Universität zu Köln

Drews, Lisa Franziska (2021). Late-life effects of earlier dietary restriction on lifespan, health span and tissue- specific phenotypes. PhD thesis, Universität zu Köln.

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Abstract

Dietary restriction (DR), a reduction in food intake without malnutrition extends lifespan and improves health in animals ranging from yeast to rhesus monkeys. In mice, DR extends lifespan if the treatment is started early in life, however, late-onset treatment of 24 months old mice fails to extend lifespan, and it is currently not clear at which age mice become unresponsive to the DR treatment. Furthermore, the molecular mechanisms underlying late-life refractoriness to DR are currently elusive. In my PhD work, I have conducted a systematic analysis of DR switches at different ages in female mice. Mice were switched from ad libitum (AL) to the DR diet at 3, 12, 16, 20 and 24 months of age and their lifespan and health were subsequently assessed in comparison to chronic AL controls. Mice in which DR was initiated at 3 months of age showed the longest lifespan extension. Interestingly, however, initiation of DR at 12M and 16M of age almost fully recapitulated the lifespan extension with early life DR onset. In contrast, onset of DR at 20M and 24M led to only a slight lifespan increase compared to chronic AL feeding, suggesting that mice become unresponsive to DR-mediated lifespan extension between 16 and 20 months of age. Glucose metabolism, body composition, heart function and memory were improved by DR independent of the age of DR onset, suggesting that lifespan and health span can at least partially be uncoupled by the late life dietary switches. On the other hand, reduced tumour load and frailty as well as increased fitness and insulin sensitivity were correlated with the lifespan increase upon chronic or mid-life onset of DR. Noteworthy, liver tumour incidence, a major tumour type in these mice, was only reduced when the DR treatment was started at 3M and 12M but not at 16M of age, thus uncoupling liver tumour incidence from DR- mediated lifespan extension. Furthermore, I investigated tissue-specific, molecular effects of DR, in the white adipose tissue (WAT) and the small intestine, to identify mechanisms responsible for the lifespan differences. I observed increased macrophage infiltration in old AL WAT, suggesting that chronic DR prevents WAT inflammation during ageing. Interestingly, DR switch groups exhibited increased macrophage infiltration four months post-switch to DR, which resolved upon longer DR duration, suggesting increased clearance of apoptotic or maladaptive adipocytes during post switch WAT remodelling. Additionally, DR onset at 16 or 20 months induced transcriptional reprogramming in the WAT but the expression profiles failed to reach chronic DR levels even after long-term treatment, indicating a retained memory of prior AL feeding in the WAT. Moreover, DR and DR switch mice displayed shorter colon lengths and reduced hypodense Paneth cell granules in the small intestine at old age compared to chronic AL animals, indicating that DR improved intestinal health and plasticity irrespective of the age of onset. However, late-onset DR did not improve the outgrowth capacity of intestinal organoids, potentially due to an inability to adapt to in vitro full feeding conditions after DR was initiated. In conclusion, I discovered that DR differentially affects lifespan and health span depending on the age of DR onset in mice. Initiation of DR within the DR responsive period at 3, 12 or 16 months of age reverses the detrimental effects of previous AL feeding and improves survival and overall health at old age. In contrast, late-life initiated DR at 20 or 24 months has only limited beneficial effects as mice were mostly unresponsive towards the newly imposed dietary intervention. In the future, we aim to further characterize the underlying mechanism of DR- mediated lifespan and health span extension with the prospect of a therapeutic potential for healthy ageing in humans.

Item Type:	Thesis (PhD thesis)
Translated abstract:	Abstract Language UNSPECIFIED English
Creators:	Creators Email ORCID ORCID Put Code Drews, Lisa Franziska lisa.drews@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-610924
Date:	2021
Place of Publication:	Köln
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 Dietary restriction English Lifespan English Health span English Mice English
Date of oral exam:	7 June 2021
Referee:	Name Academic Title Partridge, Linda Professor Kloppenburg, Peter Professor
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/61092