Lindsay Wu

Laboratory for Ageing Research, School of Medical Sciences, UNSW Sydney

One of the earliest declines with advancing biological age is female reproductive capacity. This has primarily been attributed to a depletion of the ovarian reserve, yet a decline in oocyte quality occurs well before ovarian depletion. The reasons for this are unclear. Here, we present data from our lab showing that a decline in an interaction between the NAD dependent deacylase SIRT2 and the kinetochore attachment protein BubR1 is responsible for this decline in oocyte quality. Animals which transgenically over-express SIRT2, or which have been treated with the NAD precursor nicotinamide mononucleotide (NMN) are resistant to this decline. NMN treatment also prevents chemotherapy induced infertility, and prevents other adverse events of chemotherapy including memory loss, inactivity and cardiovascular toxicity. These data suggest that the NAD precursor NMN could be used as a therapeutic to treat infertility and diseases of ageing, and to pursue this, we also present data from isotope labelled metabolic flux experiments to determine how exogenous NMN impacts endogenous NAD metabolism, and the metabolic route that this exogenous material follows.

Given the role of DNA damage from chemotherapy in mediating biological ageing, we also investigated the biochemical requirements of ageing cells, which are dependent upon activation of the pentose phosphate pathway for the generation of new nucleotides, and for the regeneration of reduced glutathione to neutralise reactive oxygen species. We recently completed a high-throughput drug screen to identify small molecule activators of the pentose phosphatepathway enzyme glucose-6-phosphate dehydrogenase (G6PD). We have identified four small molecule activators of G6PD which robustly increase lifespan in the nematode C. elegans, these may be further candidates for treating diseases of ageing.

Finally, given the role of chemotherapy in accelerating DNA damage and biological ageing, we sought to determine the contribution of type II DNA transposable elements to ageing, which are normally suppressed, but can be de-repressed during DNA damage or ageing. We performed an RNAi screen against these type II DNA transposons in C. elegans, and identified a single DNA transposon whose silencing robustly extends lifespan. Interestingly, the transposase protein encoded by this element has a signal peptide indicative of extracellular secretion, which has important implications for the non-cell autonomous nature of biological ageing.