Humanin vs Klotho
A neutral, side-by-side comparison of two anti-aging & longevity peptides — their mechanisms, dosing ranges, administration routes, side effects, and research evidence. For research and educational purposes only.
Humanin
Humanin is a 21-amino acid mitochondrial-derived peptide (MDP) encoded within the 16S ribosomal RNA gene of the mitochondrial genome — discovered in 2001 through a screen for neuroprotective factors in Alzheimer's disease. It is the founding member of a new class of peptide hormones encoded by mitochondria, not nuclear DNA. Circulating humanin levels decline sharply with age and are inversely correlated with cardiovascular disease risk, insulin resistance, and cognitive decline.
Full profileKlotho
Anti-aging protein discovered in 1997 whose deficiency causes a syndrome resembling accelerated aging across multiple organ systems. Circulating soluble klotho declines ~40% from age 40–80. Research into klotho-derived peptides and recombinant protein explores neuroprotection, cardiac protection, renal anti-fibrosis, and metabolic anti-aging benefits. The KL-VS polymorphism provides a natural human model of elevated klotho activity.
Full profile| Humanin | Klotho | |
|---|---|---|
| Category | Anti-Aging & Longevity | Anti-Aging & Longevity |
| Also known as | HN, HNG (Gly14-Humanin — more potent analog), Mitochondrial-derived peptide | α-Klotho, soluble Klotho, KL-VS, klotho protein, KL1 domain |
| Evidence | Research-stage | Research-stage |
| Dosing range | 100mcg–2mg mcg, Daily or 3–5x weekly | 1mcg/kg–10mcg/kg mcg/kg, every 3–7 days IV or SC (research) |
| Administration | Subcutaneous injection, Intranasal (for CNS applications), Intravenous (clinical studies) | Intravenous (research), Subcutaneous injection |
| Key side effects | Generally well-tolerated in animal studies, No significant adverse effects reported at research doses, Potential interaction with GH/IGF-1 axis (IGF-1 suppresses humanin production), Long-term human safety data limited | Hypophosphatemia (klotho inhibits FGF23 signaling → phosphate wasting), Hypocalcemia (secondary to phosphate effects), Altered vitamin D metabolism, Potential for altered mineral homeostasis with chronic administration |
| Cited sources | 3 references | 2 references |
Key differences
- Administration: Humanin — Subcutaneous injection, Intranasal (for CNS applications), Intravenous (clinical studies); Klotho — Intravenous (research), Subcutaneous injection.
- Dosing units differ: Humanin is dosed in mcg, Klotho in mcg/kg — they operate at different scales.
- Frequency: Humanin is typically Daily or 3–5x weekly; Klotho is every 3–7 days IV or SC (research).
- Research depth: this profile cites 3 sources for Humanin vs 2 for Klotho.
How each works
Humanin
Humanin acts through multiple receptors (CNTFR/WSX-1/gp130 trimeric complex and FPRL1) to exert neuroprotection, cardioprotection, and metabolic effects. Key findings: humanin inhibits neuronal apoptosis in Alzheimer's disease models by blocking IGFBP-3 death signaling, reduces cardiovascular disease markers in clinical studies, improves insulin sensitivity in diabetic models, and reduces oxidative stress. IGF-1 downregulates humanin production — individuals on GH/IGF-1 therapies may have suppressed endogenous humanin. Centenarians have elevated humanin levels compared to age-matched controls.
Klotho
α-Klotho functions as both a transmembrane co-receptor for FGF23 (regulating phosphate and vitamin D) and as a shed soluble circulating factor with FGF23-independent longevity effects. Soluble klotho activates longevity-associated pathways: Nrf2/antioxidant defense, FOXO transcription factors, and Wnt/TGF-β inhibition for anti-fibrotic effects. The klotho-deficient mouse ages rapidly and dies young; klotho-overexpressing mice live 20–30% longer.
This comparison aggregates public research and structured profile data for informational purposes only. It is not medical advice and does not recommend either compound for human use. Consult a qualified healthcare provider before considering any peptide.