Humanin
HN · MT-RNR2 peptide · mitochondrial-derived peptide · HNG (S14G-Humanin)
Last updated
At a glance
Overview
Why Humanin Is on the Longevity Radar#
Humanin is one of the original mitochondrial-derived peptides — a 24-amino-acid sequence encoded inside the mitochondrial genome itself, first cloned in 2001 from the surviving neurons of an Alzheimer's brain. Circulating levels drop by roughly half between young adulthood and old age, and higher endogenous humanin tracks with longer lifespan across mammalian models. That's the pitch: a signaling peptide your own mitochondria make less of as you get older, which you can top up exogenously.
The longevity and biohacking community runs it for three overlapping reasons: insulin sensitivity (central and peripheral glucose-handling improvements in preclinical models), cardiovascular and endothelial stress resistance (cytoprotection against ox-LDL and ischemia-reperfusion injury), and neuroprotection (anti-apoptotic signaling via Bax/Bid suppression and STAT3/AKT activation). It pairs naturally with MOTS-c — the two mitochondrial peptides hit complementary pathways — and slots cleanly into GH-secretagogue and epitalon-based healthspan stacks without any HPTA, estrogen, or androgen interaction.
"Circulating humanin levels decline with age in both humans and mice; higher humanin levels are associated with increased lifespan in mammals." — Kim et al., GeroScience (2022)
Set expectations correctly up front: this is not a mirror peptide. Humanin won't add muscle, won't strip fat, and won't change your next PR. The return shows up on fasting insulin, HOMA-IR, long-horizon metabolic resilience, and — mechanistically — cytoprotective signaling across heart, vasculature, and brain. In the rest of this guide we'll cover dosing (native HN vs. the ~1000× more potent HNG analog), protocols for longevity, metabolic support, and cardioprotective layering on harsh AAS cycles, the MOTS-c stack that most serious users run, side effects including the one genuine oncology caveat worth respecting, and the evidence base separating what's established from what's still extrapolated from rodent work.
How Humanin works
Anti-Apoptotic Signaling via Bax/Bid Neutralization#
Humanin's defining mechanism is direct binding to pro-apoptotic Bcl-2 family proteins — Bax, Bid, and BimEL — preventing their translocation to the outer mitochondrial membrane. Without that translocation, cytochrome c stays put, the caspase cascade never fires, and the cell survives stressors that would otherwise kill it.
"Humanin directly binds to Bax and Bid, suppressing their translocation to mitochondria and thereby prevents cytochrome c release and apoptosis." — Guo B, Zhai D, Cabezas E, et al. Nature, 2003
This is the core reason HN shows up in neuroprotective, cardioprotective, and stress-resistance contexts. The peptide was originally cloned from surviving neurons in an Alzheimer's brain for exactly this reason — it rescues cells from Aβ-induced death (Hashimoto et al., PNAS 2001). For the user, this is the cytoprotective insurance layer: tissue that would apoptose under oxidative, ischemic, or metabolic stress instead hangs on.
Extracellular Receptor Signaling — CNTFR/WSX-1/gp130 and FPR2#
Outside the cell, humanin acts as a secreted signaling peptide through two receptor systems:
- A trimeric cytokine receptor made of CNTFR, WSX-1, and gp130, driving JAK2 → STAT3 activation.
- FPR2 (formyl peptide receptor 2), which routes into ERK1/2 and PI3K/AKT survival signaling.
This is how circulating humanin exerts paracrine effects on tissues that didn't produce it — vascular endothelium, cardiomyocytes, pancreatic β-cells, hypothalamic neurons. STAT3 and AKT are the same pro-survival, pro-repair axes that GH, IGF-1, and insulin converge on, which is part of why HN plays well in a healthspan stack rather than fighting it.
Insulin Sensitization via Hypothalamic Signaling#
Humanin improves peripheral insulin action through a central (hypothalamic) mechanism, not by acting on muscle or liver directly. ICV or systemic HN lowers hepatic glucose production and improves whole-body insulin sensitivity in rodents, including the Zucker diabetic fatty rat model.
"Central administration of humanin improves peripheral insulin sensitivity and lowers blood glucose in rodent models, indicating a novel metabolic role." — Muzumdar RH, Huffman DM, Atzmon G, et al. PLoS One, 2009
Practical translation: during heavy-eating blast phases, GH runs, or any stack involving oral AAS or exogenous insulin — where insulin sensitivity tends to erode — HN is a reasonable adjunct alongside metformin or berberine. It won't replace them, but it attacks the problem from a different node (hypothalamus) than AMPK activators do (liver/muscle).
Vascular and Cardiomyocyte Protection#
Humanin is natively expressed in the vascular wall and protects endothelial cells from oxidized-LDL-induced oxidative stress, along with shielding cardiomyocytes from ischemia-reperfusion injury in preclinical models.
"Our findings demonstrate that humanin is present in the vascular wall and exerts a significant cytoprotective effect on endothelial cells exposed to oxidized LDL." — Bachar AR, Scheffer L, Schroeder AS, et al. Cardiovascular Research, 2010
This is the rationale for layering HN into the back half of a harsh cycle — heavy tren, oral-heavy stacks, or high-dose test where oxidative and lipid stress on the vasculature is non-trivial. Treat it as a soft hedge stacked on top of the real interventions (blood pressure control, lipid management, reasonable dosing), not a license to run harder.
IGFBP-3 Binding and the Aging Axis#
Humanin binds IGFBP-3 with high affinity, which ties it into the GH/IGF-1 system and is one reason it keeps showing up in longevity literature. Circulating humanin levels drop with age — roughly halving between age 20 and 70 in humans — and higher levels track with longer lifespan in long-lived mouse models.
"Circulating humanin levels decline with age in both humans and mice; higher humanin levels are associated with increased lifespan in mammals." — Kim SJ, Miller B, Kumagai H, et al. GeroScience, 2022
This is the framing that matters for the reader: HN is not an acute physique tool. The payoff is on metabolic markers (fasting insulin, HOMA-IR), vascular and neuronal stress resistance, and a long-horizon healthspan signal. The same STAT3/AKT survival signaling that makes it protective is also the reason to cycle rather than run continuously and to keep it well away from anyone with an active or recent malignancy history — anti-apoptotic signaling is exactly what you don't want feeding existing tumor clones.
Protocol
| Level | Dose | Frequency | Notes |
|---|---|---|---|
| Low | 25–50 mcg | 3× weekly | Documented entry-level range |
| Mid | 100–100 mcg | 3× weekly | Most commonly studied range |
| High | 100–200 mcg | 3× weekly | Most common community protocol: 100 mcg SC every 3–5 days. HNG analog users drop to once weekly at 25–100 mcg given dramatically higher potency. |
Cycle length & outcomes
Documented cycle
6–8 weeks
Plateau after
8 wks
Cycle Length & Protocol Design#
Humanin isn't a compound you feel on day three — it's a slow-signaling mitochondrial peptide that pays off on metabolic markers and long-horizon cellular resilience. That shapes how you cycle it: 8 weeks on, 4 weeks off, run quarterly or semi-annually, rather than continuous year-round use. The off-weeks aren't about receptor downregulation (none documented) — they're a cost hedge and, more importantly, a soft hedge against the one real theoretical concern with a chronically anti-apoptotic peptide.
"Circulating humanin levels decline with age in both humans and mice; higher humanin levels are associated with increased lifespan in mammals." — Kim SJ et al., GeroScience (2022)
Dose Ladder by Goal#
| Goal | Cycle Length | Dose & Frequency |
|---|---|---|
| Beginner / tolerance check | 4–6 weeks | 25–50 mcg SC, 2–3× weekly |
| Longevity + mitochondrial stack | 8 weeks | 100 mcg SC every 3–5 days |
| Metabolic / insulin-sensitivity support on cycle | 6–8 weeks | 100 mcg SC 2×/week |
| Cardioprotective adjunct on harsh AAS | 8 weeks + 4 weeks into PCT | 100 mcg SC every 4–5 days |
| Neuroprotective / cognitive-aging | 8 weeks on / 4 off | 50–100 mcg SC 2×/week |
| HNG (S14G) analog users | 8 weeks | 25–100 mcg SC once weekly |
Do not interchange HNG with native humanin on the same dose schedule. HNG is roughly 1000× more potent at the cellular level — drop both the dose and the frequency accordingly.
Loading, Tapering, Onset#
No loading phase is needed or useful. The anti-apoptotic and STAT3/AKT signaling engages from the first dose; what takes time is the downstream metabolic shift.
"Central administration of humanin improves peripheral insulin sensitivity and lowers blood glucose in rodent models, indicating a novel metabolic role." — Muzumdar RH et al., PLoS One (2009)
Onset timing:
- Acute signaling (anti-apoptotic, cytoprotective): within hours of the first dose.
- Insulin sensitivity / HOMA-IR shifts: 3–5 weeks in most responders.
- Subjective energy / sleep quality: variable, 2–4 weeks.
- Expect nothing in the mirror. This is not a physique peptide.
No taper is required coming off — humanin doesn't suppress any endogenous axis, doesn't touch the HPG axis, and requires no PCT. Stop on the last day of week 8 and move on.
Bloodwork Cadence#
Humanin's payoff shows up on paper, so actually pull the labs or you're flying blind.
| Timepoint | Panel |
|---|---|
| Baseline (week 0) | Fasting glucose, fasting insulin, HOMA-IR, HbA1c, lipid panel, CBC, CMP, hs-CRP |
| Week 8 (end of cycle) | Same panel — compare deltas |
| Mid-off-cycle (optional) | Fasting insulin + HOMA-IR to see if gains held |
Realistic deltas in a responder: modest drops in fasting insulin and HOMA-IR, small hs-CRP improvement, no meaningful change in lipids or blood pressure. If you're running humanin alongside MOTS-c and a GH secretagogue pair, the insulin-sensitivity signal is usually clearer.
"Our findings demonstrate that humanin is present in the vascular wall and exerts a significant cytoprotective effect on endothelial cells exposed to oxidized LDL." — Bachar AR et al., Cardiovascular Research (2010)
Practical Cycling Notes#
- Injection timing within the week doesn't matter much — native HN's plasma half-life is ~30 minutes, but functional signaling persists well past clearance. Pick two or three fixed days (Mon/Thu, or Mon/Wed/Fri) and stick to them.
- Reconstituted vials are good for 28 days refrigerated at 2–8°C. A 5 mg vial in 2 mL BAC water gives you ~25 doses at 100 mcg — time your reconstitution so you're not wasting peptide.
- Stack timing: if you're running MOTS-c on the same day, inject them at separate sites; no need to space them by hours.
- The one reason to respect the off-weeks: humanin is anti-apoptotic via Bax/Bid suppression and pro-survival via STAT3. That's exactly what you want in aging neurons and cardiomyocytes — and exactly what you don't want supporting a malignant clone. Personal or recent cancer history is a hard contraindication, full stop. For everyone else, cycling is the sensible default.
Run it patient, run it cycled, and read it off the bloodwork — not the mirror.
Risks & mistakes
Common (most users)#
- Injection-site tenderness or mild redness — native HN is slightly hydrophobic and can sting at higher concentrations. Reconstitute to a lower concentration (5 mg in 3 mL instead of 2 mL), rotate sites around the abdomen and flanks, and let the solution warm to room temperature before pinning.
- Transient fatigue or mild lightheadedness in the first week — consistent with STAT3/AKT signaling adjustment. Dose in the evening for the first two weeks so it overlaps sleep rather than training.
- Mild appetite shifts — usually a slight decrease, plausibly mediated by hypothalamic insulin-signaling effects documented by Muzumdar et al. Eat on schedule regardless; this settles within 2–3 weeks.
- Sensitivity to low blood sugar if already running insulin sensitizers — HN genuinely improves insulin action. If you're on metformin, berberine, a GLP-1, or exogenous insulin, expect your glucose curves to shift down. Check fasting glucose the first two weeks and adjust the other agents, not humanin.
Uncommon (dose-dependent or individual)#
- Mild nausea or GI discomfort — more common at 200 mcg doses or when stacking with MOTS-c on the same day. Split the stack across different days.
- Headache — infrequent, usually resolves by the second dose. If it persists past a week, drop to 50 mcg and titrate back up.
- Fasting insulin dropping faster than expected — not a problem, but worth tracking. Pull fasting glucose, fasting insulin, HOMA-IR, and HbA1c at baseline and again at week 8.
- Apparent "flat" response — often a vendor quality issue rather than a side effect. Humanin is a 24-mer and cheap synthesis routinely produces deletion impurities. If you feel nothing and your bloodwork doesn't move, suspect the vial before the compound.
Rare but serious#
- Allergic / hypersensitivity reaction — rash, hives, facial swelling, wheezing. Stop immediately. Rare but possible with any peptide.
- Severe hypoglycemia when stacked with insulin or sulfonylureas — theoretical but mechanistically plausible given HN's hypothalamic insulin-sensitizing action (Muzumdar et al., PLoS One 2009). Warning signs: shakiness, sweating, confusion, disproportionate fatigue post-injection. Glucose tabs on hand if you're running insulin on cycle.
"Central administration of humanin improves peripheral insulin sensitivity and lowers blood glucose in rodent models, indicating a novel metabolic role." — Muzumdar et al., PLoS One (2009)
- Theoretical oncology concern — humanin is anti-apoptotic via direct Bax/Bid inhibition and pro-survival via STAT3/AKT. In tumor biology STAT3 drives malignant cell survival. No clinical signal exists, but the mechanism is the mechanism, which is why the community cycles this compound rather than running it continuously.
"Humanin directly binds to Bax and Bid, suppressing their translocation to mitochondria and thereby prevents cytochrome c release and apoptosis." — Guo et al., Nature (2003)
Hard contraindications#
- Active malignancy or cancer under treatment — do not run humanin. The anti-apoptotic / STAT3-activating mechanism is the same axis many tumors exploit for survival.
- Recent cancer history (within ~5 years) or known STAT3-driven tumor type — skip this compound. Pick MOTS-c, SS-31, or epitalon pulses instead if you want a longevity peptide; none of those carry the same anti-apoptotic signature.
- Pregnancy and lactation — not studied, do not use.
- Known peptide hypersensitivity — prior anaphylactic or severe allergic response to any injected peptide is a stop.
- HNG dosed as if it were native humanin — not a biological contraindication but a practical one. HNG (S14G-humanin) is roughly 1000× more potent at the cellular level. Dosing 100 mcg HNG on a native-HN schedule is a dosing error, not a protocol. Drop ~10× and extend frequency to weekly.
Sex-specific notes and PCT#
Effects are sex-independent in preclinical work and women use the same dosing ranges as men. No androgenic, estrogenic, aromatase, 5-AR, or HPTA activity — no PCT is required and no ancillaries are needed. Humanin does not interact with the HPG axis, so it can be run during a cycle, through PCT, or off-cycle without affecting recovery of endogenous testosterone. Avoid entirely during pregnancy and lactation; it has not been studied in either context and the anti-apoptotic mechanism is not something you want to probe in a developing fetus.
Stack & combine
FAQ — Humanin
Research & citations
6 studies cited on this page.
Conclusion
Humanin is a quietly powerful longevity peptide with well-documented mitochondrial, neuroprotective, and metabolic benefits — especially for users investing in stress resilience, insulin sensitivity, and cognitive health.
Key takeaways:
- Standard protocol: 100 µg SC every 3–5 days, 8 weeks on / 4 weeks off, 1–2× per year
- HNG analog: much more potent — 25–100 µg once weekly; do not stack with native HN on the same frequency
- Primary benefits: buffers cellular stress, improves insulin sensitivity, and supports endothelial/neuronal health
"Central administration of humanin improves peripheral insulin sensitivity and lowers blood glucose in rodent models..." (Muzumdar et al., 2009)
- Cyclic use is favored: both for cost and to avoid theoretical cancer risk from chronic anti-apoptotic signaling
- Stacks cleanly with MOTS-c, epitalon, and metabolic agents (metformin, GLP-1s); no major interaction risks
- Side effect profile is very clean — injection-site sting, rare transient fatigue, but avoid if you have any active or recent cancer
If you want a low-side-effect mitochondrial/resilience boost, especially as part of a broader longevity or metabolic support stack, humanin earns its place. Dose modestly, cycle on/off, and pair with MOTS-c for a robust mitochondrial signaling pulse.