While we're waiting for Michael (who knows immeasurably more about this than I do), here are a few further comments on calorie restriction in humans.
Luigi Fontana defines two types of aging. Primary aging is the inexorable underlying aging process whose
rate increases exponentially with age, at least until late in life. It's species-specific. Secondary aging is, perhaps, more environmentally modifiable than primary aging, and is related to health span. In the past, although the average life span was quite short, there were individuals who lived to ripe old ages. For example, Micheangelo was 89 when he died. Isaac Newton made it to 84. Copernicus made it to 80. Galileo expired at 78. These lifespans were far less common in that time frame than they are today, but they did occur. Hundreds of years ago, the survival curve began declining in the twenties and fell more or less steadily into old age. What has changed dramatically is the fraction of us who make it to 80 or 90 thanks to advances in public and private health... antibiotics, sanitation, better nutrition, medical advances. In other words, the rate of secondary aging has slowed resoundingly, squaring up the survival curve. More and more, people... those with the right genes and/or (maybe) healthy lifestyles... are living into their eighties and nineties. But in the meantime, all their pieces and parts are quietly aging, and like the wonderful one-horse shay, once a stringent challenge comes along like a stroke or a heart attack (or even an infection), other organs fail. (At least, this is my fantasy about what might be happening.)
The slowing of primary aging is, as I understand it, much harder to effect than the slowing of secondary aging. Calorie restriction (or maybe protein or even methionine restriction) slows the underlying rate of aging in animals (and, we'd like to think, in humans). By now, other interventions have been found to slow aging in, e. g., roundworms (C. elegans), but calorie restriction is, as I understand it, the best-tested and best understood of these lifespan extension techniques.
Another consideration regarding calorie restriction is that the payoff is less when CR begins after an animal is full-grown than it does when calorie restriction starts just after weaning. When CR starts in infancy, the animal grows up small and stunted compared to fully-fed peers, and life-long calorie restriction can yield greater maximum life extensions than it can when CR starts in adulthood.
At the last (4th) Calorie Restriction Conference that I was able to attend, in April, 2006, the buzz among the animal researchers was that the National Institute on Aging calorie restriction experiment was going very, very badly. Their rhesus monkeys were said to be a
very angry lot, throwing their food at their keepers and at the walls. Also, as I recall, there were problems getting them to eat. I remember wondering at the time whether they were going to be able to complete the study. Michael can speak to this a lot better than I can, but it was a topic of coffee-table conversation at the time.
At that conference, there were no fewer than four papers giving (different) reasons why calorie restriction wouldn't be expected to work in humans. One of these, written by Aubrey de Grey, argued that from an evolutionary perspective, calorie restriction wouldn't have provided for more than a season or two of lean times. Calorie restriction wouldn't be expected, he suggested, to add more than a year or two to human lifespans. He and other researchers also noted that the larger the animal, the less the gain from calorie restriction in keeping with this thesis that CR won't add more than a year or two to lifespans. One case in point is the 1987-2001 Purina Dog Chow longevity study of 24 25%-calorie-restricted Labrador Retrievers and 24 ad lib-fed controls. The study began when the dogs were three years old and continued until they all died. The median lifespan of the CR subset was 18 months longer than the median lifespan of the control group... an improvement of something like 13%. (Of course, both sets of dogs were fed ad lib until they were three years old.)
My private reaction to Dr de Grey's paper at the time was that the CR-induced, ten-to-fifteen-year improvement in humans in cardiovascular and other health metrics that Drs. John Holloszy and Luigi Fontana documented in their watershed paper in the April, 2004, issue of the Proceedings of the National Academy of Sciences handily trumped arguments that CR doesn't work in humans. Drs. Holloszy and Fontana found that CR produces dramatic improvements in cardiovascular risk profiles among those of us who practice it. (My HDL levels jumped from around 50 before I went on CR into the 70's and 80's after that time. This spring, my total cholesterol was 169, my HDL was 73, my triglycerides were 38, and my fasting glucose was 81.)
Update: I just found a
disquisition that I wrote in 2008 that summarizes some CR material, with hyperlinked references.
