Side-by-side · Research reference

ACE-031vsHumanin

Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.

APhase 2HUMAN-REVIEWED10/44 cited

BAnimal-StrongHUMAN-REVIEWED14/52 cited

ACE-031

ActRIIB-Fc Fusion · Phase 2 Halted

Phase 2Highest trial stage

2011Development halted

~58.4 kDaMolecular weightReichel 2025

SQ · Weekly dosing investigated

Humanin

Mitochondrial-Derived Peptide · Cytoprotective

24-AAPeptide lengthZhu 2022

mtDNAEncoded originZhu 2022 Shahzaib 2026

Bax/BimPrimary targetZhu 2022 Morris 2021

SQ · Experimental

01Mechanism of Action

Parameter

ACE-031

Humanin

Primary target

Myostatin, GDF11, activin A — TGF-β superfamily ligands

Intracellular: Bax, Bim, tBid (pro-apoptotic Bcl-2 family). Extracellular: FPRL1/2 G-protein-coupled receptorsZhu 2022 Lue 2021

Pathway

Soluble decoy receptor binds circulating myostatin/TGF-β ligands → prevents ActRIIB activation → SMAD2/3 pathway inhibition

Humanin binds Bax/Bim → inhibits mitochondrial outer membrane permeabilization (MOMP) → blocks cytochrome c release → prevents caspase activation → cell survival

Downstream effect

Disinhibition of myogenic signaling, increased skeletal muscle mass and strength

Suppression of apoptosis, mitochondrial stabilization, reduced oxidative stress, preservation of germ cells and neurons under stressZhu 2022 Lue 2021 Velentza 2024

Feedback intact?

—

Not applicable — peptide acts as anti-apoptotic signal, not hormonal axis

Origin

Recombinant fusion protein: human ActRIIB extracellular domain + IgG1-Fc fragmentReichel 2025

Encoded by short open reading frame in mitochondrial 16S rRNA gene (MTRNR2). 24-28 amino acids. 13 homologous variants (MTRNR2L1-L13) identified.Zhu 2022 Shahzaib 2026

Antibody development

—

Not reported in animal models

02Dosage Protocols

Parameter

ACE-031

Humanin

Clinical dosing

Weekly or biweekly SQ injections (exact doses undisclosed pre-halt)

Phase 2 DMD trial protocol not fully published.

—

Black market products

Variable purity; 12/14 tested products contained target protein plus contaminantsReichel 2025

SDS-PAGE revealed multiple protein bands; quality control absent.Reichel 2025

—

Evidence basis

Phase 2 trial discontinued — incomplete dataset

Animal models (rat, mouse)Huang 2025 El 2022 Velentza 2024

Half-life

Days to weeks (Fc-fusion typical kinetics)

IgG1-Fc domain confers extended circulation time.

—

Duration investigated

12–24 weeks (trial cut short)

—

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)

Duration

—

8–12 weeks in animal studies

Human data

—

None — no clinical trials reported

Analog (HNG)

—

Gly[14]-humanin — more potent variant

Substitution at position 14 enhances cytoprotective activity.

03Metabolic / Fat Loss Evidence

Parameter

ACE-031

Humanin

Direct fat loss evidence

—

None

Mechanism overlap

—

Mitochondrial health may indirectly influence metabolic efficiency, but no quantified effect

04Side Effects & Safety

Parameter

ACE-031

Humanin

Epistaxis (nosebleeds)

Significant incidence in Phase 2 DMD trial — primary safety signal

—

Telangiectasia

Dilated capillaries / spider veins observed

—

Vascular abnormalities

Mechanism: ActRIIB/ALK1 pathway disruption affects vascular homeostasis

—

Injection site reactions

Local erythema, induration (biologics class effect)

—

Antibody development

Potential for anti-drug antibodies (Fc-fusion proteins); incidence not reported

—

Black market contaminants

12/14 tested products contained multiple unidentified proteins alongside ACE-031Reichel 2025

—

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)

Reproductive safety

—

Protective in POI model (cyclophosphamide-induced), no adverse effects on fertility notedHuang 2025

Absolute Contraindications

ACE-031

·History of vascular disorders (epistaxis, telangiectasia, HHT)
·Pregnancy (TGF-β pathway critical for fetal development)
·Active malignancy (myostatin inhibition may affect tumour growth)
·Use of non-pharmaceutical grade ACE-031 (contamination risk)Reichel 2025

Humanin

·Unknown — no human data

Relative Contraindications

ACE-031

·Coagulation disorders or anticoagulant use (epistaxis risk)
·Hereditary hemorrhagic telangiectasia (HHT) family history
·Cardiovascular disease (vascular remodeling effects unknown)

Humanin

·Active malignancy (theoretical risk of anti-apoptotic effect on tumour cells)

05Administration Protocol

Parameter

ACE-031

Humanin

1. Pharmaceutical status

ACE-031 is not FDA-approved or commercially available. Phase 2 development was discontinued in 2011 due to safety concerns. Any ACE-031 on the black market is unregulated research chemical.

Intraperitoneal (IP) in animal models. Subcutaneous route untested. No human protocols exist.

2. Black market quality

12 of 14 tested black market ACE-031 products contained the target protein but also carried multiple unidentified protein contaminants detectable by SDS-PAGE. Two products contained no ACVR2B-immunoreactive material.Reichel 2025

Synthetic peptide reconstituted in sterile saline or PBS. No commercial formulation available.

3. Detection in sport

ACE-031 is prohibited under WADA S4.3 (Myostatin Inhibitors). Gel electrophoresis and Western blotting using ACVR2B-specific antibodies can detect the ~58.4 kDa protein in biological samples.Reichel 2025

Daily administration in animal studies. Optimal timing not characterized.

4. Clinical trial route

Phase 2 protocol used subcutaneous injections at weekly or biweekly intervals. Exact dosing protocols remain unpublished.

Lyophilised powder: -20 °C. Reconstituted: 4 °C, use within 7 days. Avoid freeze-thaw cycles.

5. Human use

—

No FDA approval, no IND, no clinical trials. Experimental research tool only.

06Stack Synergy

ACE-031

— no documented stacks

Humanin

+ MOTS-c

Multi-pathway

View MOTS-c →

Both 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