Ameliorating age-related immune deficiencies and promoting disease-free longevity through epigenetic control

Epigenetic regulation plays a crucial role in maintaining homeostasis by fine-tuning gene expression. As we age, epigenetic patterns become deregulated, contributing to age-related conditions such as senescence, metabolic disorders (e.g. diabetes, atherosclerosis), immune dysfunction, and cancer, which collectively decrease life expectancy and quality of life in the elderly. Histone deacetylases (HDACs), enzymes that remove acetyl groups from lysine residues thus promoting chromatin condensation, are key regulators of gene expression and their activity contributes to age-related deficiencies in homeostasis. HDAC inhibitors offer potential to reverse aging by restoring health-promoting and anti-senescence acetylation patterns, improving both cellular and systemic functions and alleviating the aging process. Our previous research demonstrated that HDAC inhibition has strong immunomodulatory effects in aging mice where it is able to revitalise the immune response, and potentially overcome immune related senescence. Specifically, enhanced MHC I and II expression, increased activity of immune cells and infiltration into the tumour microenvironment. This project will investigate the effects of clinical HDAC inhibitors on immune aging, with a focus on restoring healthy immune responses and protection against cancer and age-related diseases, both in vitro and in vivo. The DPhil student will be trained in cutting-edge molecular, biochemical, genomic, bioinformatic and immunological techniques including but not limited to ChIP-seq, single cell RNA seq, CRISPR/Cas9 gene editing, flow cytometry, and ELIspot.

Liu G, Barczak W, Lee LN, Shrestha A, Provine NM, Albayrak G, Zhu H, Hutchings C, Klenerman P, La Thangue NB. The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity. Commun Biol. 2023 Jan 26;6(1):102.

Blaszczak W, Liu G, Zhu H, Barczak W, Shrestha A, Albayrak G, Zheng S, Kerr D, Samsonova A, La Thangue NB. Immune modulation underpins the anti-cancer activity of HDAC inhibitors. Mol Oncol. 2021 Dec;15(12):3280-3298.