Humanin

Humanin is a 24-amino acid peptide encoded by the MT-RNR2 gene within the mitochondrial 16S ribosomal RNA region, making it one of the first identified mitochondrial-derived peptides (MDPs). Research suggests that humanin exerts its cytoprotective effects primarily through binding to two distinct receptor complexes. It interacts with the trimeric receptor composed of CNTFR (ciliary neurotrophic factor receptor), WSX-1, and gp130, activating downstream JAK2/STAT3 signalling cascades that promote cell survival and suppress apoptosis.

Humanin also binds to and neutralises IGFBP-3 (insulin-like growth factor binding protein-3) and BAX, a pro-apoptotic member of the Bcl-2 family. By sequestering BAX, humanin prevents its translocation to the mitochondrial outer membrane, thereby blocking the intrinsic apoptotic pathway — specifically the release of cytochrome c and subsequent caspase activation. This anti-apoptotic mechanism is particularly relevant in neurodegenerative contexts, where mitochondrial dysfunction and excessive neuronal apoptosis are central pathological features.

Additionally, studies indicate that humanin modulates cellular metabolism by improving mitochondrial function, reducing reactive oxygen species (ROS) production, and enhancing insulin sensitivity. Circulating humanin levels have been shown to decline with age in both animal models and human cohorts, leading to its investigation as a biomarker and potential therapeutic target in age-related diseases including Alzheimer's disease, type 2 diabetes, and cardiovascular pathology.

Humanin was discovered in 2001 by Nishimoto and colleagues during a functional expression screen of a cDNA library derived from the occipital cortex of an Alzheimer's disease patient. The researchers identified a short open reading frame within the mitochondrial genome that encoded a peptide capable of protecting neurons from amyloid-beta toxicity — a hallmark of Alzheimer's pathology. This discovery was groundbreaking because it demonstrated that the mitochondrial genome, previously thought to encode only 13 structural proteins, could produce bioactive peptides with signalling functions.

Subsequent research throughout the 2000s and 2010s revealed that humanin is part of a broader family of mitochondrial-derived peptides, including MOTS-c and SHLPs (Small Humanin-Like Peptides). Studies expanded beyond neuroprotection to demonstrate humanin's roles in metabolic regulation, cardiovascular protection, and cellular stress responses. Synthetic analogues such as HNG (S14G-humanin) were developed with enhanced potency — up to 1000-fold greater than native humanin — enabling more detailed mechanistic studies. Research has also established that circulating humanin levels correlate inversely with age and age-related disease burden, positioning it as both a potential biomarker of mitochondrial health and a research candidate for age-related conditions.