Synergy Between Mutations in Insulin Signaling and TOR Pathways Extends Life Fivefold in Nematodes

Most interventions that increase longevity in short-lived laboratory species, such as the nematodes used here, are just different ways of influencing the same underlying stress response mechanisms. Thus they don't tend to synergize well with one another. There are exceptions, however, and here researchers demonstrate a strong synergy between mutations in insulin and TOR signaling. It is worth noting that the fivefold life extension achieved here is only half of the present record for nematodes. Very short-lived species like this one exhibit great plasticity of life span in response to interventions, far greater than is the case for mammals, particularly long-lived mammalian species such as our own. We should not expect enormous gains to result from the same approach in humans, even given that the underlying mechanisms of insulin and TOR signaling are surprisingly similar in nematodes and mammals.

Researchers have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research. The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.



"We should not expect enormous gains to result from the same approach in humans, even given that the underlying mechanisms of insulin and TOR signaling are surprisingly similar in nematodes and mammals."

Tell that to all those who promote Low-protein/Methionine restriction diets as a panacea & elixir of eternal life just because it extends lifespan in C. elegans, murines, drosophila and primates.

These individuals will learn the hard way that maximum life span on animal models ≠ optimal health in humans.

Posted by: mTORque at January 9th, 2020 6:51 AM

The full text paper is --

"Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity"

The conclusion supports the programmed aging, to quote --

"Through genome-wide translational state analysis and genetic screens, we identified 24 negative regulators of longevity from the 115 genes that are translationally downregulated in the daf-2 rsks-1 mutant. One observation was that the lifespan determinants are enriched with developmentally essential genes (71%). Inhibition of these genes during development causes larval arrest, whereas RNAi knockdown only during adulthood leads to significant lifespan extension (Table S2). These results support the antagonistic pleiotropy theory of aging, which proposes that aging is adaptive, because natural selection favors genes that confer benefits during development but cause deleterious effects later in life (Williams, 1957). Thus, inhibition of developmentally essential genes during adulthood might extend lifespan"

Posted by: L Pagnucco at January 9th, 2020 4:03 PM

I understand the reason that Reason argues that such interventions in worms will scale down
for humans and I agree to a point. But the effects of multiple pathway interventions are simply unknown. However, broad observations, across there board suggest that the epigenetic and
methylation state appears integrated and self correcting, and that to quote my chat with Aubrey,
"I didn't anticipate the degree of the knock on effects" - he was speaking about senescent cell removal. So, we definitely need a multi- drug human test, beyond TAME, which uses the emerging aging clocks to measure what may be going on and the biological age effect.

Posted by: Robert Kane Pappas at January 9th, 2020 4:33 PM

"We should not expect enormous gains to result from the same approach in humans" - that is the case of senolytics too. Look at Unity.

Posted by: z at January 10th, 2020 11:20 AM
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