One of the better research outcomes a biologist can hope for is to find that a particular mechanism, disease, or benefit has a single point of control somewhere in its web of interlinked genes and feedback loops. A single gene or protein that acts as a switch or a dial, and has no or few entanglements with other biological systems. That lack of entanglements is important - a switch that turns one thing off and three other things on isn't of much use, at least for those of us who like our medicine without potentially lethal side-effects, but human biochemistry contains far more multi-switches than examples of any simpler construction. Evolution is based upon the promiscuous reuse of components, and almost any protein of note involved in regulating metabolism has more than one duty to perform.

In any case, researchers engaged in picking apart the mechanisms underlying calorie restriction might still manage to uncover a simple switch somewhere in amidst the all complexity and chains of genes and proteins turning one another on and off. They've been hacking away the brush for some years now, but there's no shortage of undergrowth yet to be cleared. You might see hints of a possible simple switch in the fact that autophagy is required for the longevity benefits of calorie restriction - disable autophagy and you disable calorie restriction. But autophagy is a complex process in and of itself. More brush to clear.

Here is a recent paper that looks at another potential candidate protein that might be manipulated to induce some the biochemical benefits of calorie restriction without the dietary change. (Though given that some of those benefits stem from a lack of visceral fat tissue caused by eating less, it seems unlikely that a manipulation of this sort would capture all the benefits of actually practicing CR). You might look at the open access original at PLoS Biology, or this more carefully explained piece in the popular science press:

Dietary restriction induces a transcription factor called CREB-binding protein (CBP), which controls the activity of genes that regulate cellular function. By developing drugs that mimic the protective effects of CBP - those usually caused by dietary restriction - scientists may be able to extend lifespan and reduce vulnerability to age-related illnesses.

"We discovered that CBP predicts lifespan and accounts for 80 percent of lifespan variation in mammals," said Dr. Mobbs.

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We showed that dietary restriction activates CBP in a roundworm model, and when we blocked this activation, we blocked all the protective effects of dietary restriction,"

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Dr. Mobbs hypothesizes that dietary restriction induces CBP by blocking glucose metabolism, which produces oxidative stress, a cellular process that leads to tissue damage and also promotes cancer cell growth. Interestingly, dietary restriction triggers CBP for as long as the restriction is maintained, suggesting that the protective effects may wear off if higher dietary intake resumes. CBP responds to changes in glucose within hours, indicating genetic communications respond quickly to fluctuations in dietary intake.

That last part matches with other work that shows the changes in biochemistry and metabolism accompanying calorie restriction take effect quite rapidly. The real benefits - the enhanced health and increased longevity observed in laboratory animals - stem from maintaining that metabolic state over time.

Zhang, M., Poplawski, M., Yen, K., Cheng, H., Bloss, E., Zhu, X., Patel, H., & Mobbs, C. (2009). Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling PLoS Biology, 7 (11) DOI: 10.1371/journal.pbio.1000245

Posted by Reason