Gene editing for therapeutic sulphide elevation to reverse accelerated ageing in vivo

Studentship strategic priority area:Basic and Clinical Research
Keywords:Ageing, metabolism, hydrogen sulphide, progeria, mitochondria

The number of people over 60 will rise from 12% (900M) to 22% (2Bn) of the total global population by 2050. Advancing age greatly increases all-cause mortality but we still know very little about the common underlying mechanisms. Therapeutic intervention for ageing remains one of the last great barriers in science. One emerging mechanism for slowed ageing is increased hydrogen sulfide (H2S) production, and we have recently shown that altered levels of the mitochondrial H2S-metabolising enzyme thiosulfate sulfur transferase (TST) associates with metabolic health. TST modulation represents a unique target for determining the impact of H2S, in particular within the mitochondria; organelles that appear to be critical players in ageing and pathology. This project will test the hypothesis that mitochondrially-targeted, therapeutic elevation of H2S through Tst deletion will reverse aspects of the rapidly ageing phenotype of Zmpste24-/- mice, a model of human progeria. The PhD will utilize a number of highly integrative cutting-edge techniques (CRISPR gene-editing, metabolic analysis, mass-spectrometry, mitochondrial functional analysis) to determine the role of H2S on ageing and disease.