Calorie Restriction and Age-Related Gene Expression Changes in the Brain
The practice of calorie restriction with optimal nutrition, a lowered calorie intake while maintaining necessary dietary micronutrient levels, slows near all measures of aging in laboratory animals such as mice. The human studies of calorie restriction show pretty impressive results on shorter term measures of health, greater benefits than any presently available medical technology can provide to an essentially healthy individual at any age. If calorie restriction was a drug, it would be a household name, which probably explains why so much effort is devoted to the development of calorie restriction mimetic drugs. Sadly that is actually a very poor approach to producing treatments for aging, as the calorie restriction response is exceedingly complex: near everything in the operation of metabolism changes in response to lowered food intake, researchers are nowhere near the level of understanding required to proceed effectively, and even if successful the end results will be of only slight benefit.
Thus we shouldn't take our cues for the future of longevity science from its past investigations of natural variations in longevity: the future must look more like engineering, an undertaking in which researchers attempt to repair the cellular and molecular damage that causes aging rather than work on ways that merely gently slow down the damage accumulation. You can't use calorie restriction to reliably live to age 90 and beyond, it just modestly improves your odds. The only way to reliably live much longer in good health is to develop actual, working rejuvenation treatments based on damage repair as a strategy.
In any case, here is an example of the sort of research that helps to maintain the presently high level of interest in calorie restriction mimetic development among researchers:
Neuroscientists [have] shown that calorie-reduced diets stop the normal rise and fall in activity levels of close to 900 different genes linked to aging and memory formation in the brain. Researchers say their experimental results, conducted in female mice, suggest how diets with fewer calories derived from carbohydrates likely deter some aspects of aging and chronic diseases in mammals, including humans. "Our study shows how calorie restriction practically arrests gene expression levels involved in the aging phenotype - how some genes determine the behavior of mice, people, and other mammals as they get old. [It adds] evidence for the role of diet in delaying the effects of aging and age-related disease."While restrictive dietary regimens have been well-known for decades to prolong the lives of rodents and other mammals, their effects in humans have not been well understood. Benefits of these diets have been touted to include reduced risk of human heart disease, hypertension, and stroke, [but] the widespread genetic impact on the memory and learning regions of aging brains has not before been shown. Previous studies [have] only assessed the dietary impact on one or two genes at a time, but [this] analysis encompassed more than 10,000 genes. For the study, female mice, which like people are more prone to dementia than males, were fed food pellets that had 30 percent fewer calories than those fed to other mice. Tissue analyses of the hippocampal region, an area of the brain affected earliest in Alzheimer's disease, were performed on mice in middle and late adulthood to assess any difference in gene expression over time.
While we're on the subject... What is optimal nutrition, and how do we know?
It's a pretty loosey-goosey concept, admittedly. In the rodent studies, they never speak of "optimal nutrition," but only mention in e.g. the introduction or "Methods" section of papers that it's important to provide adequate nutrition, sometimes using phrases like "Calorie restriction without malnutrition," "Calorie restriction with adequate nutrition," "Calorie restriction with adequate provision of essential nutrients" or the like, but never intending them to be a phrase unto themselves.
Ben Best first began advocating that people always make this explicit by consistently using "CR with Adequate Nutrition" (CRAN) whenever CR was meant in 1996; this had evidently become fairly entrenched in the Calorie Restriction Society by the time I came on board (1999) -- and see this post by Brian Delaney, who despises it ;) .
Later, others began saying that we don't want merely adequate nutrition, but optimal nutrition; this was a mixture of the then-still-widespread belief that the RDAs were grossly inadequate, and more general nutritional quality issues (ie, a proper healthy diet and some "health food," rather than just the equivalent of a Big Mac diet with a Centrum for micronutrients). Hence, "Calorie Restriction with Optimal Nutrition" became a catchphrase in internal discussion and then in the media.
I would say we have a pretty good idea of what "adequate nutrition" is: the Institute of Medicine's Dietary Reference intakes, with adjustments for biochemical individuality where they can actually be made (e.g., adjusting B12 and folate intake by monitoring homocysteine and methylmalonic acid; vitamin D with 25(OH)D3; iron with ferritin, etc). I'd say that "optimal nutrition" can be debated, but can be pegged by the stuff on which the public health people and all the diet gurus from Atkins to Ornish basically converge: lots of fruits and vegetables, few to no refined carbs, lean protein, fatty fish or flax oil, a glass or 2 of wine with dinner, avoidance of trans- and minimization (over Atkins' equivocations and many Paleo people's adamant insistence) of saturated fat, use of olive oil as the main fat (pace Ornish and co.), and so on.
And, there are nutritional issues that may be specific to CR, such as the possible need for people on CR to keep protein intake down to RDAish levels.
The truth, of course, is that we have to be humble about all of this: there is plenty of room for a better understanding even of "adequate" nutrition, let alone "optimal" -- let alone "optimal for people on CR."
And, of course, whether CR will work in humans at all.
Michael, thanks for such a detailed answer. :)
Actually, here is a VERY detailed analysis on this issue if you really want to dig into it:
http://arc.crsociety.org/read.php?2,153892,154218#msg-154218