Valentini, S.; (2011) Testing two ageing theories in Caenorhabditis elegans. Doctoral thesis , UCL (University College London).

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Abstract

In my thesis I was testing two established ageing theories in C. elegans. One was about the role of oxidative damage, induced via the Fenton reaction, in C. elegans ageing. In my other project I was investigating the role of sirtuins, NAD+- dependent histone deacetylases, in ageing. The oxidative damage theory predicts that reactive oxygen species (ROS) is a main cause of ageing. Iron can generate ROS via the Fenton reaction, indicating that iron homeostasis might protect against aging. Ferritins, iron storage proteins, regulate the iron concentration by storing excess iron. C. elegans has two ferritin genes, ftn-1 and ftn-2. Long-lived daf- 2 mutants show an increase in ftn-1 mRNA levels, indicating that ftn-1 might contribute to longevity assurance. I tested the role of ftn-1 in longevity assurance and found that reduced ftn-1 levels did not affect daf-2 mutant longevity or wildtype life span, nor did over-expression of ftn-1 increase life span. Changing iron levels via ftn-1 over-expression or iron chelator treatment led to resistance to oxidative stress, but had no effect on ageing. Overall, our results show that ferritin does not contribute to longevity assurance, and imply that oxidative damage, induced via the Fenton reaction is not a determinant of aging in C. elegans. Over-expression of sirtuins has been reported to increase life span in yeast, C. elegans and Drosophila. Rumours and contradictory findings caused us to re-test the effects of sirtuin over-expression on ageing. We found that backcrossing the two mainly used sir-2.1 over-expressing strains LG100 and NL3909, to wildtype background abolished the increase in life span, without changing the over-expression of sir-2.1. Reducing sir-2.1 levels had no effect on LG100. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons in LG100. These findings question the role of sirtuins in ageing.

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