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Determination of evolutionary conserved genes that respond to reduced food intake through mitochondria signaling to affect aging

Final Report Summary - MITODR (Determination of evolutionary conserved genes that respond to reduced food intake through mitochondria signaling to affect aging)

Aging is a universal physiological process and the investigation of the signalling events that modulate aging is an intense area of research. As populations are aging worldwide, understanding the complex signal transduction networks that influence aging is essential for better management of age-dependent loss of autonomy and late-onset diseases. In the past decades, key studies have demonstrated that evolutionarily conserved genetic pathways specifically affect longevity. The fact that longevity is mediated by specific signalling pathway suggests that the key molecular events that affect aging could be targeted and/or mimicked by drug therapy. Dietary restriction is an external intervention that consists in a severely diminished food intake (reduction by 30 to 60 %) while maintaining vital levels of essential nutrients. In a large variety of species, dietary restriction results in:

i) life spans of up to twice as long as otherwise expected and
ii) resistance to age-related diseases.

Dietary restriction is an environmental intervention that extends the longevity of both invertebrates (yeast S. Cerevisiae, nematode C. elegans or fruit fly D. Melanogaster) and vertebrates (mouse, rat, monkey). Despite the extensive studies around dietary restriction in the last decades, the molecular actions of dietary restriction are still largely unknown. However, it is safe to bet that modifying the diet of an organism will tremendously affect its basic physiology such as reproduction and metabolism. In fact, over 70 years, numerous physiological consequences of dietary restriction have been reported. One of the challenges that we are facing today is to understand which of these modifications are responsible for the beneficial effects of DR Our project took advantage of the powerful genetic model C. elegans to identify new genes that mediate lifespan extension upon dietary restriction. To that extent we generated and compared two environmental manipulations that extend lifespan in C. elegans. A gene expression comparison in those two long-lived models allowed us to determine the common gene expression changes upon those two treatments. Our study revealed a list of new genes and signalling pathways that play a key role to extend lifespan in nematode without affecting other physiological aspects of the animal. Hence, our research led to the elucidation of new molecular actors of longevity pathways. A further characterisation of the molecular events revealed by our study will likely allow the development of therapeutic strategies that would mimic the beneficial effects of DR on longevity. From a public health perspective, there are great chances that it will participate to the development of therapies for aging related diseases at long term. The latter aspect will undoubtedly have important socio-economic consequences because it will significantly improve the quality of life of the elderly.