Deciphering Secrets of Longevity, from Worms

Posted on January 7th, 2014 by Dr. Francis Collins

How long would you want to live, if you could remain healthy? New clues from experiments done in microscopic worms suggest that science may have the potential to extend life spans dramatically.

Taking advantage of the power of the worm Caenorhabditis elegans (C. elegans) as a model system for genetic studies, NIH-funded researchers at the Buck Institute for Research on Aging in Novato, CA, decided to set about testing ways to extend the worms’ lifespan.

Typically, C. elegans live about 20 days in a laboratory dish. Previous research has shown, however, that worms with mutations in a gene called rsks-1 live about 6 days longer than normal, while those with mutations in another gene, daf-2, live 20 days longer. That made the researchers at the Buck Institute curious about what would happen if they used genetic engineering to create a worm strain that carried both mutations. Taking an educated guess, they estimated such double-mutants might live about 45 days. But, to their surprise, when they actually created such worms, some of the critters were still alive and squirming at 100 days [1]. That’s an amazing five-fold increase in worm lifespan—the equivalent of 400-year-old humans!

It’s not clear why these genetic mutations appear to act in synergy, delivering far more life-extending benefit than a simple additive effect would provide. But here’s what we do know. The mammalian version of rsks-1 is called S6K, and it’s part of the mTOR pathway. (I know this sounds like a lot of jargon, but hold on, this will make sense!)  mTOR stands for mammalian “target of rapamycin,” and mTOR is a major player in the aging process, as well as being critical for cell growth, proliferation, and reproduction. Interfering with mTOR signaling slows the growth of cells. If you are a regular reader of this blog, you may remember that mice with low levels of mTOR lived about 20% longer than average. mTOR is also a key nutrient-sensing protein. When nutrients are scarce, such as during a calorie-restricted diet, mTOR activity declines and growth slows. This is one way that calorie restriction is thought to increase lifespan [2].

Similarly, the mammalian version of daf-2 is the receptor for insulin-like growth factor 1, or IGF-1.   Mutations in this pathway interfere with growth. Some studies have found that humans with low IGF-1 activity appear to have a reduced incidence of cancer, as well as later onset of the disease—a sign that lowering IGF-1, or, in the case of the worms, DAF-2, may help to delay onset of age-related disease.

One noteworthy consequence of combining these two genetic mutations in a single worm is a surge in the activity of a protein called DAF-16 in multiple tissues. This is fascinating, because studies of people over the age of 100 have identified variants in the human version of DAF-16, called FOXO, that suggest this protein influences human lifespan [3, 4]. Perhaps levels of this protein are one of the keys to longer life—but that remains to be seen.

The take-home message here is that extending lifespan in any multi-celled organism, including humans, is likely to be a complex, multicomponent process. Perhaps, just as we need cocktails of different drugs to effectively treat diseases like AIDS and cancer, developing drugs that delay aging and increase lifespan will also require a multifaceted approach that targets several genes at once.

References:

[1] Germline Signaling Mediates the Synergistically Prolonged Longevity Produced by Double Mutations in daf-2 and rsks-1 in C. elegans. Chen D, Li PW, Goldstein BA, Cai W, Thomas EL, Chen F, Hubbard AE, Melov S, Kapahi P. Cell Rep. 2013 Dec 26;5(6):1600-10.

[2] Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Curr Biol. 2004 May 25;14(10):885-90.

[3] Association of FOXO3A variation with human longevity confirmed in German centenarians. Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2700-5.

[4] FOXO3A genotype is strongly associated with human longevity. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92.

Link:

Kapahi Laboratory, Buck Institute for Research on Aging, Novato

NIH support: National Institute on Aging