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 (AD), stroke, diabetes, myocardial ischemia and reperfusion (MI-R), atherosclerosis, amyotrophic lateral sclerosis (ALS) 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.

Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.

Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate and plays an essential role in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). The dysfunction of Complex II not only limits mitochondrial energy production; it may also promote oxidative stress, contributing, over time, to cellular damage, aging, and disease. Intriguingly, succinate, the substrate for Complex II which accumulates during mitochondrial dysfunction, has been shown to have widespread effects as a signaling molecule. Here, we review recent advances related to understanding the function of Complex II, succinate signaling, and their combined roles in aging and aging-related diseases.

Rationale: Although obesity has been associated with asthma, body mass index is suboptimal to fully characterize adiposity. Objectives: We examined the relation between adiposity and asthma in a large sample of the U.S. population, using indices defined by dual-energy X-ray absorptiometry. Methods: We analyzed data from 8,886 children (aged 8–19 yr) and 12,795 adults (aged 20–69 yr) from the 2001 to 2006 National Health and Nutrition Examination Survey. In addition to body mass index, percent body fat, waist circumference, and waist-to-height ratio, dual-energy X-ray absorptiometry was used to calculate whole-body and local adiposity indices: fat mass index; total, trunk, and legs percent fat; and trunk-to-total fat mass ratio, legs-to-total fat mass ratio, and trunk-to-legs fat mass ratios. Logistic regression was used for the analysis of adiposity measures and asthma. Results: Among children, general adiposity was significantly associated with asthma, with no major differences by sex. Results were driven by nonatopic children, in whom trunk-predominant (central) adiposity (assessed by waist circumference, waist-to-height ratio, trunk-to-total fat mass ratio, and trunk-to-legs fat mass ratio) was also associated with asthma. There were no significant associations among atopic children. Among adults, all adiposity indices were associated with asthma, with central adiposity significant only among women. The results in adults were driven by atopy, especially in women. Conclusions: Adiposity measured by dual-energy X-ray absorptiometry provides similar information to that obtained by using anthropometric indices among children of both sexes and among adult men. However, dual-energy X-ray absorptiometry provides additional information in adult women, in whom dual-energy X-ray absorptiometry–measured central adiposity is significantly associated with asthma, particularly atopic asthma.