University of Groningen
New molecular mechanisms of aging regulation
Sen, Ilke
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Publication date: 2018
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Sen, I. (2018). New molecular mechanisms of aging regulation. University of Groningen.
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Stellingen
1. The conserved transcription factor DAF-16/FOXO is one of the most important aging regulators known to date. It resides downstream of the insulin/IGF signaling (IIS) pathway and relays low insulin/IGF signals into the expression of stress resistance and longevity promoting genes. However, DAF-16/FOXO is not exerting its lifespan regulatory role just by itself. Instead it relies on several regulators and cofactors (Riedel et al., 2013). 2. DAF-16/FOXO synergizes as a combinatorial transcription factor with 30/TFEB. Under harmful conditions, DAF-16/FOXO and HLH-30/TFEB both translocate into the nucleus, form a complex, co-occupy many target promoters and co-regulate many target genes (Chapter 3 of this thesis). 3. Combinatorial roles of these two transcription factors are required for the full spectrum of stress resistance and the promotion of longevity (Chapter 3
of this thesis).
4. One of the first discovered and most potent positive regulators of DAF-16/FOXO is SMK-1. It is essential for DAF-DAF-16/FOXO to promote stress resistance and longevity under low insulin/IGF signaling (IIS) (Wolff et al.,
2006). However, despite this crucial role, little is known about the
mechanism by which SMK-1 functions.
5. SMK-1 is part of a protein phosphatase 4 complex (PP4SMK-1), which does not physically bind nor affect the phosphorylation status of DAF-16/FOXO. Instead it dephosphorylates the transcription elongation factor SPT-5 to regulate DAF-16/FOXO mediated transcriptional activation of a subset of its target genes under low IIS conditions (Chapter 4 of this thesis).
6. “Age is the single largest risk factor for an enormous number of diseases. So if you can essentially postpone aging, then you can have beneficial effects on a whole wide range of disease.” (Cynthia Kenyon)
7. “The scientist is not a person who gives the right answers, he/she is one who asks the right questions.” (Claude Levi-Strauss)
