About the Project
Caloric restriction (CR) is one of the only known interventions that improve health span and life span1. Graded (10–, 20– and 40% reduction) CR (GCR) reveals a linear improvement in metabolic benefits1. Identification of the elusive molecular mechanisms underpinning this graded phenomenon may reveal fundamental biological ageing processes and ultimately illuminate novel therapeutic targets for age-related diseases. Elevated production of the endogenous gaseous signalling molecule sulfide (H2S) appears to be required for the beneficial metabolic effects of CR, particularly those manifested in the liver1, 2. We identified the mitochondrial H2S clearance enzyme thiosulfate sulfur–transferase as an adipose tissue–enriched genetic driver of healthy leanness in mice3, however, TST is most highly expressed in liver (>20X adipose tissue levels). Mice lacking TST (Tst–/– mice) have markedly elevated circulating sulfide levels3 and exhibit certain CR mimetic phenotypes (increased hepatic glucose production, peripheral insulin sensitisation and improved vascular function).
We hypothesise that elevation of endogenous sulfide through TST deficiency may enhance the effects of CR, reducing the grade of caloric restriction at which maximum metabolic benefit is achieved1. To test this the project will subject adult Tst–/– mice, and mice with liver-specific Tst knockout or over–expression (theoretically graded hepatic H2S exposure: GH2S) to 5 weeks GCR; the point of phenotypic equilibration1. The effects of GCR/GH2S on energy expenditure (indirect calorimetry, doubly–labelled water), fat and lean mass (TD-NMR) and metabolic health (glucose, lipid and insulin homeostasis) will be assessed. Genetic GH2S will be compared to exogenous pharmacological sulfide donor administration (NaHS and mitochondrially–targeted Ap39). To identify cellular mechanisms linked to improved hepatic function and metabolic health we will create a hepatic persulfidome (H2S–mediated post-translational modification) matrix across the GCR/GH2S intervention spectrum. Thus, we will gain insight into the molecular basis whereby optimal H2S elevation augments hepatic metabolism and whole organismal health–span.
References
The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome. Derous D, Mitchell SE, Wang L, Green CL, Wang Y, Chen L, Han JJ, Promislow DEL, Lusseau D, Douglas A, Speakman JR.
Aging (Albany NY). 2017 Jul 31;9(7):1770-1824. doi: 10.18632/aging.101269.
Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Treviño-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR.
Cell. 2015 Jan 15;160(1-2):132-44. doi: 10.1016/j.cell.2014.11.048. Epub 2014 Dec 23
.Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness.
Morton NM, Beltram J, Carter RN, Michailidou Z, Gorjanc G, McFadden C, Barrios-Llerena ME, Rodriguez-Cuenca S, Gibbins MT, Aird RE, Moreno-Navarrete JM, Munger SC, Svenson KL, Gastaldello A, Ramage L, Naredo G, Zeyda M, Wang ZV, Howie AF, Saari A, Sipilä P, Stulnig TM, Gudnason V, Kenyon CJ, Seckl JR, Walker BR, Webster SP, Dunbar DR, Churchill GA, Vidal-Puig A, Fernandez-Real JM, Emilsson V, Horvat S.
Nat Med. 2016 Jul;22(7):771-9. doi: 10.1038/nm.4115. Epub 2016 Jun 6. Erratum in: Nat Med. 2018 Apr 10;24(4):525.
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