Defining the role of mitochondrial hydrogen sulfide in healthspan extension in C. elegans
Abstract
Hydrogen sulfide (H2S) is emerging as a fundamental gaseous mediator of multiple physiological processes controlling health and disease but yet remains understudied. For example, while exogenous H2S extends lifespan in the nematode Caenorhabditis elegans, the effect of H2S on the more functionally relevant healthspan and the underpinning molecular mechanisms remain unknown. Our preliminary data shows that, at nanomolar concentrations, mitochondria-targeted H2S (mtH2S) extends both healthspan and lifespan in C. elegans, and that this associates with preserved mitochondrial structure across the lifecourse. Available published in vitro data further support the mitochondrion as the primary mechanistic site of H2S. Given the central role of mitochondrial function in maintaining physical health, mtH2S may represent an attractive therapeutic strategy for maximising and prolonging performance capacity in high performing (e.g. soldiers, athletes) and diseased (e.g. ageing, muscular dystrophy) individuals. The objectives of this proposal are, therefore, to: i) establish how mtH2S affects health and functional performance in young adulthood and across age, ii) determine the precise mechanisms by which H2S affects health and performance and, iii) establish the role of alternate mtH2S delivery approaches for promoting health and functional performance. To achieve these objectives, we will first titrate dosing of mtH2S to verify healthspan extension using our novel automated, microfluidic C. elegans healthspan device to assess a battery of behavioural indices, combined with analysis of mitochondrial structure, content and respiratory function. Administering mtH2S at various stages of the lifecourse will further determine the timings of H2S action and the optimal window for H2S treatment. Secondly, to establish the precise underlying mechanisms, we will perform detailed pharmaco-genetic studies (drug treatments plus combinations of tissue-specific RNAi/ mutants) against all mitochondrial, and non-mitochondrial targets of H2S. Finally, using the above methods, we will test our recently developed panel of alternate mtH2S delivery compounds for efficacy in healthspan extension whilst simultaneously informing further on the mechanisms by which mtH2S improves performance. Results from these experiments will establish the in vivo relevance of H2S for increasing physical capacity, and for extending the period of time that individuals remain functional during age. Additionally, because the mechanisms of H2S metabolism are highly conserved between invertebrates and people, the findings from this work may ultimately promote health and performance maintenance in human populations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 01, 2019
- Source ID
- W911NF1910235
Entities
People
- Tim Etheridge
Organizations
- Army Contracting Command
- United States Army
- University of Exeter