Side-by-side · Research reference
HumaninvsSS-31
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
AAnimal-StrongHUMAN-REVIEWED14/52 cited
BPhase 3HUMAN-REVIEWED9/43 cited
Humanin
Mitochondrial-Derived Peptide · Cytoprotective
SQ · Experimental
SS-31
Cardiolipin-binding · Mitochondrial protective
SQ · Abdomen · Once daily
01Mechanism of Action
Parameter
Humanin
SS-31
Primary target
Intracellular: Bax, Bim, tBid (pro-apoptotic Bcl-2 family). Extracellular: FPRL1/2 G-protein-coupled receptorsZhu 2022Lue 2021
Cardiolipin in inner mitochondrial membraneSzeto 2014
Pathway
Humanin binds Bax/Bim → inhibits mitochondrial outer membrane permeabilization (MOMP) → blocks cytochrome c release → prevents caspase activation → cell survival
Cardiolipin binding → cristae stabilisation → ETC integrity → reduced ROS + preserved ATP synthesisSzeto 2014Szilagyi 2009
Downstream effect
Suppression of apoptosis, mitochondrial stabilization, reduced oxidative stress, preservation of germ cells and neurons under stressZhu 2022Lue 2021Velentza 2024
Mitochondrial bioenergetic preservation; cardio-, neuro-, and reno-protective effects in animal + clinical studiesSzeto 2014
Feedback intact?
Not applicable — peptide acts as anti-apoptotic signal, not hormonal axis
—
Origin
Encoded by short open reading frame in mitochondrial 16S rRNA gene (MTRNR2). 24-28 amino acids. 13 homologous variants (MTRNR2L1-L13) identified.Zhu 2022Shahzaib 2026
Synthetic tetrapeptide D-Arg-Dmt-Lys-Phe-NH₂; cell-permeable, mitochondrial-selectiveSzeto 2014
Antibody development
Not reported in animal models
—
02Dosage Protocols
Parameter
Humanin
SS-31
Standard experimental dose (HNG)
4 mg/kg IP (rat)
Most common dose in rodent models.
—
Ex vivo bone culture
1 µg/mL
Protective against venetoclax-induced bone growth retardation.
—
Frequency
Daily (IP)
Once daily
Duration
8–12 weeks in animal studies
Indefinite for mitochondrial disease; cycled for healthspan use
Evidence basis
Animal models (rat, mouse)Huang 2025El 2022Velentza 2024
Multiple Phase 3 trials (Barth, AMD, ischemia-reperfusion)Szeto 2014Szilagyi 2009
Human data
None — no clinical trials reported
—
Analog (HNG)
Gly[14]-humanin — more potent variant
Substitution at position 14 enhances cytoprotective activity.
—
Standard dose
—
40 mg / day SQ (clinical trials)Szeto 2014
Anecdotal community range 5-10 mg/day. Phase 3 trials use 40 mg.
Lower / starter dose
—
5 mg / day (anecdotal)
Reconstitution
—
Bacteriostatic water
Timing
—
Morning fasted preferred; pre-workout for exercise-induced mitochondrial stress
Half-life
—
~3 h plasma; tissue uptake longer
03Metabolic / Fat Loss Evidence
Parameter
Humanin
SS-31
Direct fat loss evidence
None
—
Mechanism overlap
Mitochondrial health may indirectly influence metabolic efficiency, but no quantified effect
—
04Side Effects & Safety
Parameter
Humanin
SS-31
Animal model safety
Well-tolerated in rat and mouse studies at 4 mg/kg for 8–12 weeks
—
Human safety data
None — no clinical trials
—
Theoretical fibrillation risk
Induces amyloid-like fibrillation of Bax/BID. Long-term sequelae unknown.
—
Injection site reaction
Not reported in animal studies (IP route)
Erythema, mild pruritus
Reproductive safety
Protective in POI model (cyclophosphamide-induced), no adverse effects on fertility notedHuang 2025
—
GI symptoms
—
Nausea (uncommon)
Headache
—
Reported in some Phase 3 trials
Cardiovascular
—
Cardio-protective in studies; no signal of harm
Pregnancy / OB
—
Avoid — insufficient data
Absolute Contraindications
Humanin
- ·Unknown — no human data
SS-31
- ·Pregnancy / breastfeeding
- ·Hypersensitivity to peptide
Relative Contraindications
Humanin
- ·Active malignancy (theoretical risk of anti-apoptotic effect on tumour cells)
SS-31
- ·None established
05Administration Protocol
Parameter
Humanin
SS-31
1. Route (experimental)
Intraperitoneal (IP) in animal models. Subcutaneous route untested. No human protocols exist.
Add bacteriostatic water per label. Light-protected handling.
2. Reconstitution
Synthetic peptide reconstituted in sterile saline or PBS. No commercial formulation available.
SQ — abdomen or thigh. Rotate sites.
3. Timing
Daily administration in animal studies. Optimal timing not characterized.
Morning fasted; pre-workout for exercise-augmented mitochondrial stress.
4. Storage
Lyophilised powder: -20 °C. Reconstituted: 4 °C, use within 7 days. Avoid freeze-thaw cycles.
Lyophilised: refrigerate, light-protected. Reconstituted: refrigerate ≤30 days.
5. Human use
No FDA approval, no IND, no clinical trials. Experimental research tool only.
29–31G, 4–8 mm insulin syringe.
06Stack Synergy
Humanin
+ MOTS-c
Multi-pathwayBoth are mitochondrial-derived peptides. MOTS-c enhances metabolic efficiency and insulin sensitivity via AMPK activation, while humanin prevents mitochondrial apoptosis. Combined, they address mitochondrial function (MOTS-c) and survival signaling (humanin), supporting cellular resilience under metabolic and oxidative stress.
- Humanin
- 4 mg/kg IP · daily (animal model)
- MOTS-c
- 5 mg/kg IP · daily (animal model)
- Frequency
- Once daily
- Primary benefit
- Mitochondrial health, metabolic efficiency, anti-apoptotic signaling
SS-31
+ MOTS-c
ModerateSS-31 and MOTS-c address mitochondrial decline through complementary axes. SS-31 protects existing mitochondrial structure (cardiolipin binding, cristae stabilisation). MOTS-c upregulates AMPK/PGC-1α, triggering biogenesis of new mitochondria. Together they pair preservation with renewal — anecdotally favoured in healthspan and post-cardio-event recovery protocols.
- SS-31
- 5–10 mg SQ · daily morning
- MOTS-c
- 5 mg SQ · 2× per week pre-workout
- Primary benefit
- Mitochondrial preservation + biogenesis