Universität zu Köln

Monzó Cataluña, Carolina ORCID: 0000-0002-5043-8145 (2022). The effect of Dietary Restriction on the Microbiome and the Adaptive Immune System in Mouse Ageing. PhD thesis, Universität zu Köln.

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Abstract

The human body is densely populated by microbes, and the interplay between microbiome and host physiology is important for health. During ageing, the composition of the microbiome changes and recent research in killifish and mice suggests that the intestinal microbiome might play a causal role in the determination of organismal lifespan. Dietary restriction (DR) and reduced activity of the insulin/IGF1 (IIS) and mTOR network increase lifespan and improve health in mice. However, whether changes in the microbiome induced by these longevity interventions contribute to the positive effects on survival is currently unknown. Ageing also negatively affects the adaptive immune system, but how longevity interventions affect the ageing adaptive immune system and whether amelioration of immune function contributes to the improved health of these animals is still not well understood. In my PhD thesis, I used a systems biology approach to address: (I) How does the intestinal microbiome and metabolome change in response to longevity interventions in mice. (II) Does DR affect the adaptive immune system during ageing in mice and is this associated with the increase in longevity upon DR. (I) In the first study, I performed a systematic longitudinal analysis of age-related changes in the faecal microbiome and metabolome of mice under DR. Furthermore, in order to identify changes in the microbiome that are common between longevity interventions, I analysed the microbiome of mice with reduced IIS and mTOR signalling. I show that DR mitigates age- related changes in microbiome community structure, including the decline in alpha diversity, increase in beta diversity, and loss of equilibrium between Firmicutes and Bacteroidetes phyla. Furthermore, by studying the faecal microbiome and metabolome of late-life DR switches that either increase or not increase lifespan, I identified an age-dependent memory of AL feeding in the microbiome associated with lifespan. Finally, I identified bacteria that were shared between DR, reduced mTOR and IIS signalling, suggesting that these bacteria may contribute to the health benefits observed in these long-lived mouse models. (II) In the second study, I analysed how DR affects the adaptive immune system during ageing. Therefore, I performed B cell receptor sequencing on spleen and intestine of mice during ageing and in response to DR to assess changes in the systemic and intestine-specific immune repertoire, respectively. Furthermore, as mice lose their responsiveness in lifespan to DR between 16 and 20 months of age, we also measured changes in the B cell repertoire in response to both diet switches, to identify changes in the B cell receptor repertoire that correlate with the longevity response. Interestingly, neither diet nor age had a strong influence on the B cell receptor repertoire of the intestine. In contrast, in the spleen, DR delayed the age-associated decline of within-individual spleen repertoire diversity and the increase in clonal expansions. Thus, DR-mediated longevity is characterised by the preservation of a more diverse spleen repertoire, which is less prone to clonal expansions. Importantly, I show that reduced within-individual diversity and increased clonal expansions are associated with increased pathology in these mice, suggesting that changes in B cell repertoire dynamics contribute to the health benefits of chronic DR treatment. This is further supported by the finding that mice that started DR at 16 months have spleen repertoire diversity and clonal expansion rates indistinguishable from chronic DR mice, whereas the switch to DR at 20 months was associated with milder effects, suggesting that the responsiveness of the adaptive immune system declines in mice between 16 and 20 months of age, which might contribute to the loss in lifespan extension of the late-life DR switch.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Monzó Cataluña, Carolina carolina.monzo.age@gmail.com orcid.org/0000-0002-5043-8145 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-701762
Date:	17 October 2022
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language ageing English B cells English Microbiome English
Date of oral exam:	17 October 2022
Referee:	Name Academic Title Partridge, Linda Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70176