Universität zu Köln

Baghdadi, Maarouf ORCID: 0000-0003-3518-7074 (2023). Modulation of Insulin/IGF Signalling to Improve Mammalian Healthspan. PhD thesis, Universität zu Köln.

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Abstract

Research into ageing has revealed the malleability of the process and the importance of sex differences in modulating the response to longevity interventions. The importance of sex in mediating healthy ageing is evident in the brain, where sex is a major risk factor for some disorders. For example, women are twice as likely as men to suffer from Alzheimer’s Disease and men twice as likely as women to incur Parkinson’s Disease, two common and debilitating age-associated neurological disorders. My thesis underscores the importance of including both sexes when performing exploratory scientific studies where the effect of sex on a variable is unknown. Suppressed activity of the insulin/insulin-like growth factor signalling (IIS) pathway is a highly conserved and robust intervention that ameliorates the effects of ageing. While many invertebrate studies have dissected the role of IIS in ageing and have found tissue- and sex-specific effects, the role of different tissues and impact of sex in the longevity benefits of IIS reduction in mammals remain elusive. To address this gap, I first fully characterised male and female insulin receptor substrate 1 (Irs1) knockout (Irs1KO) mice. Then, I generated tissue-specific Irs1KO models targeting the major insulin-sensitive metabolic organs (liver, muscle, fat and brain) in male and female mice, and assessed the effects on body composition, energy expenditure and peripheral metabolism I found neuronal IRS1 deletion to be unique in triggering sex-specific health benefits in male mice. In the first section of the Thesis, I shed light on a mechanism by which reduced neuronal insulin signalling mediates mitochondrial phenotypes in Irs1KO mice, and I highlight the sex-specific nature of the neuronal mitochondrial stress response. IRS1 deletion is a robust method for lifespan extension and induction of metabolic health benefits. However, the effect of IRS1 deletion on cognitive function has not been assessed. Therefore, I asked whether IRS1 deletion reduced age-associated cognitive decline in young and old female and male mice. First, I found that IRS1 deletion did not lead to deficits in locomotor or exploratory behaviour, but it did lead to an age-associated reduction in anxiety. Next, I found no significant difference in the capacity of Irs1KO mice to perform a hippocampus-dependent spatial learning task and form long-term memory. Finally, I assessed short-term memory and found a significant enhancement in old Irs1KO mice, suggesting a reduction in age-associated cognitive decline. In the second section, I present data indicating the lack of sex-specific deficits in Irs1KO cognitive and motor function as well as a mitigation of age-dependent cognitive decline. Cognitive decline, a risk factor for dementia, is a major source of dependence in the elderly population, leading to increased societal and economic burden. I tested whether neuronal IRS1 deletion would be sufficient to delay or prevent cognitive decline in an ageing mouse model. I used a genetic tool to target IRS1 deletion to a widespread neuronal population. I therefore assessed whether the genetic tool itself induced phenotypes that could confound the effects of Irs1 deletion before moving on to study nKO mice. First, I characterised behavioural and metabolic parameters in male and female mice that expressed Cre under the rat-Synapsin I promoter (Syn1Cre). I found that Syn1Cre expression alone led to a sex-specific increase in anxiety and an inability to perform a spatial learning task in male Syn1Cre mice. Moreover, I found evidence of increased human growth hormone (hGH) expression in the brain due to the expression of a Cre-hGH transcript, leading to a negative feedback loop in the growth pathway resulting in a sex-specific reduction of body size in male Syn1Cre mice. Finally, I tested peripheral metabolism and found no significant difference in glucose tolerance, insulin sensitivity, energy expenditure or locomotor activity in male or female Syn1Cre mice. In the third section, I report that the Syn1Cre genetic model may be an appropriate tool for the study of neuronal control of peripheral metabolism, but not for behavioural studies. Therefore, I was unable to move forward with the characterisation of the neuron-specific IRS1 mutant.

Item Type:	Thesis (PhD thesis)
Translated title:	Title Language تعديل الأنسولين لتحسين صحة الثدييات Arabic
Creators:	Creators Email ORCID ORCID Put Code Baghdadi, Maarouf m3roufbaghdadi@gmail.com orcid.org/0000-0003-3518-7074 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-653088
Date:	2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language Insulin signalling, ageing, mammals, neuroscience, metabolism, genetics, physiology English
Date of oral exam:	10 August 2022
Referee:	Name Academic Title Partridge, Linda Prof. Dr. Trifunovic, Aleksandra Prof. Dr. Hammerschmidt, Matthias Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/65308