Longevity Research Program
Director: John O. Holloszy, M.D.
Co-Director: Luigi Fontana, M.D. Ph.D.
Project Overview:
Over a 12 year period, we conducted extensive research on the effects of long-term, severe calorie restriction (CR) in members of the Calorie Restriction Society. We were also investigators in the multi-center CALERIE study of the effect of a 25% reduction in calorie intake for two years in healthy people which was completed last year. We have a large amount of biological, physiological, medical and genetic data on CR Society members that was presented in detail in our previous progress reports.
Our findings show that severe CR completely protects against high blood pressure, atherosclerosis/coronary heart disease and diabetes, and that middle-aged and older CR society members in our study appear 20 to 30 years younger than their chronological ages in terms of cardiovascular elasticity, heart rate variability, and gene expression profile in muscle (i.e., markers of aging).
It has also become very evident from our experience with the CALERIE study that the great majority of people find CR to be extremely difficult and not feasible long-term. Our findings on the CR Society members who practice severe CR (there are only a few hundred worldwide) that it is possible to almost completely prevent the metabolic diseases of middle and old age and to slow at least some aspects of the aging process are, nevertheless, extremely valuable. This is because they show that it is possible to powerfully protect against the major diseases associated with aging, and because the data obtained on the CR Society members can be used as standards for comparison to evaluate the relative effectiveness of other interventions.
Progress Report:
Our current research is directed to finding CR mimetics that are effective, but easier to comply with than severe CR. Our first study of a potential CR mimetic is the ongoing study of protein restriction in patients with prostate cancer. This study has been completed and we are now finishing to analyze the tissue and blood samples. We found that protein restriction (without CR) in humans lowers body weight and body fat, significantly reduces fasting glucose, LDL-cholesterol, C-reactive protein, but does not modify serum insulin, IGF-1, IGFBP-1 and IGFBP-3 concentrations (data submitted for publication). However, we did find that protein restriction powerfully increases serum levels of FGF-21, a factor that has been shown to increase maximal lifespan in mice. We are now conducting metabolomics and proteomics studies on the prostate samples to elucidate the molecular effects of protein restriction on several aging and cancer pathways.
Our second study of a potential CR mimetic is the ongoing study of long-term IF in overweight and mildy obese men and women. In this study the middle-aged participants, are fasting for two or three days per week. The rationale for this study is that in lab rodents intermittent fasting mimics the effects of CR on slowing aging and protecting against cancer. This study has aroused much interest in St. Louis, Missouri, and (in contrast to the CALERIE and the Protein Restriction Studies) recruitment of participants is going very well. Furthermore, compliance with the fasting regimen has been good and participants are not finding the fasting difficult. We are obtaining the same measurements on the participants in the fasting study that we have obtained on the CR Society members and will evaluate the effectiveness of the intermittent fasting by comparing the data obtained on the two groups. The last participant will graduate in August 2016, and we will then start to perform the measurement in plasma, urine, and tissue samples. Finally, we are currently actively recruiting for a third study to determine whether or not a healthy Mediterranean diet may potentiate the beneficial metabolic effects of IF.
