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              Advocacy & Research for Unlimited Lifespans


Less Sleep and a Longer Life, a Desirable Mutation

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Posted 24 May 2023 - 07:25 PM

A person who sleeps six hours rather than eight hours every day, give or take, is effectively gaining a bonus 12.5% additional time spent alive and active. From that perspective, there isn't all that much difference between being able to sleep two hours less every night throughout life, without consequences, and being able to live for the better part of an additional decade in good health. There are mutations that produce this effect in humans, other mammals, and lower animals such as flies, and at least one of them does so without any apparent negative side-effects.

Today's open access paper offers an exploration of one of these mutations, a small alteration in DEC2, which not only reduces the need for sleep, thereby granting additional subjective life span, but is also found to extend actual life span in flies. The size of the effect is larger than many of the calorie restriction mimetic compounds explored in recent years. Interestingly, the authors here argue that reduced need for sleep is more a reflection of increased robustness and health resulting from this mutation than any independent, top-down alteration of the regulation of sleep.

A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila

One of the most well-studied examples of natural short sleepers in the human population are individuals with rare genetic mutations in the dec2 gene. Dec2 is a transcriptional repressor that, in mammals, is recruited to the prepro-orexin promoter and represses the expression of orexin, a neuropeptide that promotes wakefulness. A single point mutation in dec2 (dec2P384R) inhibits the ability of Dec2 to bind the prepro-orexin promoter, resulting in increased orexin expression. Consequently, wakefulness increases, and individuals sleep on average 6hrs/day instead of 8hrs/day.

Intriguingly, these natural short sleepers do not appear to exhibit any phenotypes typically associated with chronic sleep deprivation, and expression of the dec2P384R mutation in mice suppresses neurodegeneration. Thus, it has been suggested that individuals harboring the dec2P384R mutation may employ compensatory mechanisms that allow them to thrive with chronic sleep loss. However, whether the dec2P384R mutation directly confers global health benefits has not yet been tested experimentally in any system.

In this study, we used a Drosophila model to understand the role of the dec2P384R mutation on animal health and elucidate the mechanisms driving these physiological changes. We found that the expression of the mammalian dec2P384R transgene in fly sleep neurons was sufficient to mimic the short sleep phenotype observed in mammals. Remarkably, dec2P384Rmutants lived significantly longer with improved health despite sleeping less. In particular, dec2P384R mutants were more stress resistant and displayed improved mitochondrial fitness in flight muscles. Differential gene expression analyses further revealed several altered transcriptional pathways related to stress response, including detoxification and xenobiotic stress pathways, that we demonstrate collectively contribute to the increased lifespan and improved health of dec2P384R mutants.

Finally, we provide evidence that the short sleep phenotype observed in dec2P384R mutants may be a result of their improved health rather than altered core sleep programs. Taken together, our results highlight the dec2P384R mutation as a novel pro-longevity factor and suggest a link between pro-health pathways and reduced sleep pressure.

View the full article at FightAging

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