In this post, I’d like to describe very briefly how C. elegans, a tiny roundworm used extensively in biological studies, can teach us lessons of momentous importance to our own longevity and wellness.
Daf-2: What can this gene do?
The short answer is, a lot! Daf-2 encodes the worm-equivalent of mammalian Insulin/IGF-1 receptor. When insulin or IGF-1 binds to this receptor, they activate a sequence of intracellular molecules (a so-called signal transduction pathway). This pathway eventually determines the worm’s metabolic rate.
Insulin receptors in mammals (and we are mammals, too) do exactly the same thing. I wrote in an earlier blog that we already know that increased metabolic rate is associated with a shortened lifespan. So we could expect that a mutation in the Daf-2 gene that reduces its activity would also reduce the metabolic rate of the worm. Indeed, such mutations exist and, as expected, they reduce the metabolic rate of the worm. As a consequence, they double the lifespan of the worms. This is a remarkable feat. If we could mimic the actions of Daf-2 mutations in us, we could potentially live to 200 years!
But wait, there is more!
In an elegant paper published in Science ( vol. 313, p.971, 2006) by Cynthia Kenyon and her colleagues at UCSF, they showed that Daf-2 worms with mutations that reduced Daf-2 activity not only had reduced metabolic rate, they also were completely resistant to the formation of cancerous tumors. Wow! That is nothing short of spectacular, at least for the worm. But what does it mean to us?
The human aspect, let me digress for a moment
The evidence that caloric restriction, or CR, results in extended life is compelling. The same observations were made in yeast, in fruit flies, in mice, and in monkeys (in mice, there is tentative evidence of resistance to cancer as well). Unless we humans are really unique (I think not), we should also benefit from CR both in life extension and in resistance to cancer. There are only a few problems:
- As we progress in the evolutionary tree, the extent of the prolongation of life gets smaller. In the roundworms, CR increased longevity by 100%; in mice, only 25%. We do not know how much of an extension in human longevity could be anticipated?
- The prescribed CR in humans is about 1300 Kcal per day. This is tough to achieve. If you consider you gain about 200 calories with the ingestion of an ounce of cheese, you can begin to understand how little food you can eat in a CR diet. The couple of people I saw who adhered to this punishing diet looked to me emaciated Indian Fakirs. No wonder; these folks may live longer but are going to live and die very hungry.
- The question of inhibition of tumors through CR is still an open question in humans. For instance, mammals have a “tumor suppressor” gene called p53. The protein encoded by this gene, also called p53, makes sure that when mutations occur in the cell its division is delayed until either the DNA damage is repaired or the cell commits suicide. This is how biology ensures that potential cancer cells are eliminated before they proliferate and do irreversible damage. But there are mutations of the p53 gene that inhibit tumors and accelerate aging. So obviously the connection between longevity and cancer is not quite as simple as the roundworm would have us believe.
Take home lessons
I think that the case for caloric restriction (CR) is getting stronger with every additional scientific study on the subject. The fact that so many species demonstrate its benefits almost demands that humans should obey those biological generalities. On the other hand, we are not carbon copies of mice. We do have variation in our metabolic pathways that were probably adaptive to evolutionary needs. There is still a lot to be discovered, and alas, we don’t even know what we don’t know.
And as if this is not complicated enough, we do know that there are other biological processes that affect longevity and have little, if nothing, to do with CR. But more on this in a later post.