Humanin

Overview

Humanin (HN) is a 24-amino-acid peptide first identified in 2001 by Hashimoto and colleagues in surviving neurons from the occipital cortex of a patient with Alzheimer's disease. Sequencing of the encoding transcript revealed something unexpected: the open reading frame lies within the mitochondrial 16S ribosomal RNA gene. Humanin was therefore the first known member of a class of mitochondrially-derived peptides (MDPs) — a class that has since grown to include MOTS-c and the SHLP family.

Beyond the unusual genomic origin, Humanin attracted attention because it protected cultured neurons from amyloid-β cytotoxicity at low-nanomolar concentrations. The original Hashimoto paper described a peptide expressed selectively in the neurons that had resisted Alzheimer's pathology, suggesting an endogenous neuroprotective role. Subsequent work has extended the picture: Humanin is expressed in multiple tissues, circulates in plasma, declines with age, and signals through both an extracellular G-protein-coupled receptor (FPRL1/FPR2 + CNTFR/WSX-1/gp130 complex) and an intracellular interaction with IGFBP-3 and pro-apoptotic Bax.

Humanin's emerging profile in longevity research is that of an inter-organellar stress-response signal: produced by mitochondria when they are challenged, released into circulation, and reducing the rate of cellular dysfunction in distant tissues. This page summarises the published evidence, the proposed mechanisms, and the safety and regulatory framing in the UK.

Mechanism of action

Three distinct mechanistic axes appear in the Humanin literature. The first is the extracellular receptor pathway: secreted Humanin binds a heterotrimeric receptor complex comprising the formyl peptide receptor FPRL1/FPR2, CNTFR and WSX-1/gp130, triggering downstream STAT3 phosphorylation. This pathway underlies many of the cytoprotective and anti-apoptotic effects reported in cell culture.

The second is intracellular: cytosolic Humanin interacts with the pro-apoptotic BH3-only proteins Bax, Bid and BimEL, inhibiting their translocation to the outer mitochondrial membrane and preventing release of cytochrome c. This provides a direct mechanism for the anti-apoptotic effects observed in models of neuronal stress.

The third is metabolic. Humanin sensitises target tissues to insulin and modulates hypothalamic appetite signalling. Intracerebroventricular administration of Humanin in rats lowers blood glucose and improves insulin sensitivity in liver and muscle, consistent with a role as a circulating metabolic stress-response signal. Plasma Humanin levels are reduced in type 2 diabetes and in chronic mitochondrial disease, supporting this interpretation.

Across these axes, Humanin appears to act as a 'mitokine' — a peptide released by stressed mitochondria that signals systemically to coordinate cellular and metabolic adaptation. Because mitochondrial function declines with age, the age-related fall in circulating Humanin is hypothesised to contribute to reduced stress resilience in older tissues.

Research history

Humanin was discovered in 2001 by Yuichi Hashimoto and Ikuo Nishimoto's group at Keio University, Tokyo, using a functional expression screen for cDNAs that protected neurons from amyloid-β toxicity. Subsequent identification of the genomic origin within the mitochondrial 16S rRNA gene reframed the field's understanding of mitochondrial genome coding capacity.

The 2000s saw rapid extension to multiple disease models — ischaemic stroke, Alzheimer's, type 2 diabetes, atherosclerosis — and identification of the S14G-Humanin (HNG) analogue, which is approximately 1,000-fold more potent than wild-type peptide and is the most commonly used research analogue. The Nir Barzilai group's 2014 paper linking elevated plasma Humanin to longevity in centenarian offspring re-positioned the peptide squarely within the longevity research agenda.

Summarised studies