AhR-mitochondria crosstalk in diet promoted longevity

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Aging is the most important risk factor for the development of neurodegenerative disorders and it is shaped by genetic and nutritional factors. Understanding the mechanistic aspects underlying the aging process will help extending healthy lifespan and reducing the heavy economic burden inflicted to our society to sustain the growing elderly population. Nutritional interventions may especially serve this scope by providing more malleable and feasible age-preventive approaches than genetic interventions.The nematode C. elegans is an elective model organism for aging studies and most evolutionarily conserved mechanisms regulating the aging process were first identified in this organism. One of these mechanisms is partial reduction of mitochondrial function. Of note, mitochondria are primarily involved in food metabolism. Reduced expression of the AhR transcription factor also provide evolutionarily conserved anti-aging effects. Although most research on AhR has focused on its role in mediating the toxic effects of high affinity ligands such as xenobiotics, low affinity natural compounds mainly derived from food are emerging as direct or indirect modulators of its activity. Few studies also suggested a role for AhR in modulating mitochondrial function. Interestingly, our preliminary data indicate that ahr-1 regulates C. elegans healthspan in a diet-dependent manner. Thus, the state of the art and our preliminary work provide a strong rationale for exploring the possibility that dietary components may delay neuronal aging acting through the interplay between mitochondria and the AhR. C. elegans represents a unique tool to investigate non-toxicological roles for ahr-1 in the nervous system as C. elegans AHR-1 does not respond to classic AhR ligand activators and its main function was so far described in neurons.To achieve the overall goal of this proposal we will: 1) Characterize the impact of ahr-1 deficiency on neuronal aging.2) Identify dietary components promoting healthy aging through AhR.3) Assess the role of AhR-mitochondrial crosstalk in diet promoted longevity.Based on the high conservation between nematode and human genes this project is expected to provide insight into possible future preventive therapeutic strategies aimed at extending healthy lifespan in human. Results obtained with our study will therefore directly impact on basic research, but will also eventually have repercussion on nutritional medicine and socio-economical aspects of our society.