Comparison
FOXO4-DRI vs. Humanin
Two peptides side-by-side — identity, evidence base, legal status and known adverse events.
Identity
Category
Research other
Research other
CAS no.
2074706-72-8
330936-69-1
Molecular weight
3735 g/mol
2687.27 g/mol
Half-life
0.5 h
no data
Sequence
D-Retro-Inverso-Variante eines FOXO4-Peptid-Fragments (LTLRKEPASEIAQSILEAYSQNGWANRRSGGKR — D-Aminosäuren in umgekehrter Sequenz)Met-Ala-Pro-Arg-Gly-Phe-Ser-Cys-Leu-Leu-Leu-Leu-Thr-Ser-Glu-Ile-Asp-Leu-Pro-Val-Lys-Arg-Arg-AlaMechanism of action
FOXO4-DRI
FOXO4-DRI is the D-retro-inverso variant of a peptide fragment of the FOXO4 transcription factor. In senescent cells, FOXO4 is bound to p53, which suppresses p53-mediated apoptosis — the cells survive in a secreting 'zombie-like' state (senescence-associated secretory phenotype, SASP). The DRI peptide disrupts this FOXO4-p53 binding, freeing p53, and the senescent cell initiates apoptosis. Healthy cells are largely unaffected because p53 is not held back by FOXO4 in them. This selectivity was the central finding of the original 2017 publication.
Humanin
Humanin arises from a short open reading frame within the 16S rRNA region of the mitochondrial genome (MT-RNR2) — it is therefore not encoded by nuclear DNA. Mechanistically, preclinical work describes a cytoprotective, anti-apoptotic effect via multiple pathways: an extracellular interaction with a trimeric receptor complex of gp130, CNTFR and WSX-1 with downstream activation of JAK2/STAT3 signalling, as well as intracellular interactions including inhibition of the pro-apoptotic protein BAX (and of tBID), binding to IGFBP-3 with modulation of the IGF-1 axis, and interaction with FPRL1/FPRL2 receptors. These models derive predominantly from cell culture and rodents; the extent to which they reflect human physiology after administration of exogenous synthetic humanin is not established by controlled human trials.
Evidence base
Highest evidence
Animal model
Human trial
Studies
3
4
of which in humans
0
1
Effects recorded
3
4
Open conflicts
1
1
Documented adverse events
1
0
Legal status
Full entries
Frequently asked questions
- What is the difference between FOXO4-DRI and Humanin?
- FOXO4-DRI is classified as "Research other", while Humanin is classified as "Research other". FOXO4-DRI: Synthetic peptide with D-Retro-Inverso structure (all amino acids as D-form, sequence reversed), developed in 2017 as an experimental senolytic candidate. Goal: selective apoptosis of senescent cells via disruption of the FOXO4-p53 interaction. So far evaluated exclusively preclinically. Humanin: Humanin is a 24-amino-acid mitochondrial-encoded peptide (mitochondrial-derived peptide, MDP) whose open reading frame lies within the 16S rRNA region (gene MT-RNR2) of mitochondrial DNA. It is considered the founding member of the MDP family and was discovered in 2001 by the Hashimoto/Nishimoto group while searching for neuroprotective factors in the brain of an Alzheimer's patient. In basic research (including the laboratory of Pinchas Cohen) humanin is described as a cytoprotective, anti-apoptotic peptide and is studied in the contexts of Alzheimer's/neuroprotection, metabolism/insulin action and aging. The evidence comes almost entirely from cell and animal models and from observations of endogenous levels in humans; controlled human trials of exogenous humanin as a therapeutic are lacking. It is not approved as a medicine anywhere and is traded on the grey market as a research chemical. This page contrasts both neutrally and source-based — with no usage or dosing recommendation.
- Which peptide is better supported by science, FOXO4-DRI or Humanin?
- The highest available evidence level is "Animal model" for FOXO4-DRI and "Human trial" for Humanin. A higher evidence level means more robust data, but says nothing about suitability for an individual. The full body of evidence is on each peptide's own page.
- What is the legal status of FOXO4-DRI and Humanin in Germany and the United States?
- Germany: FOXO4-DRI — Research only, Humanin — Unapproved. United States: FOXO4-DRI — Research only, Humanin — Research only. These are factual summaries with source and review date on the individual pages.