Universität zu Köln

Gkioni, Lisonia (2023). Dietary and pharmacological interventions to improve mammalian healthspan and lifespan. PhD thesis, Universität zu Köln.

All available versions of this item

• Dietary and pharmacological interventions to improve mammalian healthspan and lifespan. (deposited 06 Dec 2023 11:31) [Currently Displayed]

PDF KUPS_Thesis_LG_editted_final_version_.pdf - Accepted Version Download (14MB)

Abstract

Advances in the field of ageing over recent years have led to the discovery that pharmacological and dietary interventions can slow the ageing process. Genetic alterations to the insulin/insulin-like growth factor (IGF) signalling (IIS) and mechanistic target of rapamycin (mTOR) network in multiple organisms have provided promising targets for pharmacological interventions. mTOR inhibition by rapamycin robustly extends lifespan and is associated with marked health improvements in multiple model organisms. Similarly, pharmacological manipulation of Ras signalling by trametinib prolongs lifespan in flies, and treatment with a combination of trametinib, rapamycin and lithium induced an additive increase in fly lifespan. However, whether trametinib alone or in combination with rapamycin can also extend mouse lifespan is currently unknown. Although combinatorial drug treatments hold great promise to maximise longevity, and potentially to reduce drug dosage and hence side-effects, to date, the most effective environmental intervention known to extend healthy lifespan in various animal species is Dietary Restriction (DR). DR alleviates a plethora of age-related pathologies, including immune dysregulation with age. The adaptive immune system is highly sensitive to DR feeding and DR delays age-associated T-cell immune senescence. Nevertheless, the impact of DR on B-cell immune responses, and whether the improved health and lifespan of DR mice can be attributed to some extent to enhanced B-cell immunity under DR, remain largely unexplored. My PhD thesis first explores the potential of a novel pharmacological intervention to promote mouse healthy ageing. Second, the work elucidates the role of adaptive immunity as a contributor to the benefits of a robust dietary intervention on mouse health and longevity. Specifically the thesis work addresses the following: (I) Does trametinib administration extend lifespan in mice and is there an additive effect by combining trametinib and rapamycin on mouse health and/or longevity. (II) Does B-cell immunity change in response to DR and could these changes contribute to the increased health and lifespan under DR.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Gkioni, Lisonia lisonia.gkioni@age.mpg.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-717951
DOI:	10.1016/j.celrep.2023.112722
Date:	25 July 2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language Drug treatments, lifespan expansion, Rapamycin, tumour progression, inflammation, ageing, mice English Adaptive immunity, B-cell receptor repertoire, dietary restriction, late-onset, ageing, mice English
Date of oral exam:	3 February 2023
Referee:	Name Academic Title Gkioni, Lisonia UNSPECIFIED
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/71795