refrigerate, use within ~4 weeks (community practice)
Regulatory status: Not approved anywhere; research chemical only

Doses are as reported in studies or by the community — never recommendations.

1What it is

The SHLPs (small humanin-like peptides) are six short peptides discovered in 2016 by Pinchas Cohen's group at the University of Southern California while searching the mitochondrial genome for other open reading frames like the one encoding humanin. All six sit within the 16S rRNA gene. SHLP2 and SHLP3 showed the strongest biological activity in the initial screen; SHLP6 did the opposite (promoting cell death). SHLP2 has since received most of the follow-up and is the one that circulates as a research compound.

These are natural molecules — your cells make them — and their blood levels fall with age in both mice and people. The synthetic versions used in research and in the community are copies of the natural sequence. They are not approved medicines and there are no human trials of giving them.

2How it's thought to work

Humanin-like cytoprotection. SHLP2 and SHLP3 reduce apoptosis, lower reactive oxygen species, and increase ATP production and mitochondrial oxygen consumption in cultured cells (Cobb 2016).

Metabolic signalling. central SHLP2 improved insulin sensitivity in rats, as humanin does, and a 2023 study described SHLP2 acting on hypothalamic POMC neurons to regulate energy balance and protect against diet-induced obesity in mice (Kim 2023, Nat Commun) †.

Chaperone-like activity. recent work suggests SHLP2 can bind and inhibit aggregation of misfolded mitochondrial proteins, with a naturally occurring human SHLP2 variant associated with lower Parkinson's risk †.

Inflammation. SHLP2 and SHLP3 lowered inflammatory cytokine markers in rodent and cell models.

SHLP1, SHLP4, SHLP5 are little studied; SHLP6 is pro-apoptotic and is not used as a protective compound.

Proposed: small humanin-like peptide 2, encoded in the same mitochondrial region as humanin and released under the same conditions. It is reported to support mitochondrial respiration and resist apoptosis; the human evidence is limited to association studies.Schematic — not to scale

3What the research shows

Graded C/D

Discovery, cytoprotection and metabolism in cells and rodents

The 2016 paper described all six peptides, showed that SHLP2 and SHLP3 protected cells from apoptosis and oxidative stress, improved mitochondrial metabolism, and that SHLP2 given centrally improved insulin sensitivity in rats; levels declined with age (Cobb 2016, Aging). Follow-up reviews place SHLPs alongside humanin and MOTS-c as a class (Kim 2017, J Physiol). [1][2]

Circulating SHLP2 and prostate cancer risk in humans

Lower plasma SHLP2 was associated with higher prostate cancer risk in a case-control analysis of a US cohort, and SHLP2 levels differed by ancestry (Xiao 2017, Oncotarget). Observational: it says nothing about whether giving SHLP2 changes risk. [3]

Retinal cell protection (AMD model)

SHLP2 protected AMD-patient-derived retinal cell cybrids from mitochondrial dysfunction and cell death in culture (Nashine 2018, Sci Rep). [4]

Energy homeostasis and obesity in mice

Reported in 2023: SHLP2 administration protected mice from diet-induced obesity through hypothalamic neurons, and a mouse lacking the peptide had the opposite phenotype (Kim 2023, Nat Commun) †. [5]

Graded C/D

Neurodegeneration (Parkinson's)

Cell and mouse data suggest SHLP2 reduces aggregation of misfolded proteins and is protective in Parkinson's models; a human genetic association was reported for a protective SHLP2 variant †.

Human outcomes from administration

None. All human data are measurements of the natural peptide, not trials of the synthetic one.

4Reported side effects and interactions

Literature-reported

No human safety data for administration. Rodent studies report no overt toxicity at the doses used.

Community-reported

Sparse. Mentions of injection-site irritation, mild nausea and, occasionally, improved sleep or energy; unverified and unblinded.

Theoretical. Anti-apoptotic signalling carries the same theoretical concern about protecting abnormal cells as humanin, though the human observational data point the other way for prostate cancer. Effects on glucose and appetite are plausible from the mouse data.

Interactions. None established. Additive glucose-lowering with antidiabetic medicines is plausible.

Markers researchers commonly monitor

No markers are established for administration. Based on the rodent pharmacology, members commonly discuss:

Marker	Why it's watched
Fasting glucose, fasting insulin, HbA1c	the main mechanism-relevant markers given the insulin-sensitivity data.
Body weight and waist circumference	the mouse obesity data make these the obvious outcomes to log.
hs-CRP and IL-6	inflammation rationale.
PSA (men, only where already clinically appropriate)	because of the observational prostate-cancer association, not as a treatment-response marker.
CBC and CMP	general baseline.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Supplied as powder, typically 5 mg or 10 mg vials. with , swirl gently, protect from light. Like HNG, the hydrophobic sequence may dissolve slowly.

Open in calculator, pre-loaded →

6Commonly studied alongside

Humanin (#15) and HNG (#86); MOTS-c — the three mitochondrial-derived peptides are usually discussed as a class; SS-31/elamipretide in mitochondrial contexts. No combination studies exist.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved; research chemical. Not on the 2023 Category 2 list to our knowledge †
European Union	Not authorised
United Kingdom	Not licensed
Australia	Not approved †
South Africa	Not registered
Sport (WADA)	Not specifically named; S0 as a non-approved substance †

8Open questions

Does injected SHLP2 survive long enough in human plasma to do anything, and does it reach the brain?
Independent replication of the 2016 and 2023 findings outside the discovering group.
Whether low circulating SHLP2 is a cause or a consequence of disease.
Any effect of the other SHLPs .

9References

1Cobb LJ et al. (2016). Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY). PubMed · DOI
2Kim SJ, Xiao J, Wan J, Cohen P, Yen K (2017). Mitochondrially derived peptides as novel regulators of metabolism. J Physiol. PubMed · DOI
3Xiao J et al. (2017). Low circulating levels of the mitochondrial-peptide hormone SHLP2: novel biomarker for prostate cancer risk. Oncotarget. PubMed · DOI
4Nashine S et al. (2018). Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration. Sci Rep. PubMed · DOI
5Kim SJ et al. (2023). Mitochondrial-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons. Nat Commun. PubMed · DOI
6Yen K, Lee C, Mehta H, Cohen P (2013). The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol. PubMed · DOI

† Being confirmed by our reviewers against current sources.

10Community

forum threads →

community protocols include this →

Threads and protocols are visible to members. Joining is free.

Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

26 Oct 2026Profile published — awaiting medical review

Licensed CC BY-NC-SA 4.0. Found an error? Report it · Editorial standards — corrections are logged here.