Objective Nowadays, ageing is one of the main problems in Western society. The increase in the percentage of elderly people serves to strain the Social Security to the point of bankruptcy. The only way to alleviate the suffering caused by age-related degenerative disease is to fully understand the underlying forces which drive ageing and design strategies to delay it. Mitochondria are considered as central modulators of longevity in different species. It has been proposed that free radicals cause the accumulation of oxidative damage and as a result ageing. In accordance with this, production of Reactive Oxygen Species (ROS) by complex I negatively correlates with longevity. However, the overexpression of antioxidants or the reduction of ROS levels does not increase lifespan. These contradictory data can only be reconciled if complex I is modulating longevity through a ROS independent mechanism. We have expressed the alternative internal NADH dehydrogenase 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. The expression of NDI1 does not change the level of ROS but increases both the ratio of NAD+/NADH and Drosophila longevity. The main objective of this proposal is to study the mechanisms by which complex I regulates longevity. My general hypothesis is that complex I regulates longevity through a ROS independent mechanism. I propose that complex I controls the cellular levels of NAD+/NADH, keeping their levels at an equilibrium that favours the optimal functioning of the cell. When the ratio is moved towards NADH ageing is promoted, whereas when it is moved towards NAD+ pro-survival pathways are activated. I proposed two specific mechanisms downstream of complex I that promote cellular longevity or senescence: 1) activation of sirtuins, which would increase genome stability and 2) reduction of methylglyoxal generation, which would decrease the accumulation of cellular garbarge . Fields of science natural sciencesbiological sciencesgeneticsgenomes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2010-StG_20091118 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution UNIVERSITY OF NEWCASTLE UPON TYNE EU contribution € 678 176,86 Address KINGS GATE NE1 7RU Newcastle Upon Tyne United Kingdom See on map Region North East (England) Northumberland and Tyne and Wear Tyneside Activity type Higher or Secondary Education Establishments Principal investigator Alberto Sanz Montero (Dr.) Administrative Contact Fiona Airey (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNIVERSITY OF NEWCASTLE UPON TYNE United Kingdom EU contribution € 678 176,86 Address KINGS GATE NE1 7RU Newcastle Upon Tyne See on map Region North East (England) Northumberland and Tyne and Wear Tyneside Activity type Higher or Secondary Education Establishments Principal investigator Alberto Sanz Montero (Dr.) Administrative Contact Fiona Airey (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data TAMPEREEN YLIOPISTO Participation ended Finland EU contribution € 813 423,14 Address Kalevantie 4 33014 TAMPERE See on map Activity type Higher or Secondary Education Establishments Administrative Contact Hannele Auffermann (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
