Investigating the potential senomorphic properties of SCFA butyrate on aged T cells.

Paddison Rees, Nia (2024). Investigating the potential senomorphic properties of SCFA butyrate on aged T cells. University of Birmingham. M.Sc.

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Abstract

Ageing is accompanied by remodelling of the T cell pool and a hallmark of immune ageing is the expansion of senescent T cells in aged hosts. Senescent T cells express markers of DNA damage and cell cycle arrest markers, elevated production of pro-inflammatory cytokines as a result of the senescence-associated secretory phenotype (SASP), and accumulation of dysfunctional mitochondria. Importantly, animal studies have brought to light the causal role of senescent T cell accumulation in driving ageing of non-lymphoid organs; highlighting the need to combat the build-up of senescent T cells with advancing age.

Advancing age is also characterised by changes in gut microbiome composition, one consequence of which is a reduction in short-chain fatty acid (SCFA) levels, the products of bacterial fermentation in the gut. Interestingly, our group have reported a negative correlation between stool butyrate levels and senescent CD4 and CD8 T cells in older adults. To elucidate this connection further, in this thesis, we have examined the effect of butyrate on T cell senescent features in healthy young ( 35 years) and healthy old ( 65 years) adults using an in vitro model of proliferation-induced senescence.

Evaluation of the potential anti-senescent effect of butyrate revealed significant reductions in the cell cycle arrest maker p53 and DNA damage marker -H2AX in aged T cells following 3 day culture with 1mM butyrate. We observed potential senomorphic properties of butyrate mediated via attenuation of SASP post butyrate treatment in aged T cells, alongside reductions in the expression of a key SASP regulator, the transcription factor nuclear factor kappa B (NF-B) at both the gene and protein level. Additionally, our findings demonstrated the potential ability of butyrate to decrease mitochondrial mass and ROS production in the T cells of older adults, however this requires further investigation. Consequently, we present butyrate supplementation as a future senomorphic postbiotic treatment to delay the onset of the senescent phenotype and help reduce the healthspan-lifespan gap by combating immunesenescence.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):