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101 Facts About Ageing #25: Single Gene Mutations And Lifespan Extension

Posted on 9 August 2021

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As Daniel Patrick Moynihan, an American sociologist, politician, and diplomat once said: “Everyone is entitled to his own opinion, but not his own facts”. And we wholeheartedly agree. A shared set of facts is the first step to building a better world with longevity for all. In that spirit, we are creating a series that covers 101 indisputable facts about ageing, health and longevity.

It was once widely believed that ageing was too complicated a process for any one gene to have a significant impact on an organism’s average or maximum attainable lifespan. We now know that this is not the case – in 1993, it was shown for the first time that loss of function mutations in a gene called daf-2 could roughly double the lifespan of C. elegans worms. Daf-2 encodes the receptor for insulin-like growth factor 1 (IGF-1) in worms, part of a metabolic pathway found to regulate ageing in multiple organisms and suspected to do so in humans. 3 years later, it was shown that the Ames dwarf mutation can extend the lifespan of mice by over 50%. This mutation results in defective development of the anterior pituitary gland, an organ which regulates growth and response to stress through the hormones that it releases.

Graph showing the percentage of surviving C. elegans worms carrying mutations in daf-2, rsks-1 (which encodes another protein that is important in insulin/IGF-1 signalling) and daf-16 (which is required in order for the daf-2 mutation to extend lifespan).

Many other single gene mutations that increase or decrease average and/or maximum lifespan have been studied in worms, fruit flies and mice. Most of these mutations affect signalling via insulin and insulin-like growth factor, with reductions in signalling being associated with lifespan extension. Other examples include mutations that increase resistance to oxidative stress, such loss of the p66Shc protein, and mutations that increase telomere length, for example by increasing the expression of telomerase, an enzyme that elongates the telomeres.

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    A C. elegans mutant that lives twice as long as wild type:

    Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production:

    Single-gene mutations and healthy ageing in mammals:

    Germline Signaling Mediates the Synergistically Prolonged Longevity Produced by Double Mutations in daf-2 and rsks-1 in C. elegans:

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