G. Biomateriales Aunque algunas de las terapias anteriormente descritas
1.6. LA TERAPIA CELULAR Y LA ARTROSIS
1.6.1. Tipo de células utilizadas en Terapia Celular
There was a clear alteration in stress responses in the S lines, with desiccation, starvation and heat stress affected to various degrees. Due to the loss of the desiccation resistance phenotype by generation 5 (Appendix 1) it is unlikely that desiccation resistance mechanisms contributed to the longevity phenotype, however the alterations in heat and starvation stress resistance were reasonably consistent across the generations making these more likely contributors.
The reduction in heat stress resistance in the S1 line (Figure 16) was not accompanied by enrichment of heat stress related genes in the RNA-Seq analysis (Appendix 3), however there were numerous heat shock proteins with altered expression (Appendix 2). Additionally, JNK signalling is required for the heat stress response in Drosophila (Gonda, Garlena and Stronach, 2012), and numerous JNK cascade or JNK related categories were enriched, providing a potential explanation for the observed heat sensitive phenotype. It is possible that modulation of the JNK pathway in the S1 line was at least partially responsible for the lifespan extension but at the cost of hindering the heat stress response downstream of JNK.
The starvation resistance of the S1 line was likewise unaccompanied by obvious GO category enrichments. Again, this phenotype could be related to alterations in the JNK cascade; JNK inhibits insulin-like signalling (Karpac and Jasper, 2009) which in turn can cause both starvation resistance and heat stress susceptibility (Broughton et al., 2005), matching the phenotype observed here.
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Although these data suggest that the longevity of the S1 line is due to altered JNK signalling, there is conflicting evidence as well. There was no change in oxidative stress resistance, or carbonyl
accumulation in the S lines (Figure 19Figure 20). Increased activity of the JNK cascade has been shown to increase oxidative stress resistance in Drosophila in addition to its lifespan extending effects (Wang, Bohmann and Jasper, 2003) and so lifespan extending JNK modulation in the S1 line might have also been expected to increase oxidative stress resistance and reduce carbonyl
accumulation. That said, it is possible that the fold-change observed in this study is sufficient to promote longevity, but insufficient to increase the oxidative stress response. Furthermore, oxidative stress resistance is not an inevitable correlation with longevity, for instance naked mole rats do not show improved oxidative stress resistance relative to mice (Andziak et al., 2006).
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Future Work
Perhaps the main goal of this project was the generation of long-lived Drosophila which could become a resource for further study. The selection lines produced offer a wide range of possibilities for future work, the most obvious being continued investigation into the mechanism behind the lifespan extension observed in S1 and to a less consistent extent in S2. As previously stated, a time- course RNA-Seq experiment including all four lines could provide valuable insight into the
modulation of developmental pathways observed in this study, with any early-life developmental changes being of interest as these might be able to explain the longevity phenotype in terms of hyperfunction.
A complementary metabolomics study to any future RNA-Seq data could provide valuable
information on the downstream effects of the observed expression changes. A metabolomics study on the Aarhus selection strains yielded interesting results, suggesting that their long-lived lines did not retain a young metabolic profile, as they did with expression, but rather young long-lived flies had some metabolic similarities to old control flies (Sarup et al., 2012).
Studying the effect of other lifespan extending interventions on the selection lines could also be interesting, for instance by subjecting them to dietary restriction or rapamycin treatment. Such crossed-factorial experiments can be used to identify the degree of lifespan extension caused by currently understood mechanisms, as was carried out to determine the overlap between the IIS based lifespan extension and dietary restriction in chico mutant Drosophila (Clancy et al., 2002). Furthermore, the dependence on known genetic mechanisms of ageing to achieve the longevity phenotype in the S lines could be determined by crossing them with transgenic flies possessing
127
knockouts for such genes of interest. For instance, crossing the selection lines with chico knockouts could help determine if the IIS pathway was involved in the longevity phenotype
55
Conclusion
Overall, the project had mixed results. The selection was moderately successful, producing one line with a consistent longevity phenotype, and one line that appeared to have extended longevity when measured at 25°C. Although several of the phenotypes measured yielded negative results, this in itself is interesting. The lack of change in the development phenotype between the regimes, coupled with the large number of developmental genes that had altered expression, suggests a complex relationship between development and ageing whereby shared genetic pathways can influence one but not the other.
The core goal of selecting long-lived lines was successful and has provided a resource that can potentially be studied further to help identify more specific genetic changes associated with longevity, and perhaps even potential targets for intervention to modulate the ageing process. Further, this study has successfully replicated the methods of Zwaan, et al. (1995), and provided proof of principle that this selection method can work on recently wild-caught flies and achieve lifespan extension over a reasonably short number of generations.
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