Caloric restriction in humans leads to rejuvenation and life extension
At least 18 people practicing calorie restriction with optimal nutrition have been studied by Dr Luigi Fontana at Washington University in St Louis. Medical records of the participants’ previous health data were collected, including body weight, blood pressure, glucose, cholesterol etc to see what effect years of calorie restriction had had on health. Those doing calorie restriction were very lean with a BMI of 19.6 ± 1.9 vs 25. ± 3.2 kg/m for the western diet group. Average time on CR was 6 years ± 3 (range 3 to 15 years).
The study found that major risk factors for cardiovascular disease were reduced significantly in people on CR. The average Total cholesterol and LDL-C concentration for the CR group was in the lowest 10% for people in their age group (50 years). Also, even more dramatic, the levels of triglycerides in the CR group were lower than 95% of Americans who are in their 20s. And their HDL (good cholesterol) was higher than 85-90% of people in middle age. Fasting insulin was 65% lower than the western diet group and glucose was also significantly lower too. People on CR have also been found to have lower body temperature, lower thyroid hormone T3 as well, but people who exercise vigorously and maintained a similar BMI did not see these reductions. Participants of the study also had extremely low blood pressure, equivalent to that of a 10-year old. They had almost non-detectable or very low levels of inflammation measured by c-reactive protein. The IMT carotid artery thickness was measured and found to be 40% less in the CR group compared with the controls: 0.5 ± 0.1 mm in the CR and 0.8 ± 0.1 mm for controls. None of those eating a CR diet had any evidence of atherosclerotic plaque. To show the powerful effect that CR had on their health, the researchers were able to gather medical records from 12 of the individuals in the CR group and show that just like the western diet group, values for the CR group were average (50th percentile) before embarking on the diet.
Possibly even more impressive was results showing that CR in humans might possibly slow down aging of the heart itself. They looked at the diastolic function of the heart and its ability to relax and fill the left ventricle, and found that people on CR had hearts that were similar to those who were 15 years younger. And those on the diet also had the heart rate variability of a person 20 years younger. It looks as if CR must have had a rejuvenating effect on heart function and wasn’t just merely slowing its decline in function and performance.
Just recently participants from the CR society had their muscle biopsied and analyzed to look at gene expression profiles compared to that of 30 year old controls and age-matched controls (58 years); and also they compared the molecular changes in rats on 40% CR. They hypothesised that CR in humans would have induced a down-regulation of the Insulin/IGF-1/FOXO pathway which has been linked with longevity in animals and humans. What they found was a very significant down-regulation of the Insulin/IGF-1/FOXO pathway at the transcriptional and post-transcriptional level. The key changes in skeletal muscle gene expression profile that are observed in long-lived rats are also observed in humans. So not only are humans responding at a physiological level to CR as animals do; but the molecular adaptations seem to mirror that of mice and rats. They also looked at SIRT 1 and AMPK: these two energy-sensing pathways were significantly up-regulated in people on CR. FOXO3A and FOXO-4 were significantly up-regulated: these are known to modify many ‘longevity genes’ in animals and increase activities such as DNA repair, antioxidant defenses, immunity, protein turn over, and cell death genes. Autophagy, which helps remove dysfunctional cell components to recycle was also significantly up-regulated by CR. People on CR had more similar gene expression profiles to the younger individuals in the study. The ‘gene expression’ of people on CR is more like that of a 30 year old than the age-matched 58-year old control group. This is a very important finding to see if the same response to CR is conserved across species to humans.
Looking at the data from mice, rats, rhesus monkeys, and humans, the research group was able to make comparisons to see the differences between each species in how they react at a molecular level and at the physiological level to CR; and also how they react to the various degrees of calorie restriction. It’s clear that people on calorie restriction do display a more CR-like state than either the NIA or Wisconsin rhesus monkey studies. Not only that, people in the CALERIE study who were overweight and merely reduced their body weight to a ‘healthy’ weight from a BMI of 27 to 24 with 25% CR, never exhibited several CR signatures, nor did they have as significant reductions or changes in total cholesterol, LDL-cholesterol, triglycerides, inflammation, thyroid hormone levels, testosterone, estrogen, IGF-1 and cortisol. All of these are strongly influenced in people studied at WUSTL who are from the CR Society and practice moderate-severe CR. Many of these signatures that were not observed in the CALERIE study were also either not observed in the CR primate studies, very inconsistent, or modest in their change or effect. This indicates that the level of CR in the primate studies, as well as the CALERIE human study were insufficient to elicit the key changes that are responsible for the age-retarding effect of CR. Apart from the CR being insufficient to elicit these changes, another possibility could be that the declining difference between energy intakes of the NIA rhesus monkeys (20% less than ad lib for males and only 12% for females) could be the reason why little differences were seen. It was reported also that the calorie restricted monkeys did not exhibit much sign of hunger during the study either; another argument pointing to the fact that the CR group needed to be restricted further. Before embarking on this very long study, it may have been wise to restrict monkeys to various degrees to see if there is a ‘cut-off point’ to where CR does not improve their health further. If they display the CR-phenotype in a more consistent and powerful way, then establish this level of restriction for the CR group for a lifespan study, as long as the level of restriction was not inhumane and the animals did not display poor health from it.
Fortunately we have a lot more control over our own diets, exercise and supplements than animals who are subjected to these diets. The interactions between all of these are only just now being discovered. It’s only a matter of time before we’ll have reliable markers of ageing which we can use to see if our diets are working. In response to the results we see with the diet, we are able to change accordingly to get into the most optimal and CR’d-like to have the best chance for living longer and healthier lives.