Nov 13, 2018 // Uncovering mechanisms that regulate age-related decline and reproductive senescence

Dr. Nicole Templeman, Lewis-Sigler Institute for Integrative Genomics & Dept. of Molecular Biology, Princeton University.
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Since most biological processes require nutrients, signaling networks that respond to nutrient levels play important roles in regulating many functions, including growth, reproduction, and tissue maintenance with age. In organisms ranging from invertebrates to mammals, genetic loss-of-function of signaling components in nutrient-sensing pathways—such as the insulin/insulin-like growth factor-1 signaling (IIS) pathway—can thereby slow the physiological deterioration that characterizes aging, and extend lifespan. In Caenorhabditis elegans, loss-of-function of the daf-2 IIS receptor also significantly delays the age-related decline in reproductive capacity, one of the earliest hallmarks of aging. To identify mechanisms that directly control aging of the reproductive system, we compared the transcriptomes of aged daf-2(-) and wild-type oocytes. Remarkably, inhibiting one group of oocyte-specific IIS transcriptional targets, cathepsin B cysteine proteases, can improve oocyte quality in aging C. elegans, even when inhibition takes place partway through the reproductive period. This suggests that it is possible to slow age‑related reproductive decline with mid‑life interventions. In addition to evaluating molecular changes downstream of key nutrient-sensing signaling networks like the IIS pathway, I am interested in determining whether we can uncover new mechanisms of age-related decline by looking at other major regulators of growth, energy balance, and metabolism. The cAMP response element-binding protein (CREB) is a highly conserved transcription factor that regulates numerous processes, including growth and nutrient storage. I found that in C. elegans, CREB also regulates oocyte quality and reproductive capacity with age, which is a previously unknown function of CREB signaling. Interestingly, this targeted effect on reproductive aging is due to CREB’s activity in the C. elegans hypodermis, an epithelial tissue transcriptionally similar to mammalian liver and adipose tissue. Collectively, these projects have revealed some of the intricacies by which tissue-specific signaling events exert nuanced effects on complex systemic functions, and uncovered new mechanistic regulators of age-related decline.