Is Caloric Restriction Hormetic or is Ad libitum feeding toxic?

Richard L. Sprott, Ph.D.

The Ellison Medical Foundation, 3 Bethesda Metro Center, Suite 700, Bethesda, MD 20814

Tel: 301-657-6248, Fax: 301-652-6240

E-mail: rsprott@interofc.com

In 1935 Clive McCay ¹ first reported the effects of Caloric Restriction (CR) on life-span in rats. After several years of additional research, McCay² reported lower incidences of tumors in CR than in Ad libitum fed rats. A systematic exploration of the reduction in tumor incidence awaited the research of Morris Ross nearly thirty years later³. Ross' subsequent research on the effects of CR on tumor prevalence^{4, 5}, growth ⁶, and longevity ⁷, brought his own and McCay's research to the attention of the gerontological research community. The emphasis of the research was heavily weighted toward the interaction of CR and tumor incidence.

As the gerontologists began to explore this paradigm, the emphasis shifted toward the life-span effects with little attention to the pathology of the rodent subjects. The life-span research reported by Masoro ⁸, Weindruch ⁹, and Walford ^{10, 11}, brought the life extension effects of CR to the attention of a much broader range of scientists and the general public.

In the vast majority of research reports dealing with the CR paradigm post Morris Ross the interest has been in life extension.

In 1987 the National Institute on Aging (NIA), together with the National Center for Toxicological Research (NCTR), established colonies of aging mice and rats fed either Ad libitum or a CR regimen for use in biomarkers of aging and biomarkers of toxicology research. These colonies were the first colonies to make CR rodents widely available for research use and resulted in a burst of research with more than 300 publications in the ensuing decade. While the NIA/NCTR initiative was primarily aimed at developing biomarkers using CR animals, interest in the mechanisms of the CR longevity effect was clearly a part of the research landscape. An explicit part of the overall research strategy was the collection of cross sectional and longitudinal pathology data for the Ad libitum and CR mice and rats of each genotype. Bronson and Lipman ¹² have summarized the reduction in lesions in CR mice, Lipman ¹³ in rats, and Bronson ¹⁴ cross sectional pathology in both species. Lipman and Bronson ¹³ in fact argue that " the effect of CR is simply to reduce the odds of developing most of the lesions to which the individual is susceptible."

CR research has taken place in an evolving research environment. Very significant changes in the husbandry of laboratory rodents have extended the life-span of research species and changed the pathologies observed in research vivaria¹⁵.The changes from creosoted wooden boxes to polycarbonate boxes, from cedar and pine shavings to sterile bedding, and from open vivaria to SPF facilities has dramatically increased the longevity of laboratory animals. It seems not unreasonable to ask whether the Ad libitum feeding regimen is as inappropriate for laboratory rodents as creosoted boxes and intercurrent disease.

Dr. Hart in the stimulus paper for this comment, clearly suggests that many of the effects of CR are due to the reduction in body weight which result from CR. The "co-hormetic" effects he describes are like-wise largely due to body weight reduction. If, in fact, this is the case, then it could be argued that what is really being observed is a continuum of diet intake effects from under nutrition to over nutrition. Many species, our own included, seem reasonably able to maintain appropriate body weight profiles in the presence of adequate nutrition. While abundance can produce obesity in humans, such a response does not appear to be the norm. Admittedly this may be changing in our society in the presence of "convenience" foods and cultural changes in attitude.

In laboratory rodents, with different evolutionary histories, obesity appears to be a much more common response to abundance. Ad libitum feeding may then be seen as a direct cause of laboratory rodent obesity and subsequent pathology. In that sense, ad libitum feeding could be seen as a toxic stimulus. The result would be the production of a U shaped life expectancy curve with extreme under nutrition and extreme over nutrition (ad libitum feeding) resulting in shortened life-spans, and moderate intakes (CR) resulting in "extended" life-span. The shape of this curve conforms to the definition of hormesis in form, but it seems to me, to the real meaning of the term only in the most trivial sense. In my opinion, it does not take the assumption of a process such as hormesis to understand the wisdom of the notion that we can have too much or too little of almost anything. To subsume the effects of CR under the hormesis paradigm would I believe trivialize what is an interesting concept in drug response. While this alternative perspective may seem to be mere semantic quibbling, it becomes more important to humans as our feeding regimens come more and more to resemble those of Ad libitum fed rodents.

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