DAF-2

Daf2 The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 and also Age-1 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”Reduced activity of the DAF-2 protein, an insulin/IGF-1 receptor, can be achieved through various mechanisms, primarily involving mutations or manipulations that decrease its signaling. These include mutations in the DAF-2 gene itself, reducing its expression, or interfering with downstream signaling pathways like PI3K/Akt. Additionally, certain environmental factors like a low-sugar diet and specific drug treatments can also modulate DAF-2 activity. Here's a more detailed breakdown: 1. Genetic Manipulation: Mutations in daf-2: Mutations that disrupt the DAF-2 protein's function, such as those found in long-lived daf-2 mutants, can reduce its activity. Reduced DAF-2 Expression: Lowering the amount of DAF-2 protein produced, either through gene silencing or targeted degradation, can also decrease signaling. Downstream Pathway Interference: The DAF-2 pathway involves several downstream molecules, including PI3K and Akt. Disrupting the function of these molecules can indirectly reduce DAF-2 signaling 2. Environmental and Pharmacological Factors: Low-Sugar Diet: Studies have shown that a low-sugar diet can reduce DAF-2 activity and increase lifespan in C. elegans. Antioxidants: Certain antioxidants, like NAC and BHA, have been shown to reduce the lifespan extension caused by reduced DAF-2 signaling, suggesting they may interfere with the pathway.  Auxin-induced Degradation: Using auxin to degrade DAF-2 protein in specific tissues like the intestine can effectively reduce signaling and alter lifespan 3. Other Factors: Tissue-Specific Effects: The effects of DAF-2 signaling can be tissue-specific, with some tissues like the intestine playing a more prominent role in lifespan regulation. Developmental Regulation: DAF-2 activity can be regulated differently during development, with some alleles exhibiting gain-of-function or loss-of-function phenotypes depending on the developmental stage. In summary, reducing DAF-2 activity can be achieved through genetic modifications, dietary interventions, and pharmacological agents that interfere with its function or downstream signaling pathways, ultimately impacting lifespan and other biological processes. Daf 2 mutation do 2 things 1 induce a stress response apoptosis and 2 reduce tumor mitosis . insulin and igf1 signaling promote growth & food storage Low insulin & iGF1 activate protective cell response that prolong life
https://www.youtube.com/watch?v=_WPV15GZ4B8
Genes From the Fountain of Youth with Cynthia Kenyon, PhD - May 11, 2011
https://www.youtube.com/watch?v=HxfLm30FHwA
Cynthia Kenyon (UCSF) Part 2: :The Regulation of Aging by Signals from the Reproductive System
https://www.youtube.com/watch?v=Yg-d2XA_uqk
Scientist Stories: Cynthia Kenyon, Staying Ahead of the Curve