Biology Of Uterine Tumour Formation In Aging Caenorhabditis Elegans

Aging(senescence)is a deteriorative process involving diverse pathologies,many of which appear to arise from core senescent mechanisms(etiologies),whose nature remain unclear.In C.elegans,as in humans,various pathologies occur during aging,and tudying their origins is important for understanding aging.Ideas of Williams and Blagosklonny suggest that many senescent pathologies develop as the result of wild-type gene action in later life,due to non-adaptive action(or hyperfunction)of biological programs that promote fitness earlier in life.This study has explored the role of such mechanisms in the etiology of a prominent senescent pathology in C.elegans,the large tumors that develop within the uterus.Normaski microscopy was performed to describe the dynamic changes of tumor development.It revealed that uterine tumors began to develop following the end of reproductive period(day 4),with size increasing a lot during aging till the body cavity was filled.To better characterize the internal anatomy of such tumors,we used a strain with germline-expression of HIS-58::GFP to mark chromatin,and mCherry::PH to mark cell membranes.Casual observation of 3D structures reconstructed using selective plane illumination microscopy(SPIM)confirmed the occurrence of marked nuclear hypertrophy with age.The chromatin reporter(HIS-58::GFP)revealed nuclear hypertrophy that closely corresponding to DNA content(DAPI staining)and genomic copy number(Q-PCR),implicating mitotic endoreduplication as a driver of hypertrophy.Overall,tumour size is partly determined by number of oocytes in the uterus and partly by the extent of oocyte hypertrophy.C.elegans uterine tumors are similar to human ovarian teratomas(or dermoid cysts)in that both result from run-on of embryogenetic programs in unfertilized oocytes rather than mutations.Notably,expression of genes(unc-119,elt-1,elt-2,pha-4,hlh-1)expressed in several embryonic tissues but not in oocytes was detected within uterine tumors in later life,revealing their teratoma-like character.The framework of quasi-program theory was used to further explore the mechanisms of tumor formation.Firstly,tumors were found to develop earlier in fog-2 females than in N2 hermaphrodites.By contrast,tumor formation was suppressed by mating in both strains.It indicated that altering the timing of the transition from program to quasi-program could alter the rate of development of uterine tumors.Later RNAi of candidate genes involved in embryogenesis was performed and inhibition of most(10/13)genes could reduce the tumor size significantly.Furthermore,quasi-programmed yolk uptake is another factor that contributes to tumor growth.A manner that did not involve any genetic or environmental interventions was set up to probe the relationship between uterine status and lifespan and a positive correlation was detected.Consistent with this,inhibition of tumor size by RNAi of genes related with protein synthesis(rps-1,egl-45,iff-1,phi-2)and DNA replication(mcm-4,pri-1)resulted in lifespan extension.This study also indicated that administration of FUdR initiated from day 2 led to a 8.56% increase in mean lifepan with reduced tumor size and no changes in other senescent pathologies.These results imply that uterine tumors develop as the result of non-adaptive expression of embryogenetic and vitellogenic quasi-programs in unfertilized oocytes,i.e.that they are the result of post-reproductive action of wild-type genes(rather than molecular damage).Given that the similarities of C.elegans uteine tumors with human ovarian teratomas,C.elegans will be a potential model organism to study mammalian teratomas.This study also suggests that the formation of utetine tumors is not a typical senescent pathology and yet still a life-limiting factor in C.elegans.It therefore provides a new strategy to understand aging.