Effects of calorie restriction on markers of aging and longevity

Luigi Fontana, M.D., Ph.D.

Project Overview:
Caloric restriction (CR) reduces the rate of aging and increases life span in all small animal species studied to date, but the effects of CR in humans remain uncertain. Recently, we have shown that long term CR results in profound and sustained beneficial effects on the major atherosclerosis risk factors and cardiac function in humans. All the above mentioned findings are consistent with long-term CR in monkeys and rodents. However, little is know about the effects of long-term CR in humans on markers of aging and longevity, including growth factors, hormones and inflammatory cytokines, which are involved in mediating some of the anti-aging effects observed in CR rodents.

Finding lean subjects who have successfully maintained long-term CR is extremely difficult. However, we have developed a unique research relationship with 26 highly motivated individuals, who have been practicing CR for an average of 6 years (range 3-15 years). Most of these individuals were already lean at the start of their CR program, and are dedicated to practicing severe CR with adequate protein and micronutrient intake in an effort to prevent age-associated chronic diseases and promote longevity. All of these individuals that we have tested are well educated and responsible individuals (business owners, physicians, college professors, lawyers and other professionals, etc.) who are extremely well read and informed in the areas of aging and CR. Moreover, they are very interested in participating in long-term research studies, and have already come to St. Louis from other cities in the US and Canada, at their own expense, for an initial evaluation at Washington University.

The major goal of this proposal is to determine potential markers of aging and longevity by providing comprehensive evaluation of the effects of long-term CR in humans. These markers include hormones, growth factors, and cytokines that affect insulin sensitivity, resting metabolic rate, body temperature, inflammation, cell proliferation, oxidative stress, that are involved in slowing the aging process. We will test the overall hypothesis that long-term CR in humans causes the same growth factor, hormonal, and metabolic changes that have been found in long-lived CR rodents. This hypothesis will be evaluated by studying a unique group of healthy subjects who have been practicing CR for an average of 6 years (range 3-15 years). These subjects eat high-quality diets that are high in protein and contain more than 100% of the RDA of all essential nutrients. Our goal is to determine whether CR results in the same adaptive responses of growth factors, hormones, and inflammatory cytokines in humans as those observed in CR rodents in which CR increases maximal longevity. These data will provide the foundation for future grant applications involving longitudinal follow-up measurements on these markers of aging and longevity.

Progress Report: 
We evaluated the long-term effect of calorie restriction (CR), defined as CR with optimal nutrition, on potential markers of aging and longevity in 28 middle-ages volunteers who had been on a CR diet for an average of 7 years (BMI 19.6±1.8 kg/m2, 8.7±7.3% body fat) and 28 age-matched healthy subjects consuming a typical Western diet (BMI 25.9±3.2 kg/m2, 24.6±6.5% body fat).

We found that long-term CR without malnutrition results in major improvements in indices of glucose tolerance and insulin action. Fasting glucose and insulin, the area under the curve (AUC) for insulin and the index of insulin sensitivity (ISI), calculated according to the method of Matsuda and Defronzo, were all significantly lower in the CR group than in the age and sex-matched Western diet group (Table 1). Accordingly, plasma adiponectin concentration was higher and plasma leptin, IL-6 and TNF-a/adiponectin ratio were lower in the CR group than in the Western diet group.

We also found that long-term CR in humans results in some of the same metabolic, hormonal and growth factors adaptations that are thought to be involved in mediating some of the anti-aging effects observed in CR rodents. In particular, we found that plasma IGF-1, PDGF-AB, TGF-ß, total and free T3 concentration were lower, whereas plasma cortisol concentration was higher in the CR group than in the Western diet group (Table 2). The CR-mediated selective reduction in circulating triiodothyronine (T3) levels in rodents and monkeys, and now in humans are thought to play a key role in reducing metabolic rate and free radical production, whereas the reduction in chronic mitogenic and inflammatory stimuli is supposed to decelerate aging through down-regulation of p53 and NF-kB pathways. We didn’t find any difference in plasma IGFBP-3, THS, FT4 and DHEA-S concentration between the CR and the Western diet groups.

These data add relevant information to the growing research field of “healthy aging”, and the identification of metabolic and hormonal factors that can improve organ function, and consequently healthspan and lifespan in humans.