It's all in the brain—2 neurons mediate increased life span upon various stressors in C. elegans

Abstract

Work in the nematode Caenorhabditis elegans has led to fundamental insights into key biological mechanisms of ageing, which may be instrumental to develop strategies to increase life span and, more important, health span in humans. Dietary restriction (DR) and its surrogate, mild impairment of nutrient sensing pathways (insulin/IGF and/or mTOR axes) by genetic manipulation in the presence of normal food intake are among the most thoroughly investigated interventions, leading to life span extension in yeast, worms, flies and mice [1]. Surprisingly, it was shown that the effect of dietary restriction depends on the presence of two neurons (ASI) in C. elegans, whose ablation completely abrogates the effect [2]. Energy deprivation following dietary restriction leads to increased mitochondrial respiration, and the resulting, moderate increase in reactive oxygen species formation seems to be instrumental for life span extension as well [3,4] due to a process called “mitohormesis” [5]. Accordingly, moderate disturbance of the mitochondrial respiratory chain by mild mutations in several subunits was shown to be another fountain of youth [6–8]. In this issue of Molecular Metabolism, the Ristow group is closing the circle: They show that low amounts of three bona fide inhibitors of complex I of the respiratory chain extend life and health span in the worm [9]. They also show that this mimics dietary restriction, since it does not further extend survival of dietary restricted animals, and that again the effect of these inhibitors is gone if the two ASI neurons had been ablated [9]. They conclude that redox stress sensing in these two neurons may be the signal for the rest of the body to activate the “survive program”. Interestingly, in the same line the Dillin group had shown before that genetic interference with the respiratory chain specifically in neurons activates a beneficial, mitochondrial unfolded protein response in distant tissues, postulating a diffusible, however still unidentified, “mitokine” [10]. There are numerous other examples showing that neurons are necessary for the life span extending effect of various genetic and dietary interventions, and finally even a small molecule, the antidepressant mianserin, inhibiting neuronal serotonin transmission, let live worms longer [11]. This and the recent study of the Ristow team raises hope that maybe also in humans, pharmacologic interventions – specifically aiming at neuro-endocrine signaling instead of targeting peripheral organs – may be available in the near future to treat ageing-related diseases.