Human Aging and Longevity Are Characterized by High Levels of Mitokines

Abstract

Mitochondrial stress elicits the production of stress response molecules indicated as mitokines, including FGF21, GDF15 and Humanin (HN). Many diseases are characterized by progressive mitochondrial dysfunction with alterations of mitokine secretion. It is still controversial whether healthy aging and extreme longevity are accompanied by altered production of mitokines. We analyzed FGF21, HN and GDF15 plasma levels in 693 subjects aged from 21 to 113 years, and the association of these mitokines with parameters of health status. FGF21, HN and GDF15 resulted increased in old age, with the highest levels found in centenarians. These molecules are associated with worsened parameters (such as handgrip strength, insulin sensitivity, total triglycerides), particularly in 70-year-old persons, and their levels are inversely correlated with survival in the oldest subjects. Considering the positive biological effect of these molecules, our results can be interpreted in the framework of the hormetic paradigm as an attempt of the cells/tissues to cope with a stress that can have beneficial or detrimental effects depending on its intensity. Finally, persons with Down Syndrome (characterized by accelerated aging) have higher levels of GDF15 and HN with respect to their siblings, suggesting that these molecules, especially GDF15, could be considered markers of biological age.

Humanin gene expression in fibroblast of Down syndrome subjects

“…Humanin (HN) plasma levels have been recently positively correlated with age in humans [3] (Conte et al, 2018). Interestingly, higher HN serum levels have been reported in DS subjects compared to normal control (NC) brothers [3]. Overall, this supports clinical observations that subjects with DS have an accelerated aging phenotype.…”

“…It did not differed for sex (p>0,05) or age (p>0,05). Conte et al (2018) [3] analyzed HN, FGF21, and GDF15 plasma levels in 693 subjects (whose age ranged from 21 to 113 years). They resulted to be increased in elderly, being particularly high in the centenarians.…”

“…They resulted to be increased in elderly, being particularly high in the centenarians. These molecules are associated with pathological physical and biochemical parameters (such as handgrip strength, insulin sensitivity and elevated triglycerides) [3]. It cannot be excluded a role for high cellular HN levels to compensate for the high production of free radicals.…”

“…Several biomarkers associated with aging have been identified in nervous system of DS persons [2]. Humanin (HN) plasma levels have been recently positively correlated with age in humans [3] (Conte et al, 2018). Interestingly, higher HN serum levels have been reported in DS subjects compared to normal control (NC) brothers [3].…”

Impact of modular mitochondrial epistatic interactions on the evolution of human subpopulations

“…However, the evolutionary behavior of mt-genome often involves cooperative changes within and between genes which are diffi-cult to detect using haplogroup analysis. For example, correlated mt-genome mutations were reported among different oxidative phosphorylation subunits, which were found to affect population specific human longevity (Raule, et al, 2014;Fan, et al, 2016;Giuliani, et al, 2018;Conte, et al, 2018). Besides, cooperative activities of both mitochondrial proteins and tRNA genes are critical for mt-genome evolution.…”