Longer Life Foundation Longevity Research Program

Longer Life Foundation Longevity Research Program: 
John Holloszy, M.D., Director
Luigi Fontana, M.D. Ph.D., Associate Director

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 the CR Society members that was presented in detail in our progress report last year. Our findings show that severe CR completely protects against high blood pressure, atherosclerosis/coronary heart disease and diabetes, and that the middle-aged and older CR society members in our study appear 20 to 30 yr younger than their chronological ages in terms of their cardiovascular elasticity, and 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 world-wide) 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.

Our current research is directed to finding “CR mimetics” that are effective, but easier to comply with than CR.  Our first study of a potential CR mimetic is the ongoing study of protein restriction in patients with prostate cancer.  This study is almost completed and we will start analyzing the tissue and blood samples this summer.  However, the prostate cancer patients have found the protein restriction regimen extremely difficult to stick to, and it is my (JOH) impression from our preliminary data that it is not an effective CR mimetic.

In our current study we are investigating the effects of intermittent fasting.  In this study the middle-aged participants, who are in the high normal to moderately obese weight range, are fasting for two 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 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 (see weight loss data in Table 1), and the 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.

Progress Report:
We have continued to analyze muscle and blood samples obtained on members of the Calorie Restriction Society and the two control groups: age and sex matched highly trained long distance runners and age and sex matched sedentary individuals eating Western Diets.

Calorie restriction (CR), which retards aging and is believed to act as a hormetic low-intensity stressor, increases serum corticosterone concentrations and HSP70 expression in rodents. However, nothing is known regarding the effects of long-term CR without malnutrition on these and other stress-related factors, which are key for maintaining cellular quality control, in humans. In this study, serum cortisol, aldosterone and leptin were measured in 37 men and women (mean age 52.3±11 yrs) who had been on CR diet for 3-15 years, in 37 age-, sex- and body fat-matched exercising (EX) subjects, and in 37 age- and sex-matched sedentary individuals eating Western diets (WD). The CR and EX groups were leaner and had significantly lower serum leptin concentration than the WD group. Serum cortisol concentration was higher in the CR group than in the WD and EX groups (Table 2), while serum aldosterone concentration was similar among groups.  In addition, the expression of major molecular chaperones and autophagic proteins was measured in skeletal muscle of subgroups of 15 CR individuals and age- and 10 sex-matched WD controls. Heat shock proteins (Table 3), beclin-1 and LC3 mRNA and protein levels (Table 4) were significantly higher in skeletal muscle of the CR than in the WD group. In conclusion, our data provide the new information that long-term CR with adequate nutrition in humans is associated with increases in serum cortisol concentration and key molecular chaperones and autophagic proteins that are involved in cellular protein quality control, and removal of dysfunctional proteins and organelles.