Honoring Clive McCay and 75 Years of Calorie Restriction Research

This volume and issue of The Journal of Nutrition marks the 75th anniversary of the publication by McCay, Crowell, and Maynard entitled “The Effect of Retarded Growth upon the Length of Life Span and upon the Ultimate Body Size” (1). The data presented by McCay et al. described, for the first time, that the restriction of calories without malnutrition prolongs mean and maximal lifespan in rats compared with ad libitum feeding (Fig. 1). FIGURE 1 Survival curves generated from the data of McCay et al. (1) for male (A) and female (A) rats consuming ad libitum or CR. While almost 50 years would pass before the importance of this work would be fully recognized as a viable research model for aging (2,3), the importance of this publication to research in nutrition and aging cannot be overstated. Calorie restriction (CR), also referred to as dietary restriction, remains the only nongenetic method that extends lifespan in every species studied, including yeast (4), worms (5), flies (6), and rodents (7). Data collected from nonhuman primates suggest that CR will have similar effects in this species (8,9) and data from the first human trials have been published (8). The ability of CR to extend life and delay the age-related functional decline has, arguably, contributed more than any other model to the overall understanding of the biological processes of aging and longevity. To honor and celebrate the 75-y legacy of the publication in The Journal of Nutrition of McCay, Crowell, and Maynard's pioneering work, we present this brief historical review on CR. McCay et al. (1) state that: “The object of this study was to determine the effect of retarding growth upon the total length of life and to measure the effects of retarded growth upon the ultimate size of the animal's body. In the present study growth was retarded by limiting the calories.” The uniqueness of McCay's design compared with previous investigations was that retarded growth was achieved through the reduction of calories only. Increased longevity by retarding growth in prior investigations had been achieved by the use of nutrient deficiency along with food restriction (10–12). McCay thought that nutrient deficiency together with food restriction most likely caused metabolic problems beyond limiting growth and stated: “It is doubtful if such studies…test the hypothesis [life span and retarded growth], because the two groups, separated on the basis of growth, are not homogenous. The slower growing group tends to include the inferior individuals that die prematurely.” By this statement, McCay et al. established, long before organized aging research, a fundamental prerequisite for valid longevity studies, i.e. all animals must be given the opportunity to achieve old age. Premature death during development is not considered normal aging and must be prevented to collect meaningful data on mean and maximal lifespan. While McCay's interest in aging/longevity has been well documented (13), his 1935 publication also addressed the impact that undernutrition had on retarding growth. The title of the 1935 paper tells us that lifespan was used as an end point marker for the effect that undernutrition had on retarded growth. Documenting the effects of retarded growth on aging/longevity reflected the times in which these studies were being conducted. Mean lifespan had reached only 53 y of age in 1935. The 1920s and 1930s were still plagued by high infant mortality, childhood diseases that killed millions of children under the age of 10 y, and persistent bacterial infections that affected all age groups (widespread use of penicillin was still 7 years away in 1935). The short mean lifespan was the direct result of these medical realities. Moreover, rigorous basic research into the impact that nutrition and specific nutrients had on growth and the health of children had only just begun. Recall that most vitamins were discovered during the first 2 decades of the 20th century. CR's possible impact on the growth and health of children was an important topic in 1935. Mechanisms that underlie aging were not on the radar screen yet. The purpose of this brief historical review is to recognize the 75 years of CR research that can draw its roots to the 1935 The Journal of Nutrition publication by McCay et al. (1). To this end, we will limit this historical review to general topics marking important steps in the development of the model or considerable changes to the fields of nutrition and/or aging caused by research using CR. Page limitations preclude a thorough discussion on the outcomes of research using CR and several excellent reviews accomplish this goal (7,14–17). Hundreds of investigators have contributed greatly to research in CR and we apologize for any failure to mention a particular investigator; the omission is not premeditated.