Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes

Abstract

The current societal environment is marked by overabundant accessibility of food coupled with a strong trend of reduced physical activity, both leading to the development of a constellation of disorders, including central obesity, insulin resistance, dyslipidemia, and hypertension (metabolic syndrome). Prolonged calorie restriction (CR) has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats, and mice. Mechanisms of this CR-mediated lifespan extension are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity, inflammation, and functional changes in both the neuroendocrine and sympathetic nervous systems. Here we review some of the major physiological, psychological, and behavioral changes after 6 months of CR in overweight otherwise healthy volunteers. Special emphasis is given to the first completed clinical studies that have investigated the effects of controlled, high-quality energy-restricted diets on both biomarkers of longevity and on the development of chronic diseases related to age in humans. With the incremental expansion of research endeavors in the area of energy or caloric restriction, data on the effects of CR in animal models and human subjects are becoming more accessible.

FIG. 1.

Caloric restriction literature. As shown by the ISI Web of Knowledge–MedLine^® from 1966 until 2008, the numbers of published studies on caloric restriction have increased almost exponentially topping more than 200 citations per year for the last 2 years.

FIG. 2.

The effect of caloric restriction on lifespan. Prolonged lifespan in animals was first reported in rodents more than 70 years ago and since then similar observations are noted across a wide range of species, including yeast, worms, spiders, flies, fish, and dogs. Results reported thus far from three nonhuman primate colonies suggest that CR might have a similar effect in longer-lived species. Whether the benefits of CR extend to humans is not known. CR, calorie restriction.

FIG. 3.

Life expectancy at birth in Okinawa, Japan. Okinawa is an isolated island off mainland Japan that has the lowest risk for age-related diseases and the longest life expectancy. The figure shows the average life expectancy at birth in Okinawa, Japan, United States, and France for men (top panel) and women (bottom panel) (103).

FIG. 4.

Caloric restriction in Biosphere 2. Biosphere 2 (A), a 3.15-acre ecological enclosure, provided an unexpectedly low availability of food for eight individuals who were housed inside for 2 years in the early 1990s. This study of nature of caloric restriction resulted in ∼15% weight loss (B), in changes in energy expenditure and physical activity (C), and many hematological, biochemical, and metabolic alterations (D) consistent with caloric-restricted rodents and primate, including reductions in insulin, core temperature, and metabolic rate (98, 101).

FIG. 5.

The CALERIE Study. The first randomized trial of caloric restriction in humans is sponsored by the National Institute on Aging. In response to a request for applications (RFA), three clinical sites, Washington University, Tufts University, and Pennington Biomedical Research Center, were awarded funding. In the first phase of CALERIE, three independent studies were conducted and 61 individuals participated in a trial of 20%–30% caloric restriction for 6 or 12 months. In the second phase of CALERIE, 250 volunteers aged 21–45 years, with a body mass index between 23 and 27.9, were randomized 2/1 to a 2-year 25% caloric restriction or an ad libitum diet. CALERIE, comprehensive assessment of the long-term effect of reducing intake of energy.

FIG. 6.

CALERIE: Effect of 25% CR on body weight and body composition. Our 6-month study of 25% caloric restriction resulted in a progressive decline in body weight (A) that reached ∼10% the completion of the study (71). Body composition analysis by dual X-ray absorptiometry (B) showed that the loss of tissue mass was attributable to significant reductions in both fat mass (CR: −24% ± 3%) and fat-free mass (CR: −4% ± 1%).

FIG. 7.

Can caloric restriction improve biological age and extend chronological age? This figure summarizes some of the potential biomarkers of aging. It is hypothesized that caloric restriction will change the biological trajectory of these biomarkers and therefore improve biological age and extend chronological age. For example, the left panel shows an individual aged 75 years. With prolonged caloric restriction, it is hypothesized that fasting insulin and oxidative damage will be reduced in this individual. Therefore, an individual although 75 will have a biological age 14 years younger. Similarly, the individual on the right at 90 years with prolonged caloric restriction will be biologically similar to an individual aged 66 years. DHEA-S, dehydroepiandrosterone-sulfate; GH, growth hormone; IGF-1, insulin-like growth factor-1.

FIG. 8.

CALERIE: Effect of 25% CR on daily energy expenditure. The effect of caloric restriction on all components of daily energy expenditure (top panel). The changes in total daily energy expenditure after 3 and 6 months of CR (bottom panel) are shown and those representing a metabolic adaptation (larger than due to weight loss) are highlighted in gray (72). Combining two state-of-the-art methods (indirect calorimetry and doubly labeled water) for quantifying precisely the complete energy expenditure response to CR in nonobese individuals, we identified a reduction in sedentary energy expenditure that was 6% larger than what could be accounted for by the loss in metabolic size, that is, a metabolic adaptation (31) and a metabolic adaptation in the free-living situation as well. This adaptation comprised not only a reduction in cellular respiration (energy cost of maintaining cells, organs, and tissue alive) but also a decrease in free-living activity thermogenesis (behavioral adaptation). TDEE, total daily energy expenditure.

FIG. 9.

Caloric restriction and life expectancy in humans. How can caloric restriction impact life expectancy in humans? By extrapolating the data from rodents to humans (55), one can predict the potential effect of caloric restriction in humans (70). As an example, if Albert Einstein started a 20% CR diet at 25 years of age, he could have increased his life expectancy by approximately 5 years. On the other hand, undertaking a 30% CR diet 45 years later (age 60) would have extended his life by only 2 months. Therefore, CR needs to be initiated early in adult life to significantly increase life expectancy.