Q -
Dr Paulson,
I understand that conventional wisdom with HD patients is to maintain or even gain weight. There is a body of neuroscience literature extolling the virtues of reduced (usually by 30-40%) caloric intake as a method of life extension, in various animal models, by reducing, among other things, the availability of free radicals brought on by metabolic processes in the mitochondria.
Many of the HD studies with the transgenic (R6/2) mice and in people have looked at free radical scavengers. I wonder what would happen if we tried calorie reduction in the mice or what you think might happen if similarly applied to humans.
J.
A -
The question is a very good one that touches on very complicated issues. The short answer is that, based on our current understanding of HD, we simply do not know whether chronic caloric restriction (CR) in people who carry the HD gene would, in the long term, be good or bad. And, in affected persons with fairly advanced HD where metabolic demands are higher, CR might even worsen the problem.
Now, the longer answer, which first requires a little background. The only treatment that time and time again has been proved to slow down aging in various animals is CR. Somehow, severely curtailing an animal's daily food intake (without actually starving the animal!) makes the animals lean and long-lived. Soon, hopefully, a decades-long CR study in primates will answer whether this same approach also works in species closely related to humans. The data on CR longevity in animals have led some to suggest that CR might also improve longevity in people with neurodegenerative diseases like HD. Indeed there is recent, limited evidence in HD transgenic mice showing that
CR can slow some aspects of disease (Duan et al, 2003, PNAS 100:2911-6). Precisely why CR might help is unknown, but among the possibilities are that CR reduces free radical damage or stresses the brain in ways that are ultimately good -- for example, by inducing chaperone proteins that help to ward off toxic effects of mutant huntingtin protein. (On a parenthetical note, in the last four years at least 18 different research papers have reported success in slowing one or more aspects of HD in transgenic mice, using a variety of agents form genes to drugs. Things are clearly moving in the right direction!)
A note of caution: so far this CR effect has only been shown in just one study in one mouse model expressing only a small fragment of the HD protein. Ideally, similar studies in mice expressing the entire HD protein will be performed. If further studies confirm the finding, then perhaps we can start thinking about possibly testing CR in people with HD. Any such trial would probably be a long-term, longitudinal study.
A second note of caution: there may be an insurmountable problem in attempting CR in persons with HD. It has long been known that weight loss commonly occurs as HD progresses, despite that fact that people with HD tend to increase caloric intake. Aspects of body metabolism apparently change during the course of HD, although the basis for this is still poorly understood. If a person with moderately advanced disease were to attempt CR, it might lead to nutritional deficiencies that worsen, not lessen, the disease. For now, what we can say is that it is safest to maintain a well-balanced diet that includes nutritional supplementation, as needed, to ensure daily intake of necessary vitamins.
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