Humanin ARA-290

Why these two sit together

Humanin and ARA-290 are both “endogenous biology, refined.” Your body makes both of them (or made the parent protein) — the peptides on the market are just intelligent pharmacological versions of signals your cells already use to protect themselves.

• Humanin is a 21-amino-acid mitochondrial-derived peptide encoded by the MT-RNR2 gene inside your mitochondrial DNA — same taxonomic class as MOTS-c. Centenarians have markedly more of it. Exogenous humanin restores what aging depletes.
• ARA-290 (cibinetide) is an 11-amino-acid peptide engineered from the tissue-protective domain of erythropoietin (EPO). Michael Brines at Araim Pharmaceuticals deliberately stripped out EPO’s red-blood-cell-stimulating activity and kept only the tissue-protective signaling. Clean peptide engineering: the “good” half of EPO without the hematocrit, thrombosis, and cancer concerns that come with full erythropoiesis.

Together with MOTS-c (metabolic / insulin sensitivity) and SS-31 (mitochondrial ROS scavenging, FDA-approved for Barth syndrome), these two complete the four-corner endogenous-protection map: CNS/longevity (Humanin), peripheral nerve (ARA-290), metabolic (MOTS-c), mitochondrial ROS (SS-31).

Alyve availability: Neither Humanin nor ARA-290 is in Alyve’s current launch 15-SKU catalog. Both are roadmap candidates — ARA-290 in particular is the cleanest catalog-expansion candidate in the whole non-Alyve-15 universe (published Phase 2 RCT, FDA Orphan Drug status, transparent safety reporting). Until they’re stocked, the OHM CTA for this article ties to the broader Alyve trust story and to the cluster siblings already in catalog (MOTS-c, NAD+).

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Peptide 1: Humanin (and HNG, the potent analog)

What it is

Humanin is a 21-amino-acid peptide your mitochondria encode — specifically, from the MT-RNR2 gene region of your mitochondrial DNA. That makes it a mitochondrial-derived peptide (MDP), the same class as MOTS-c. Both are signals your mitochondria send out to the rest of the cell during oxidative or metabolic stress, like a coordinated cellular alarm system.

Two facts make humanin one of the more interesting longevity peptides to track:

• Centenarians have markedly higher circulating humanin levels than age-matched controls. Children of centenarians also show elevated humanin — meaning there’s a heritable longevity-biomarker component. Lower humanin correlates with higher Alzheimer’s risk across multiple datasets.
• Humanin was discovered the right way. Hashimoto, Nishimoto et al. published the original Science paper in 2001 after screening cortical tissue from an Alzheimer’s-resistant patient looking for natural neuroprotective factors. The peptide was found by asking “what is this brain making that’s protecting it?” — not by computational design.

How it works

Four pathways:

• JAK2/STAT3 survival cascade. Humanin binds a trimeric receptor complex (CNTFR-α + gp130 + WSX-1) → phospho-STAT3 activation → anti-apoptotic gene expression. The “keep this cell alive” signal.
• Direct Bax inhibition. Humanin physically binds Bax (a pro-apoptotic Bcl-2 family member) and prevents its translocation to the mitochondria — blocking apoptosis upstream of the point where the cell has committed to dying.
• IGFBP-3 binding → IGF-1 axis modulation. Humanin binds IGFBP-3 and produces a measurable reduction in circulating free IGF-1. This is a notable stacking flag — humanin reduces IGF-1, which is the opposite of what CJC-1295 / Ipamorelin, Sermorelin, Tesamorelin, and MK-677 are trying to do. Stacked together, humanin can blunt the GH-secretagogue protocol. The flip side is that for the longevity audience worried about IGF-1-driven proliferation, that’s a feature, not a bug.
• Mitochondrial stress response. Humanin acts in concert with MOTS-c during oxidative and metabolic stress — same alarm system, different downstream effects.

HNG — the high-potency analog

HNG (Humanin G, or S14G-Humanin) is a single-amino-acid substitution at position 14 (serine → glycine) that produces roughly 1000× greater potency in neuroprotection assays plus better CNS penetration. In practice that means HNG users dose 100–500 mcg per injection versus 1–3 mg for native humanin to achieve a comparable effect. The cost-per-effective-dose math is the reason most longevity protocols default to HNG when available.

What the research shows

• Centenarian epidemiology — higher circulating humanin in 100+ year-olds and their children; inverse correlation with Alzheimer’s risk across multiple datasets.
• C. elegans lifespan extension — 40–60% extension in humanin-overexpression experiments.
• Mouse models — reduced age-related pathology, improved survival with humanin-agonist administration.
• Alzheimer’s preclinical — rescues cortical neurons from Aβ25-35 and Aβ1-42 toxicity; protects against tau-induced neuronal death (FTD + CTE relevance); reduces APP processing upstream. Described in the literature as “the most-studied neuroprotective profile of any MDP”.
• Cardiovascular — humanin demonstrated CV-protective effects in vivo; broader use case than the Alzheimer’s framing suggests.

Where the data stops, honestly: there are 500+ peer-reviewed publications on humanin but zero completed Phase 2 or Phase 3 human clinical trials for any specific indication as of mid-2026. The evidence base is overwhelmingly mechanistic and preclinical, plus the striking centenarian epi signal. That’s a strong preclinical + epidemiology profile and a thin clinical-trial profile — typical for a bleeding-edge longevity peptide.

Real-world protocol

The doses and schedules here are for educational and informational purposes only. These peptides are sold for research use only and are not FDA-approved drugs. This is not medical advice. Consult a qualified physician before beginning any protocol.

Form	Dose	Frequency	Weekly	Notes
Native humanin	1–3 mg per injection	2–3×/week	3–9 mg	Or 0.5–1 mg daily low-dose continuous
HNG (Humanin G)	100–500 mcg per injection	2–3×/week	Variable	~1000× potency vs. native — preferred for cost-per-dose

• Reconstitution example (native humanin): a 5 mg vial + 2 mL bacteriostatic water = 2.5 mg/mL. A 1 mg dose = 0.4 mL = 40 units on a U-100 insulin syringe.
• Route: subcutaneous standard; intranasal explored in research but not clinically established.
• Cycle: 8–12 weeks on / 4–6 weeks off, or continuous low-dose for chronic neuroprotection. There is no formally established cycling protocol — both patterns are used in the community.

Stacking:

• Pairs cleanly with MOTS-c — non-overlapping mechanisms (MOTS-c primarily metabolic/insulin sensitivity; humanin primarily neuroprotection + IGF-1 axis). The clinical “TRT + MOTS-c + Humanin triple stack” gaining adoption per source aggregates the androgen receptor + metabolic + STAT3/Bax/IGF-1 axes with no antagonism. Adding NAD+ precursors gives the mitochondrial-energy layer.
• Avoid (or sequence carefully) with GH-secretagogue protocols — humanin’s IGFBP-3 binding reduces free IGF-1, working against what CJC-1295, Ipamorelin, Sermorelin, Tesamorelin, and MK-677 are trying to accomplish. If your goal is GH-axis-mediated anabolism, this is mechanistic antagonism. If your goal is longevity with lower IGF-1 exposure, it’s an alignment.

Side effects

• Minor injection-site reactions (redness, mild swelling) — self-limiting.
• No serious adverse events reported at clinical doses in the existing literature.
• Long-term multi-year safety data does not yet exist.

Contraindications and cautions:

• STAT3-active malignancy. Humanin’s STAT3-activation mechanism overlaps with cancer survival signaling. Discuss with an oncologist.
• Pregnancy / breastfeeding — no safety data.
• Autoimmune disease + active immunomodulatory medications — medical oversight is genuinely useful here given the immune-modulation overlap.
• Rare mitochondrial-genome disorders — unpredictable MDP effects, formally unstudied.
• Low IGF-1 / GH-secretagogue stack — see stacking note above; flag explicitly for users running humanin alongside any Sermorelin / Tesamorelin / CJC-1295 / Ipamorelin / MK-677 protocol.

Regulatory status

Not FDA-approved for any indication. Sold as a research chemical. Not specifically on a major sport-doping prohibited list as of mid-2026 (humanin remains under-investigated in the WADA context).

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Peptide 2: ARA-290 (cibinetide)

What it is

ARA-290 is the prettiest piece of peptide engineering in this cluster. EPO (erythropoietin) does two things in the body via two different receptors: one path stimulates red-blood-cell production (the use everyone knows about, via the classical EPO receptor homodimer), and a separate, distinct path drives tissue protection (via a different receptor complex). Michael Brines at Araim Pharmaceuticals deconstructed EPO and built an 11-amino-acid synthetic peptide that activates only the tissue-protective receptor and leaves erythropoiesis alone.

The result: you get EPO’s neuroprotection, anti-inflammation, and small-fiber nerve regeneration without raising hematocrit, without thrombosis risk, without the cardiovascular and cancer concerns that come with full erythropoietic activity. This is what makes ARA-290 usable in sports contexts where EPO is banned, and what makes it a clean tool for diabetic and sarcoidosis neuropathy.

How it works

• Innate Repair Receptor (IRR). A heterodimer of EPOR (erythropoietin receptor) + CD131 (the β common receptor, βcR). Distinct from the classical EPO receptor homodimer that drives red-blood-cell production. ARA-290 selectively activates the IRR.
• Small-fiber nerve regeneration — measured directly in trials via corneal nerve fiber density (CNFD), one of the hardest endpoints in this space.
• Anti-inflammatory cytokine modulation.
• Vascular protection without erythropoiesis — the entire point of the molecule.
• Mitochondrial protection in ischemia/reperfusion models.

What the research shows

Brines 2015 Mol Med — the cornerstone published RCT — PMID 25387363, PMC4365069. Title: “ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in Patients with Type 2 Diabetes.”

• Design: Double-blind, placebo-controlled Phase 2; investigator-initiated; Netherlands Trial Register NTR3858.
• Sample: n=48 randomized (24 ARA-290 + 24 placebo).
• Population: Type 2 diabetics with neuropathic symptoms; baseline HbA1c 7.3% (ARA-290) vs. 6.9% (placebo).
• Dose: 4 mg subcutaneous self-injection daily × 28 days.
• Duration: 28-day treatment + 28-day observation.

Outcomes:

Endpoint	ARA-290	Placebo	p-value
HbA1c day 28	−0.16%	−0.01%	p=0.002
HbA1c day 56	−0.21%	+0.21%	(continued improvement vs. reversal)
Cholesterol/HDL ratio	reduced	—	p=0.039
Triglycerides	decreased	—	p=0.043
PainDetect day 28	−3.3 pts	−1.1 pts	(significant)
PainDetect day 56	−4.2 pts	−0.74 pts	p=0.037
PainDetect tingling	improved	—	p=0.01
PainDetect allodynia	improved	—	p=0.04
Corneal nerve fiber density (subgroup)	+2.6 ± 1.0 fibers/mm²	+0.7 ± 1.3 (ns)	p=0.02
RAND-36 vitality	improved	—	p=0.02
RAND-36 physical role functioning	improved	—	p=0.05

Two methodological details worth pulling out:

• Symptom-density correlation: PainDetect improvement tracked with the corneal-nerve-fiber-density increase in the ARA-290 group but not the placebo group. That’s mechanistic + clinical congruence — the nerve regeneration explains the symptom improvement, not just a placebo response.
• Anti-drug antibodies negative at baseline and day 28. No immunogenicity signal at 28 days, which is the kind of null result that matters for a peptide drug.

Earlier sarcoidosis trial — double-blind 4 mg ARA-290 SubQ daily × 28 days in sarcoidosis-associated small-fiber neuropathy showed SFNSL score decrease of 9.1 ± 8.5 points plus increased small-nerve-fiber density. This trial is the basis for ARA-290’s FDA Orphan Drug designation for neuropathic pain in sarcoidosis.

Other preclinical contexts (cited in Brines 2015): diet-induced insulin resistance, diabetic retinopathy, diabetic autonomic neuropathy (Akita mice), myocardial infarction + chronic heart failure, traumatic brain injury, burns, shock-induced multi-organ failure.

Safety — the honest version

Brines 2015 reported AE breakdown:

• ARA-290: 54 mild + 9 moderate + 1 severe + 4 serious adverse events (SAEs)
• Placebo: 61 mild + 5 moderate

The four ARA-290 SAEs deserve transparent reporting:

1. Renal insufficiency — patient on furosemide with borderline baseline renal dysfunction; creatinine rose from 119 → 159 μmol/L after week 2; judged “possibly related”; renal function did not improve after ARA-290 was stopped while furosemide continued.
2. Cellulitis + fatal MI — 70-year-old male developed severe lower-extremity cellulitis ~2 weeks after his last dose and suffered a fatal myocardial infarction; adjudicated “unrelated” to ARA-290. 3–4. Two additional SAEs judged “unlikely” associated.

Even adjudicated as “unrelated” or “possibly related,” the fatal MI in a 70-year-old participant is the kind of event we report honestly — not to scare people away from the molecule, but because the credibility of OHM editorial is the transparency. The molecule did Phase 2 trials, it had four SAEs in a 24-person arm with one possibly-related, and the data is published in full. That’s the honest read.

• No clinically significant changes in hematology or chemistry vs. baseline.
• No immunogenicity signal at 28 days.

Real-world protocol

The doses and schedules here are for educational and informational purposes only. These peptides are sold for research use only and are not FDA-approved drugs. This is not medical advice. Consult a qualified physician before beginning any protocol.

• Trial-validated dose: 4 mg subcutaneous daily × 28 days (the dose from Brines 2015 and the sarcoidosis trial).
• Reconstitution example: a 4 mg vial + 1 mL bacteriostatic water = 4 mg/mL. A 4 mg dose = 1 mL = 100 units on a U-100 insulin syringe (a full syringe).
• Anti-aging / nootropic anecdotal dosing: 0.5–1 mg SubQ daily, or 1–2 mg every other day, is the community range — well below the trial dose and not formally validated.
• Route: SubQ self-injection (validated by trial).
• Storage: refrigerated; reconstituted with bacteriostatic water; ~30-day post-reconstitution window.
• Cycle: 28-day blocks are the trial-validated pattern. Extended dosing past 28 days lacks published data.

Regulatory status

• FDA Orphan Drug designation for neuropathic pain in sarcoidosis — a real regulatory advance, well past “research chemical” status.
• Phase 2 trials completed in sarcoidosis SFN and Type 2 diabetes neuropathy.
• Not yet Phase 3 / not yet FDA-approved for general use.
• Not WADA-banned — the non-erythropoietic engineering is the entire point and makes ARA-290 usable in sports contexts where EPO is prohibited.
• Conflict-of-interest disclosure (per Brines 2015): Brines, Dunne, Cerami are officers of Araim Pharmaceuticals and own stock. Funding included Dutch government grant NIRM FES0908, the Swedish Research Council ALF, and the Swedish Diabetes Association. Mixed industry + government-funding profile, disclosed transparently.

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Where experts disagree

• Humanin’s clinical readiness: the longevity-medicine camp treats the centenarian epi + Bax + STAT3 + C. elegans lifespan data as a strong reason to use humanin proactively. The conservative-medicine camp points to zero completed Phase 2/3 trials and pushes back. Both are looking at the same evidence base; the disagreement is about whether 500+ mechanistic publications + striking epi data + a clean animal record clears the bar for informed adult use. OHM’s read: it’s first-class preclinical + epidemiology evidence, the human-trial layer is what’s missing, and that distinction belongs in the article rather than in the conclusion.
• ARA-290 dosing at the low end: the trial-validated dose is 4 mg/day × 28 days. The biohacker community uses 0.5–1 mg/day continuous as a “longevity / nerve maintenance” dose. There’s no published data backing the low end; the community pattern is extrapolation. The trial dose is what was actually tested.
• The SS-31 / Humanin / MOTS-c / ARA-290 categorization: different sources cluster these differently. We sit them together as “endogenous protection” because all four are signals your cells already use (or were engineered from); other taxonomies split them by tissue (CNS vs. nerve vs. metabolic) or by origin (mitochondrial-derived vs. engineered-from-protein). The cluster framing is editorial, not biological law.

Where this cluster sits in the OHM map

Peptide	Role	Status in catalog
MOTS-c	Mitochondrial-derived; metabolic / insulin sensitivity	In Alyve catalog
Humanin	Mitochondrial-derived; CNS / longevity / IGF-1 axis	Not in current launch catalog — roadmap
ARA-290	Engineered from EPO tissue-protective domain; peripheral nerve repair	Not in current launch catalog — roadmap; FDA Orphan Drug for sarcoidosis SFN
SS-31 / elamipretide	Mitochondrial-TARGETED ROS scavenger; FDA-approved for Barth syndrome	; not in Alyve launch — separate pharmaceutical lane

Two of the four are mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA: humanin and MOTS-c. SS-31 is mitochondrial-targeted (it accumulates in the inner mitochondrial membrane), but it’s not mitochondrial-derived. The DERIVED vs. TARGETED distinction matters mechanistically and is worth flagging.

The Alyve product (commercial layer)

Humanin — not in Alyve’s current launch catalog — flagged as a roadmap candidate. Strong longevity-customer-cluster fit (overlaps with MOTS-c and NAD+ audiences already in catalog). HNG potency makes the cost-per-effective-dose math attractive. The IGF-1-reduction mechanism + STAT3-cancer caution are the safety surfaces to handle transparently when added.

ARA-290 — not in Alyve’s current launch catalog — flagged as a strong roadmap candidate. This is the cleanest catalog-expansion candidate in the whole non-Alyve-15 universe: FDA Orphan Drug designation + a published placebo-controlled Phase 2 RCT with significant outcomes (HbA1c, PainDetect, CNFD) + transparent SAE reporting + a non-erythropoietic profile that sidesteps the EPO regulatory baggage. The diabetic-neuropathy use case overlaps directly with the Retatrutide / GLP-1 / Type-2-diabetes customer cluster.

While you wait — what’s available now. The clinical “TRT + MOTS-c + Humanin” longevity triple stack uses one Alyve SKU today (MOTS-c) plus testosterone (separate market) and humanin (not yet stocked). The cluster-adjacent path that is fully available now: MOTS-c for mitochondrial / metabolic, NAD+ for cellular energy / NAD+ pool, and the CJC-1295 / Ipamorelin axis for GH/IGF-1 support — with the explicit note that adding humanin later will blunt the IGF-1 side of any GH-secretagogue stack.

The trust story that applies to all of this. Independent gray-market peptide testing has consistently found roughly 1 in 4 vials underdosed, mislabeled, or contaminated. Alyve answers that with US manufacturing + third-party Freedom Diagnostics COAs + verified >99% purity across the catalog. When humanin and ARA-290 enter the catalog, they’ll sit inside that same verified-supply system.

Use code OHM-15 for 15% off — Alyve’s pricing is very competitive, and buying 3 vials of any given peptide in one purchase gets you over 30% off retail. Today the practical bulk-stack play for this cluster’s audience is 3 vials of MOTS-c for the mitochondrial layer plus the NAD+ precursor lane.

Sources

• the source digest behind this entire article.
• Primary literature anchors: Brines et al. 2015 Mol Med, PMID 25387363, PMC4365069 (ARA-290 RCT — secured).: Hashimoto et al. 2001 Science (humanin discovery); centenarian epi (Cohen group likely); C. elegans 40–60% lifespan extension; HNG/S14G 1000× potency characterization; sarcoidosis SFN trial (basis for FDA Orphan Drug).
• cluster-level grading baseline.
• verified-supply baseline for the cluster-adjacent SKUs that are in catalog.

Related: MOTS-c · NAD+ · Retatrutide · CJC-1295 / Ipamorelin · Ipamorelin · Sermorelin · Tesamorelin.