Roles for endogenous aldehydes in haematopoietic ageing and immunity

Thesis

Formaldehyde is a fundamental driver of genomic instability. This has led to the evolution of a two-tiered defence system that engages metabolic detoxification (“tier-1” via ALDH2 and ADH5) and DNA repair pathways (“tier-2” via Fanconi’s anaemia repair (FA) and transcription coupled repair). Strikingly, ~540 million people of East Asian descent carry a variant in the ALDH2 allele (ALDH2*2), which impairs tier-1 protection. When these carriers also incur mutations in ADH5 or FA repair, they develop significant disease, characterised by leukaemia, bone marrow failure, developmental abnormality and shortening life span. Given this predisposition, the high prevalence of ALDH2*2 is surprising, suggesting this allele has evaded selection by conferring an underappreciated selective advantage, or that its effects become significant only over time. In this thesis, I explore whether ALDH2 deficiency may confer a selective advantage through enhancing humoral immunity. I compare the humoral immune response of Aldh2^-/- mice to model antigens (HEL, OVA, BSA and HA), finding ALDH2-deficiency influenced humoral immunity in an antigen dependent manner, which may be significant in helping ALDH2*2 carriers to resist certain infections. I also investigate how tier-1 deficiency drives ageing in the blood. An existing model of tier-1 deficiency, Aldh2^-/-Adh5^-/-, shows features of accelerated ageing, including cell-fate bias and somatic mosaicism, but its extreme perinatal lethality prevents its use to study ageing as a time-dependent process. To address this, I use Vav1iCre to delete ALDH2 specifically in the blood of Adh5^-/- mice. This rescued the peri-natal lethality, and revealed features of haematopoietic ageing, though without clonal haematopoiesis. Together, these models demonstrate that endogenous formaldehyde can drive instructional changes on stem cell fate, providing insight into how endogenous formaldehyde may act as a fundamental driver of ageing. This work has significant implications for understanding mechanisms of ageing and disease in the 540 million individuals with compromised tier-1 protection.

Authors: Beaven, O

• DOI: 10.5287/ora-expnowzrb
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: ageing; formaldehyde; haematopoiesis; aldehyde; immunity
• Subjects: Molecular biology; Hematology; Physiology