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.