Humanin and Age-Related Diseases: A New Link?

Abstract

Humanin (HN) is 24-amino acid mitochondria-associated peptide. Since its initial discovery over a decade ago, a role for HN has been reported in many biological processes such as apoptosis, cell survival, substrate metabolism, inflammatory response, and response to stressors such as oxidative stress, ischemia, and starvation. HN and its potent analogs have been shown to have beneficial effects in many age-related diseases including Alzheimer’s disease, stroke, diabetes, myocardial ischemia and reperfusion, atherosclerosis, amyotrophic lateral sclerosis, and certain types of cancer both in vitro and in vivo. More recently, an association between HN levels, growth hormone/insulin-like growth factor-1 (GH/IGF axis), and life span was demonstrated using various mouse models with mutations in the GH/IGF axis. The goal of this review is to summarize the current understanding of the role of HN in aging and age-related diseases.

Mitochondrial function in hypoxic ischemic injury and influence of aging

“…We found significant upregulation of genes involved in glycolytic pathways in cardiomyocytes subjected to hypoxia demonstrating a shift in energy production from mitochondria to glycolysis (Jian et al , 2011b). Recently it has been found that humanin, a mitochondria derived peptide, exhibits strong cytoprotective actions against various stress and disease models and suggested to be part of a retrograde signaling that involves nuclear-mitochondria crosstalk (Gong et al , 2014). This inter-organelle communication is important in the mitochondrial response to hypoxic-ischemic conditions, whether induced by stroke, myocardial-infarction or sepsis.…”

The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice

“…The extracellular actions of humanin are largely mediated through its cell membrane receptors (16 -17). Humanin has potent neuroprotective (18), antiapoptotic (19), and IGFBP3-binding (20) cytoprotective effects with broad-spectrum actions on the brain, pancreas, heart, and testis (21)(22). Eriksson and colleagues (23) recently showed that cotreatment of a potent humanin analog HNG with a proteasome inhibitor bortezomib was effective in preventing bortezomib-induced bone growth impairment without interfering with bortezomib's anticancer effects in immune deficient nude mice.…”

Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome

“…Within a cell, HN binds to and interferes with a number of pro-apoptotic signaling molecules including Bax and Bid, to suppress cytochrome c release and inhibit the apoptotic pathway [284]. HN is also secreted, with measureable levels detected in plasma, cerebrospinal fluid, and seminal fluid [285]. When secreted outside the cell, HN exerts its effects by binding to specific trans-membrane receptors.…”

“…HN and its analogs have also been found to play a cytoprotective role in a number of other diseases, especially those that are age related and/or involve oxidative stress and mitochondrial dysfunction [285], including: cardiovascular disease (CVD); stroke; inflammation; and type 2 diabetes. Interestingly, HN levels have been found to be considerably elevated in skeletal muscles of patients with two diseases caused by mtDNA abnormalities: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [286], and chronic progressive external ophthalmoplegia [278].…”