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Title: Rilmenidine is a calorie restriction mimetic that improves survival and indicators of healthy ageing in C. elegans via a novel IRAS ortholog, f13e9.1
Author: Bennett, Dominic
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2020
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Ageing is currently the inevitable consequence of human existence. The ageing process is a disease that internally imposes limitations and reductions in liberty through enfeeblement, frailty and pathology, leading to dramatic physiological and psychological suffering. Therefore, it is paramount we identify immediate strategies which defer the progression of age-associated diseases and compress morbidity. At present, calorie restriction (CR) offers the most feasible and robust intervention to decelerate ageing. However, despite the attractive pro-longevity effects of CR, several concerns surrounding the applicability, tolerability and safety have precluded its widespread adoption. Using the Connectivity Map to identify drugs with a similar transcriptome to CR, I sought to repurpose a clinically approved drug that demonstrated broad tolerability and safety whilst representing an easily translatable, potential calorie restriction mimetic. I identified rilmenidine: a widely-prescribed, centrally-acting antihypertensive that mimicked gene expression changes previously observed in CR. Furthermore, rilmenidine significantly opposed the transcriptional direction of ageing such that it rescued age-associated overexpression of genes enriched for immune-regulation, inflammation and ECM degradation. I validated the potential geroprotective properties of rilmenidine in the model organism C. elegans. Rilmenidine administration extended lifespan in WT worms, when commenced from early adulthood or only once the worm had aged. Furthermore, it decelerated the development of decrepitude, without altering developmental periods. Lifespan extension was not possible in genetic models of CR (eat-2), suggesting a longevity effect was induced through CR mimicry. Moreover, this was supported by rilmenidine-induced lifespan effects being dependent on 3 key CR nexuses: DAF-16, AMPK and TOR. In C. elegans, Rilmenidine elicited increases in ERK activity, typical of in-vitro imidazoline agonist exposure, which was abrogated following blockade of an imidazoline binding site. This effect was mimicked following the knockout of f13e9.1, which was characterised herein as the nematode ortholog of the human imidazoline type 1 receptor (IRAS). Indeed, rilmenidine also increased nematode thermotolerance as well as autophagy, both dependent on imidazoline binding, and demonstrated a capacity to attenuate the accumulation of polyQ aggregates. Autophagy was essential to the longevity effect of rilmenidine and was increased independent of the previously hypothesised cAMP pathway. Thus, this research presents a strong novel case for rilmenidine to be a CR mimetic that warrants substantial clinical investigation as to the auxiliary benefits of rilmenidine which may belie its overt purpose as an anti-hypertensive, such that it be preferentially prescribed to hypertensives which provides a safe, tolerable method of CR mimicry to over 25% of the population.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral