Luigi Fontana, M.D., Ph.D.
Project Overview:
Calorie restriction (CR) has been shown to slow aging and extend maximal life spans in rodents. Data from studies conducted in laboratory rodents found that CR increases longevity, in part, by preventing or delaying the occurrence of many chronic degenerative diseases. However, the reduction of chronic diseases does not completely explain the increased lifespan and the preservation of function at more youthful-like states in CR rodents, because approximately one-third of CR rodents die without evidence of organ pathology.
The mechanisms responsible for CR-mediated beneficial effects on intrinsic aging observed in rodents probably involve the metabolic adaptations to CR itself. CR reduces metabolic rate and oxidative stress, improves insulin sensitivity, and alters neuroendocrine function in rodents and monkeys. Recently, we have shown that long-term CR results in profound and sustained beneficial effects on the major atherosclerosis risk factors in humans. However, little is know about the effects of long-term CR in humans on markers of aging and longevity such as growth factors, hormones and inflammatory cytokines, which are involved in mediating some of the anti-aging effects observed in CR rodents.
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 also obtain information on a range of cardiovascular physiological and anatomical variables that deteriorate with advancing age in order to determine whether the CR volunteers’ cardiovascular system is aging at a slower than normal rate. These variables include endothelial function, arterial stiffness and heart rate variability. We will test the overall hypothesis that long-term CR in humans causes the same growth factor, hormonal, metabolic and cardiovascular 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 nine years (range 6-18 years). These subjects consume high-quality diets that are high in protein and contain more than 100% of the RDA of all essential nutrients.
Our main goals are to: (1) understand the metabolic and physiological effects of CR with optimal nutrition in healthy human beings, and compare them with those observed in CR rodents in which CR increases maximal longevity, and (2) determine whether the CR individuals are aging less rapidly than healthy control volunteers, as reflected in physiological measures such as arterial stiffness, heart variability, endothelial function, pulmonary function and renal function. Finally, these data will provide the foundation for future grant applications involving longitudinal follow-up measurements on markers of prognosis that can be applied in the general population to persons of normal weight to predict health and longevity.
Final Report:
In the near future, human aging and age-associated diseases will become one of the biggest challenges faced by developed and developing countries. Life expectancy has markedly increased in most developed countries in the last century, from about 45 years at the beginning of the 20th century to about 77 years today. This increase is due primarily to reduced deaths from infectious diseases and in infancy, but also to improved sanitation and working conditions, better nutrition and housing, organized sewage disposal, the development of antibiotics and vaccines, and better health care.
However, the overall increase in average life span is far greater than that for healthy life expectancy, as evidenced by the incremental burden of age-associated diseases, including coronary heart disease, stroke, heart failure, diabetes, hypertension and cancer. Cardiovascular disease, cancer, stroke and diabetes account for nearly 70% of the deaths in the United States and Europe. The financial burden caused by these age-associated chronic diseases is already overwhelming and, if present trends continue, is likely to become unbearable in the next few decades.
