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 prevalence4, 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.

REFERENCES

1. McCay CM, Crowell MF, Maynard LA. The effects of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition 1935; 10:63-79.

2. McCay CM, Ellis GH, Barnes LL, Smith CAH, Sperling G, Chemical and pathological changes in aging and after retarded growth. Journal of Nutrition 1939; 18:15-25.

3. Ross MH. Length of life and nutrition in the rat. Journal of Nutrition 1961; 75:197-210.

4. Ross MH, Bras G. Lasting influence of early caloric restriction on prevalence of neoplasms in the rat. Journal of the National Cancer Institute 1971; 47:1095-1113.

5. Ross MH, Bras G. Influence of protein under- and overnutrition on spontaneous tumor prevalence in the rat. Journal of Nutrition 1973; 103:944-963.

6. Ross MH, Lustbader E, Bras G. Dietary practices and growth responses as predictors of longevity. Nature 1976; 262:548-553.

7. Ross MH. Nutrition and longevity in experimental animals (pp.43-57). In Winick M (ed.) Nutrition and Aging. Wiley and Sons; New York, 1976.

8. Masoro EJ. Food restriction in rodents: an evaluation of its role in the study of aging. Journal of Gerontology 1988; 43:B59-B64.

9. Weindruch RH. Aging in rodent fed restricted diets. Journal of the American Geriatric Society 1985; 33:125-132.

10. Walford RL, Liu RK, Gerbase-Delima M, Mathies M, Smith GS. Long term dietary restriction and immune function in mice: response to sheep red blood cells and to mytogenic agents. Mechanisms of Aging and Development 1974; 2:447-451.

11. Walford RL, Harris SB, Weindruch R. Dietary restriction and aging: historical phases, mechanisms and current directions. Journal of Nutrition 1987; 117:1650-1654.

12. Bronson RT, Lipman RD. Reduction in rate of occurrence of age related lesions in dietary restricted laboratory mice. Growth, Development and Aging 1991; 55:169-184.

13. Lipman RD, Dallal GE, Bronson RT. Effects of genotype and diet on age-related lesions in Ad libitum fed and calorie restricted F344, BN, and BNF3F1 rats. The Journal of Gerontology: Biological Sciences In press.

14. Bronson RT. Rate of occurrence of lesions in 20 inbred and hybrid genotypes of rats and mice sacrificed at 6 month intervals during the last years of life (pp.279-358). In Harrison DE (ed.) Genetic Effects on Aging II. Telford Press, Caldwell, NJ, 1990.

15. Sprott RL, Austad SN. Animal models for aging research (pp. 3-23). In Schneider EL, Rowe JW (eds.). Handbook of the Biology of Aging, Fourth Edition, Academic Press: Orlando, 1995.

16. Turturro A, Hass BS, Hart RW. Does caloric restriction induce hormesis? This Issue.