Aging is a multifactorial process that affects all lifeforms beginning at birth. Research into methods to extend life began decades ago with lower life forms such as yeast, nematodes, mice and continued for decades on differing species including non-human primates with each study showing positive life extending properties associated with calorie restriction (CR). The search for a “new age” Tree of Life or Fountain of Youth treatment continued with renewed energy until an advanced definition was formed for applying this search to humans. Since the quality of life with the absence of age-related diseases is a goal of human life extension as well as adding years onto those years free of disease, a new term was given to the outcome of human longevity research, “healthspan” (1).
What is CRON?
CRON, or calorie-restricted-optimal-nutrient diet is an acronym for a diet developed by Roy and Lisa Walford after participation in the “Biosphere 2” project in 1991-92. (2) Proponents of this diet believe that most people have a “set-point” weight that they will gravitate to when eating normally that is determined by genetics and childhood habits. Evidence for this theory was never proven.
Proponents of this diet also believe that sticking to about 10-15% under this “set-point” is one indicator of diet effectiveness, an indicator that is certainly lacking determination of quality of diet or adequacy of nutrients.
Walford’s original Biosphere 2 diet contained 10% fat calories, 1 gm/protein/kg body weight and was almost totally vegetarian. Furthermore, the study was not long-term but lasted 6 months. The diet was supplemented with 50% of the RDI for multivitamins and minerals plus 100% of vitamin D, vitamin B12, folic acid, vitamin E and vitamin C. Foods were nutrient dense and claimed to be low glycemic index. There were 8 subjects in his study group. (2)
The CRON diet is typically started by improving the quality of nutrient intake first by incorporating nutrient dense, lower calorie foods into the diet rather than by restricting calories. General changes are recommended first such as cutting out sugar, white flour and eating more fresh fruits and vegetables. Omega-3 fatty acids are encouraged. Decreasing weight/percent body fat to a healthy BMI should be done slowly at a rate of 2% per month for overweight individuals and 1% for others. Special guidelines exist for pregnancy, the elderly, those in growth cycles, and other “at risk” groups.A typical restriction percentage from assessed needs is 20%, although calculations for the restriction seem to differ depending on source.
Risks of the CRON diet plan
Risks of the diet first and foremost are malnutrition and eating disorders. After that comes a possible loss of libido, feeling cold, reduced bone mass, hunger or food obsession, menstrual irregularity, or rapid weight loss more than recommended by the CRON plan.
What are cellular biomarkers for aging?
To examine a therapy for effectiveness, we need to know what we are looking for. To slow down the aging process the treatment should do one or more of the following functions…the more functions it can perform, the stronger the treatment. The following mechanisms are associated with aging and to increase healthspan a therapy must positively affect the following: (1)
· Telomere shortening or erosion
· Genetic changes such as the breakdown of genes and the emergence of genetic disease tendencies
· Stem cell depletion
· Cellular aging
· Mitochondria dysfunction
· An instability in the genome
· Proteostasis imbalance related to an imbalance in the biological pathways of protein homeostasis within and without the cell. It is a key process related to successful aging without disease
· Impaired nutrient sensing, i.e. The cells ability to sense the presence of glucose or other nutrients so that nutrient-specific molecules essential for metabolism and life can be produced
· Abnormal cell to cell communication
Impact of CRON on cellular markers of aging
This is where the review of studies on the outcome of the CRON diet get interesting, contradictory, inconclusive, poorly defined, poorly designed and easily misinterpreted. First, there seems to be no standard reference base for calorie restriction or how the CR is determined. Quality of the diet was not a consistently studied or addressed variable. The amount and type of protein in the diet was generally not addressed. The number of subjects in the studies were frequently small and/or predominantly male. (4-9)
The reported impact of CRON on healthspan has been the following: lowering of cholesterol, blood pressure, blood glucose and total leukocyte count (2); a reduction in fat mass and overall adiposity (3); prevention of increase in BMI after an athlete retires (5); prevention of age related heart muscle changes resulting in better blood pressure control (7); a promising adjunct to cancer therapy (8).
In addition to calorie restriction, one of the mechanisms proposed for the CRON diet’s positive effects on healthspan is the limited amount of the amino acid methionine found in many follower’s diets. Also, the composition of the protein load correlated with age is another variable to consider. A lower protein intake has been associated with lower mortality up until the age of 65 and then the reverse becomes true according to some studies. The same relationship exists for the composition of the protein load. A primarily vegetarian diet is associated with lower mortality up until age 65-70 and the correlation disappears. (8)
Other mechanisms identified to date associated with CR include activation of the SIRT 1 biochemical pathway, the decline in growth hormone and growth hormone receptors, a reduction in fasting blood sugar thus potentially impacting diabetes expression, and a reduction in IGF-1 (7,8).
A novel and controversial study recently published by Tomiyama and his team set out to measure telomere length in CRON society members who had been following Walford’s diet for a mean of ten years. The surprising result was that the telomere length was statistically significantly shorter in Walford’s CRON group than in the control group.
Delayed immune aging was also not proven which recalls Walford’s low total lymphocyte counts (TLC) in his study which dropped from a normal range to a level sub-normal indicative of a possible nutritional deficiency. (6) Tomiyama’ s study has its shortcomings as the number of subjects was small, predominantly male and older than 50. However, it is one of the few studies available that measure telomere length after a significant time on the CRON diet. The conclusions, which, admittedly must be approached with caution, are disturbingly different than expected.
Application of research
All in all, there have been relatively few human studies on the effects of the CRON diet in its original form on biomarkers of aging. No real longevity or healthspan conclusions can be drawn from these studies on caloric restriction relative to healthspan at this point.
It is clear that future studies need to look at a larger sample size of differing age groups and an even distribution between male and female. A consistent percentage or calculation for caloric restriction should be used across all studies. A standardized supplement regime should be used with subjects and controls. Diet records need to be computer analyzed for nutrient content, distribution of macronutrients, protein content relative to needs, type of protein consumed and the amount of methionine eaten.
Outcome measures should address those elements associated with aging and aging related disease variables which should be clearly defined in the study methodology.
In summary, the CRON diet seems to be a restrictive form of lifestyle that few can follow safely and justifies the scientific search for caloric restriction mimetics, or nutraceuticals /pharmaceuticals that can mimic the effects that we see in caloric restriction in other species in our human species to slow down the ravages associated with the aging process. Right now, our most promising nutraceutical for this mimetic is Resveratrol.
More studies are needed on the effects of the CRON diet on biomarkers of healthspan and until then the risks seems to outweigh the benefits for humans.
1. Pica A, Pesce V, et al. Does eating less make you live longer? Clinical Investigations in Aging. 2017; 12:1887-1902.
2. Walford R, Harris S, et al. The calorically restricted low-fat nutrient dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol and blood pressure in humans. Proceedings of the National Academy of Sciences. 1992;89(23):11533-37.
3. Das S, Roberes SB, et al. Body composition changes in the Comprehensive Assessment of Long Term Effects of reducing intake of energy (CALERIE)-2 study: a 2-year randomized controlled trial of calorie restriction in non-obese humans. Am J of Clin Nutr. 2017; 105:913-27.
4. Jain S, Sing SN. Calorie restriction – an approach towards obesity management. J. Nutr Disorders Ther.2015; S1:006.
5. Czerwinska M, Holowko J et al. Caloric Restriction Diet (CR Diet) or Mediterranean Diet (MD)-which is better choice for former athletes? Central European J of Sports Medicine and Science. 2018;13(1);23-35.
6. Tomiyama A, Milush J, et al. Long-term calorie restriction in humans is not associated with indices of delayed immunological aging: A descriptive study. 2017. 147-156.
7. Meyer T, Kavacs S, et al. Long -term caloric restriction ameliorates the decline in diastolic function in humans. J of the American College of Cardiology. 2006;47(2):388-402.
8. Levine M, Suaz J. Low protein intake is associated with a major reduction in IGF-1, cancer and overall mortality in the 65 and younger but not older population. Cell Metab. 2014; 9(3):407-417.
9. Kopeina GS, Senichkin VV, et al. Caloric restriction – a promising anti-cancer approach from molecular mechanisms to clinical trials. Biochimica et Biophysica Acta. 2017; 1867: 29-41.
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