Coupling Protein Catabolism to Lifespan and Reproduction in Caenorhabditis elegans
Baxi, Kunal Sanjay 1982-
There is an undisputable link between aging and reproduction and it has both puzzled and fascinated biologists for decades. Evolutionary biologists suggest that the rate of aging depends on the complex tug-of-war between maintenance of the soma and maintenance of the germ cells. The former is essential for longevity while the latter is essential for transmitting genetic information from parents to progeny. Any perturbation in the fertility and fecundity of C. elegans influences lifespan and vice-versa. Interestingly, germline deficient animals have increased resistance to environmental and proteotoxic stress. All eukaryotic cells reproduce for a finite amount of time before irreversibly ceasing reproduction, a phenomenon called reproductive senescence. Recent research has been aimed at trying to elucidate the genetic factors that regulate reproductive and post-reproductive lifespan. As part of this ongoing process, the initial part of my work aims to characterize the increased reproductive lifespan of a C. elegans mutant that is deficient for the gene rer-1. I further demonstrate that rer-1 mutants show a higher level of autophagy which is responsible for the enhanced reproductive lifespan of these mutants. Aging is thought to be a stochastic process, and cessation of reproduction is one of the biological hallmarks of aging. Although both reproduction and aging are well studied processes, there is very little mechanistic understanding of how these processes are connected and coordinated. The latter part of this study aims to answer some of these questions about the cross-talk between the germ cells and somatic tissue in C. elegans using a panel of sterile hermaphrodites impaired for specific stages of reproduction. My findings show that cessation of fertilization triggers a signalling cascade from the germ cells to the soma and that this signalling is brought about by steroid hormones, presumably synthesized by the somatic gonad. In actively reproducing worms, the forkhead transcription factor DAF-16 drives expression of vha genes which encode a multi-subunit proton pump that is responsible for maintaining lysosomal acidity. Nuclear exclusion of DAF-16 in post-reproductive worms co-ordinately reduces the expression of vha genes resulting in lysosomal alkalinization that culminates in acute loss of fitness and contributes to organismal senescence. My data shows a plausible mechanistic pathway by which lysosomal acidity is regulated via gonad to soma signalling in young (reproducing) animals.
DegreeDoctor of Philosophy (Ph.D.)
CommitteeHarkness, Troy; Wilson, Ken; Todd, Chris; Andres, Jose; Chivers, Doug
Copyright DateJanuary 2017
Caenorhabditis Lysosomes pH DAF-16 v-ATPase