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The Role of Synergistic Cellular Signaling in Longevity

Image credit: CC BY 2.5, https://en.wikipedia.org/w/index.php?curid=12885905

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Ruby Grewal Dec 10, 2020
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Aging is a multi-factorial process with at least 9 interconnected components, and modulation of many different cellular networks contributes to the aging process. Much of the clinical research in human trials has examined one target at a time with mixed results. Is it possible that focusing research on targeting multiple cellular pathways simultaneously will show clinical benefit beyond what would be expected by targeting them individually?

Two cellular signaling pathways that are correlated with longevity are the insulin/IGF-1 signaling pathway (IIS) and the target of rapamycin (TOR) pathway. The core functions of both of these pathways are nutrient sensing, energy homeostasis, growth, and regulation of stress responses. Inhibition and downregulation of these pathways increases lifespan in C.elegans and Drosophila.

In the IIS pathway, studies in C.elegans have shown that increased lifespans due to reduced IIS is mediated via the daf-2 and daf-16 genes. The daf-2 gene encodes for the insulin-like growth factor1 (IGF-1) receptor, and daf-16 is the ortholog of the FOXO family of transcription factors. The TOR pathway acts as an energy sensor, which regulates processes such as biogenesis, autophagy, protein translation, lipid synthesis, and mitochondrial metabolism. Inhibition of TOR results in lower mRNA translation, which is mediated through S6 kinases (S6k). Adenosine monophosphate protein kinases (AMPK) negatively regulates the TOR pathway.

In C.elegans, down-regulating the IIS pathway increases lifespan by 100%, and down-regulating the TOR pathway increases lifespan by 30%. Therefore, a double mutant in these two pathways would be expected to live 130% longer. However, a recent study found that these double mutants actually live 500% longer, which is mediated by DAF-16 via AMPK. This suggests there is a synergistic relationship between these two pathways in aging and longevity.

Is it possible that targeting both the IIS and TOR pathways simultaneously will have more of a beneficial effect on human longevity compared to targeting each pathway individually? Metformin and Rapamycin are two drugs that have been shown to increase lifespan in model organisms. Metformin has also been shown to inhibit cancer cell growth, and this is accomplished via AMPK, by inactivating mTOR, by decreasing S6k1, and by downregulating the IIS pathway. Rapamycin-metformin combination therapy was shown to be beneficial in treating autoimmune arthritis in mice, and in inhibiting the growth of pancreatic cancer in vitro and in vivo. A clinical study found that rapamycin-metformin was well-tolerated in patients with metastatic adenocarcinoma, and was associated with better than expected overall survival. Therefore, these studies suggest that rapamycin-metformin combination therapy may be beneficial in treating age-related diseases and based on the mechanism of action of each drug, they may be beneficial in increasing longevity in humans.

These studies show the importance of investigating networks of signaling pathways. What other signaling pathways, known to be involved in aging and longevity, could have synergistic effects?

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