Importance of caloric restriction (CR)

Previous blogs have focused on specific organ-systems such as skeletal muscle (Insights 2-5) and the brain (Insights 6,7).  Insight 8 describes a proven but difficult path to longevity that impacts ALL organ-systems. This path is one of rigorous caloric restriction. Thus caloric restriction promotes longevity. It is a longevity builder.

Not quite a century ago, a Cornell University researcher, Clive McKay who was studying nutrition in rats, reported that rats who ate 30% less calories than those with free access to food, appeared healthier and lived longer than the controls with unlimited access to food.  All rats consumed adequate intake of vitamins, minerals, essential amino acids and fats throughout the study.

Significance of caloric restriction

First, CR is a repeatable experiment. It has been replicated in many different animal models that include yeast, round worms, fruit flies, mice, dogs, and monkeys.  In all studies, CR restriction of 25-30 or more percent produces a significant extension of lifespan with positive effects on a variety of organ-systems.  

Secondly, the CR studies revealed at least one important mechanism of aging. Thus scientists now know that lifespan (at least from yeast to monkey) can be successfully lengthened with reduction in consumption of calories.

Thirdly, CR opened the door to the identification of drug “mimetics” of CR. These new drugs would work like CR but, importantly, bypass the known difficulty for humans to eat less.

Known benefits of caloric restriction

CR produces many benefits in addition to an increase in lifespan.  This has been studied in depth in rodents and monkeys.  Generally, compared to control animals, CR animals exhibit

   (a) a delay in the occurrence of major diseases,

   (b) a delay in the decline in muscle mass,

   (c) a delay in the decline of the immune system, and

   (d) a delay in the decline in some DNA repair mechanisms (protecting cells from random damage). 

Body temperature may decline slightly but overall physical activity in CR animals compared to controls is normal or slightly increased.  Significantly, and considered the driving force behind the above beneficial changes is a shift in how sugars are metabolized.  CR animals utilize new pathways that  reduce the requirement for insulin, a known pro-aging factor.

Results of CR in monkeys

One of the most important studies on CR are the ongoing ones using Rhesus monkeys at the National Institutes of Aging (NIA) and Wisconsin University (Colman et al., 2014; Mattison et al., 2017).  Monkeys began a 30 percent reduction in calories when they were adults.  After 20 years, the number of CR-treated monkeys exceeded that of the controls (survival in the CR group was 80% versus 50% in the control group).  Other benefits, to name a few, include:

   (a) a delay in age-related pathologies such as diabetes, cardiovascular disease, cancer and brain-related disorders;

   (b)  lower blood pressure, heart rate, fasting blood glucose and a favorable lipid profile (low LDL and triglycerides and high HDL);

   (c)  normal levels of testosterone and estrogen, maintenance of “youthful” levels of melatonin (sleep agent) and dihydroepiandrosterone (DHEA popular supplement considered the precursor to hormonal steroids such as estrogen and testosterone);

   (d) maintenance of immune system function (lower levels of inflammatory mediators and higher levels of anti-inflammatory agents); and

   (e) decreased oxidative damage to muscles and decreased onset of sarcopenia (see Insight 2). 

Application of caloric restriction to man

The first study in man was an observational, retrospective and case-controlled study of 18 volunteers (average age ~ 50 years) in self-imposed CR for 3-15 years paired with 18 healthy same age, sex, but eating a western diet (high fats and carbohydrates).  Compared to those eating the western diet, CR individuals had a lower body mass index, less body fat, more lean muscle mass, lower levels of LDL, triglycerides and fasting glucose and insulin and higher HDL and lower levels of a key inflammatory mediator, C-reactive protein (Fontana et al., 2004).

NIA sponsored the clinical trial, CALERIE = (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) Study  which has completed several small (~50 volunteers) phase I trials of 6 months to 1 year duration and a larger (218 volunteers) phase II trial that lasted 2 years.  In both phases the target caloric reduction was a minimum of 25% but in phase I, individuals achieved a 10-17% caloric reduction and in the longer trial, only a 12% caloric reduction was achieved.  Even with this modest CR, there were positive changes such as decrease in fasting glucose, decrease in inflammatory makers, improved cell function and decrease in cardiovascular risk factors.  However, the CR reduction was too modest and phase II too short to achieve the milestones evident in the monkey studies.

Caloric restriction – next steps

The difficulty for humans to adhere to a 30% reduction in calories has ushered in interest in developing drugs to “mimic” CR.  As the thinking goes, in the future, individuals will be able to take a drug that mimics CR and also be able to eat whatever is desired.  Three candidate drugs have been proposed:

a) metformin

b) rapamycin

c) sirtuins

A discussion of these 3 compound will be the topic of my next blog.

References