Longevity Peptides Research Guide: Epitalon, MOTS-c, SS-31 & Humanin Overview
Research overview of the four most-studied longevity peptides: Epitalon (telomerase), MOTS-c (mitochondrial metabolism), SS-31 (mitochondrial membrane), and Humanin (cytoprotection). Includes dosage tables and reconstitution math.
TL;DR
- Epitalon (Ala-Glu-Asp-Gly) activates telomerase and is typically used in 10–20-day courses at 5–10 mg/day
- MOTS-c is a mitochondria-derived peptide studied for metabolic regulation and insulin sensitivity; 5–10 mg/week
- SS-31 (Elamipretide) concentrates in the inner mitochondrial membrane and reduces oxidative stress; 1–5 mg/day in research
- Humanin is a cytoprotective peptide derived from the mitochondrial genome; typical research doses 2–5 mg/week
- All four require standard subcutaneous reconstitution with bacteriostatic water — use the reconstitution calculator before preparing any vial
⚠️ Disclaimer: All content on this page is for educational and research purposes only. These compounds are not FDA-approved for human use. This is not medical advice. Consult a qualified physician before considering any peptide research protocol.
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Longevity peptide research has accelerated rapidly over the past decade, shifting from isolated telomerase biology into a multi-pathway field that includes mitochondrial function, cellular stress response, and metabolic signaling. Four compounds have emerged as the most studied: Epitalon, MOTS-c, SS-31, and Humanin. Each targets a distinct mechanism, and preliminary research suggests they may complement each other across interconnected aging pathways.
This guide covers the mechanism, typical research protocols, reconstitution math, and key considerations for each compound.
Quick Comparison: All Four Longevity Peptides
| Compound | Origin | Primary Target | Structure | Typical Research Dose |
|---|---|---|---|---|
| Epitalon | Pineal gland extract | Telomerase activation | Tetrapeptide (Ala-Glu-Asp-Gly) | 5–10 mg/day, course-style |
| MOTS-c | Mitochondrial genome | Metabolic regulation | 16-amino acid peptide | 5–10 mg/week |
| SS-31 | Synthetic | Inner mitochondrial membrane | Tetrapeptide | 1–5 mg/day |
| Humanin | Mitochondrial genome | Cytoprotection, IGF-1 signaling | 21-amino acid peptide | 2–5 mg/week |
Epitalon: Telomerase Activation
Mechanism
Epitalon (Epithalamin synthetic form) is a tetrapeptide — Ala-Glu-Asp-Gly — originally isolated from the bovine pineal gland by Russian researcher Vladimir Khavinson. Its primary studied mechanism involves stimulation of telomerase (hTERT), the enzyme responsible for maintaining telomere length. In multiple in vitro studies, Epitalon increased telomerase activity and extended the replicative lifespan of human somatic cells.
Secondary mechanisms under investigation include regulation of melatonin production via the pineal gland, antioxidant activity, and normalization of T-cell function in aged subjects.
Research Dosage Protocol
Epitalon is unusual among peptides in that research protocols use course-style dosing (a defined treatment period) rather than continuous daily use.
| Protocol | Dose | Frequency | Duration |
|---|---|---|---|
| Standard course | 5–10 mg/day | Once daily (SC or IM) | 10–20 days |
| Maintenance (between courses) | None | — | 4–6 months off |
| Extended observation | 10 mg/day | Once daily | Up to 20 days |
The most common protocol in research literature is 5–10 mg/day for 10 consecutive days, repeated 2–3× per year.
Reconstitution Math (5 mg vial)
| Bacteriostatic Water Added | Resulting Concentration | Volume for 5 mg Dose | Volume for 10 mg Dose |
|---|---|---|---|
| 1 mL | 5 mg/mL | 1.0 mL | N/A (exceeds vial) |
| 2 mL | 2.5 mg/mL | 2.0 mL | N/A |
| 5 mL | 1 mg/mL | 5.0 mL | — |
For a 10 mg vial:
| Bacteriostatic Water Added | Concentration | Volume for 5 mg | Volume for 10 mg |
|---|---|---|---|
| 2 mL | 5 mg/mL | 0.5 mL (50 units) | 1.0 mL (100 units) |
| 5 mL | 2 mg/mL | 0.25 mL (25 units) | 0.5 mL (50 units) |
Use the reconstitution calculator for any vial size.
MOTS-c: Mitochondrial Metabolic Regulator
Mechanism
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino acid peptide encoded within the mitochondrial genome — specifically from the 12S rRNA region. This makes it unusual: most peptides are nuclear-encoded, but MOTS-c is mitochondria-derived and acts as a retrograde signaling molecule.
Key findings in research literature:
- Insulin sensitization: MOTS-c activates AMPK (AMP-activated protein kinase) and improves glucose uptake in skeletal muscle
- Folate cycle modulation: Acts via the folate-methionine cycle to regulate de novo purine synthesis
- Exercise mimicry: Circulating MOTS-c levels increase with exercise; exogenous administration shows similar metabolic effects in animal models
- Age-associated decline: Serum MOTS-c levels decrease with age in both human and rodent studies
Research Dosage Protocol
| Protocol | Dose | Frequency | Notes |
|---|---|---|---|
| Low dose | 5 mg | 2–3× per week (SC) | Most common in literature |
| Higher dose | 10 mg | 2× per week | Used in older rodent models |
| Daily protocol | 5 mg/day | 7 days/week | Less common, used in short-term studies |
Reconstitution Math (5 mg vial)
| BAC Water Added | Concentration | Volume for 5 mg Dose |
|---|---|---|
| 1 mL | 5 mg/mL | 1.0 mL |
| 2 mL | 2.5 mg/mL | 2.0 mL (large volume for SC) |
| 0.5 mL | 10 mg/mL | 0.5 mL (50 units) |
The 0.5 mL reconstitution (10 mg/mL) is preferred for subcutaneous administration to keep injection volumes manageable. Use the reconstitution calculator to verify volumes.
SS-31 (Elamipretide): Mitochondrial Membrane Protector
Mechanism
SS-31 (also called Elamipretide or MTP-131) is a synthetic tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH₂) developed by Hazel Szeto at Weill Cornell. It carries a net positive charge that causes it to preferentially accumulate in the inner mitochondrial membrane — specifically at cardiolipin, a phospholipid critical for the electron transport chain.
Proposed mechanisms:
- Cardiolipin stabilization: Prevents cardiolipin oxidation, maintaining cristae structure and ATP synthesis efficiency
- ROS reduction: Reduces mitochondrial reactive oxygen species without scavenging other oxidants
- Mitophagy support: Improves mitochondrial quality control signaling
- Cardiac and renal protection: Multiple Phase 2 clinical trials have investigated SS-31 for heart failure (MMTT trial, HOPEFUL-1) and acute kidney injury
Research Dosage Protocol
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| Low | 1 mg/day | Daily | SC |
| Standard | 2–3 mg/day | Daily | SC |
| Higher | 5 mg/day | Daily | SC or IV (clinical trials use IV) |
Note: Most clinical trial data uses intravenous administration. Subcutaneous research protocols are extrapolated from animal studies; the bioavailability difference is meaningful.
Reconstitution Math (5 mg vial)
| BAC Water Added | Concentration | Volume for 1 mg | Volume for 2.5 mg | Volume for 5 mg |
|---|---|---|---|---|
| 1 mL | 5 mg/mL | 0.2 mL (20 units) | 0.5 mL (50 units) | 1.0 mL |
| 2 mL | 2.5 mg/mL | 0.4 mL (40 units) | 1.0 mL | 2.0 mL |
| 5 mL | 1 mg/mL | 1.0 mL | 2.5 mL | — |
For daily low-dose protocols (1–2 mg/day), reconstituting a 5 mg vial with 1–2 mL gives a manageable injection volume of 0.2–0.8 mL. Use the reconstitution calculator.
Humanin: Cytoprotective Mitochondrial Peptide
Mechanism
Humanin is a 21-amino acid peptide encoded in the mitochondrial 16S rRNA gene. It was originally identified through screening for genes that rescue neuronal cells from Alzheimer's-associated cell death (hence the name). Its cytoprotective effects are now studied across multiple tissue types.
Key mechanisms:
- Anti-apoptotic signaling: Binds gp130 receptor and activates STAT3 and MAPK pathways, suppressing apoptosis in neurons and cardiomyocytes
- IGF-1 signaling interaction: Humanin modulates IGF-1 binding protein activity; centenarians show higher circulating humanin levels, which is associated with IGF-1 pathway changes
- Metabolic effects: Like MOTS-c, humanin appears to improve insulin sensitivity and reduce inflammation in metabolic models
- Neuroprotection: Reduces amyloid-β toxicity in neuronal cultures; studied in models of Alzheimer's and stroke
Humanin levels decline with age, and lower levels correlate with multiple age-related disease markers in human observational studies.
Research Dosage Protocol
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| Standard | 2 mg | 2–3× per week | SC |
| Higher | 5 mg | 2× per week | SC |
| Pulsed | 5 mg | Every 3–4 days | SC |
Reconstitution Math (5 mg vial)
| BAC Water Added | Concentration | Volume for 2 mg | Volume for 5 mg |
|---|---|---|---|
| 1 mL | 5 mg/mL | 0.4 mL (40 units) | 1.0 mL |
| 2 mL | 2.5 mg/mL | 0.8 mL (80 units) | 2.0 mL |
| 5 mL | 1 mg/mL | 2.0 mL | — |
Use the reconstitution calculator for precise syringe markings.
Stacking Considerations
These four compounds are sometimes studied in combination because they target distinct but interconnected pathways. For help building a longevity stack, see the peptide stack calculator guide.
| Pathway | Compound | Complementary Partner |
|---|---|---|
| Telomere length | Epitalon | Any (indirect effect on all aging pathways) |
| Mitochondrial membrane | SS-31 | MOTS-c (upstream/downstream of same organelle) |
| Mitochondrial metabolism | MOTS-c | SS-31 (structural + functional support) |
| Cytoprotection | Humanin | Epitalon (overlapping anti-apoptotic effects) |
Given that Epitalon is course-style (10–20 days on, months off) and the others are typically dosed weekly, a combined research protocol would logically run Epitalon during its defined course window while maintaining MOTS-c/SS-31/Humanin on independent weekly schedules.
Storage & Handling
All four compounds are lyophilized (freeze-dried) powders:
- Pre-reconstitution: Store at -20°C to 4°C, away from light; stable for 12–24 months
- Post-reconstitution: Refrigerate at 2–8°C; use within 28–30 days (bacteriostatic water extends this vs. sterile water)
- Freeze-thaw cycles: Avoid repeated freeze-thaw; aliquot into single-dose volumes if needed for long storage
- Handling: Do not shake; swirl or roll gently to dissolve
See the peptide storage guide and bacteriostatic water guide for full protocols.
Calculator CTAs
Epitalon 10 mg vial at 2 mL BAC water: Reconstitution Calculator → Epitalon 10 mg/2 mL
MOTS-c 5 mg vial at 0.5 mL BAC water: Reconstitution Calculator → MOTS-c 5 mg/0.5 mL
SS-31 5 mg vial at 1 mL BAC water: Reconstitution Calculator → SS-31 5 mg/1 mL
Conclusion
Epitalon, MOTS-c, SS-31, and Humanin represent four mechanistically distinct approaches to longevity research: telomere biology, mitochondrial metabolism, mitochondrial structure, and cytoprotection. Each has a distinct dosing rhythm (course-style for Epitalon; ongoing weekly for the others) and requires standard subcutaneous reconstitution with bacteriostatic water.
The peptide database contains individual entries for Epitalon and related compounds. The reconstitution calculator handles any vial size and dose combination for all four compounds.
Disclaimer: For educational and research purposes only. Nothing in this article constitutes medical advice, diagnosis, or treatment recommendation. All compounds discussed are research chemicals or investigational compounds unless explicitly noted otherwise. Consult a qualified healthcare professional before making any health-related decisions. Researchers must comply with all applicable laws and regulations in their jurisdiction.
Written by the Peptide Performance Calculator Research Team
Our team compiles research guides based on published literature for educational purposes. All content is for research use only — not medical advice. Read our disclaimer.
Frequently Asked Questions
What are the main longevity peptides being researched?
The most-studied longevity peptides include Epitalon (telomerase activation), MOTS-c (mitochondrial metabolism), SS-31 (mitochondrial membrane protection), and Humanin (cytoprotection and insulin sensitivity).
What does MOTS-c do?
MOTS-c is a mitochondria-derived peptide that activates AMPK signaling, improving glucose metabolism, fatty acid oxidation, and metabolic flexibility. Preclinical data shows effects on obesity and insulin resistance.
Can longevity peptides be stacked together?
Some researchers combine Epitalon with MOTS-c or SS-31 targeting different hallmarks of aging simultaneously. However, there are no human combination studies — individual compound data is still largely preclinical.
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