*3.4. Humanin Receptors and Regulation*

Humanin exerts its cytoprotective effects by binding to receptors intracellularly/extracellularly, regulating the intrinsic mitochondrial pathway, and mediating downstream signaling. Humanin binds to the Formyl-Peptide Receptor-Like Receptor-1 (FPRL-1) and the IL-6 (Interleukin-6) receptor family trimeric receptor complex, comprised of CNTFRα (Ciliary Neurotrophic Factor Receptor α), WSX-1, and GP130 (glycoprotein 130kDa), which are key contributors to the neuroprotective action of Humanin [31–33]. Substantial evidence suggests that mitochondrial retrograde signaling is involved in the endocrine regulation of aging and age-related pathologies. IGF-1 (Insulin Growth Factor-1) is a key player in the conserved endocrine pathway, which contributes to lifespan and healthspan. Humanin, a potent mediator of mitochondrial retrograde signaling, is directly regulated by IGF-1, and the levels of Humanin and IGF-1 simultaneously decline with age [34]. Humanin and IGF-1 are known to have distinct ye<sup>t</sup> overlapping functions. By interacting with the C-terminal domain of IGFBP-3 (Insulin-like Growth Factor Binding Protein-3), Humanin interferes with the binding of Importin-β to IGFBP-3, thereby suppressing IGFBP-3-mediated apoptosis [35]. Humanin regulates peripheral insulin action. In this study, peripherally administered HNGF6A in rats conferred insulin sensitivity via hypothalamic STAT3 (Signal transducer and activator of transcription 3) activation [29].
