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Title: Klotho proteins KLO-1 and KLO-2 interact with DAF-2/DAF-16 pathway to regulate energy metabolism, stress resistance and ageing
Author: Buj, David
ISNI:       0000 0004 7963 5980
Awarding Body: University of Huddersfield
Current Institution: University of Huddersfield
Date of Award: 2019
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Klotho was originally identified in mice presenting multiple age-related traits and shortened lifespan due to disruption of α-Klotho gene. ß-Klotho was identified later, and it shares sequence and structural similarity and characteristics with α-Klotho. Klotho proteins are involved in the regulation of multiple signalling pathways due to being key regulators of endocrine fibroblast growth factor (FGF19, -21 and -23) signalling and participating in insulin/insulin like growth factor signalling (IIS). Caenorhabditis elegans has a simpler metabolism and reduced amount of paralog proteins than mammals, therefore reducing the complexity of the metabolic interactions. Hence C. elegans was used in this study to assess the role of Klothos for physiology of ageing and stress responses. C. elegans klo-1 and klo-2 are the gene orthologs of mammalian a-and ß-Klotho and encode for proteins with only one KL domain rather than the two that form the mammalian Klotho. The effects of genetic deletions of klo-1 and klo-2 were assessed in C. elegans. In addition, klo-1 and klo-2 genetic mutations were studied in combinations with daf-2/insulin receptor and daf-16/foxo hypomorphic mutations. klo-2 deficiency (klo-2(ok1862) mutation) significantly extended lifespan and improved resistance to heat stress. Both parameters were further improved in double mutants of klo-2(ok1862) and daf-2(e1370). Synergy between klo-1(ok2925) and daf-2(e1370) also induced extended lifespan. klo-1 deficiency alone was able to improve survival to oxidative stress. In addition, a trend was observed in progeny reduction, delayed development time and impaired lipid metabolism in klo-1 and klo-2 mutant worms. All alterations caused by klo-1, klo-2 and daf-2 alone or in combination were suppressed by daf-16(mu86) mutation. The phenotypic effects observed in the mutant worms suggest that KLO-1 and KLO-2 regulate DAF-2/InsR pathway directly or indirectly through FGFR pathway. Both pathways are highly dependent of the activity of DAF-16, which will explain the dependency of KLO-1 and KLO-2 on functional DAF-16.
Supervisor: Kinnunen, Tarja Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; QH426 Genetics