Obesity Discussion Forums

[Obesity Discussion]

Excessive Adiposity, Calorie Restriction, and Aging
Luigi Fontana, MD, PhD


JAMA. 2006;295:1577-1578.

Obesity is a major public health problem. As reported by Ogden et al1 in this issue of JAMA, results of the 2003-2004 National Health and Nutrition Examination Survey (NHANES) indicate that an estimated 66% of US adults are overweight or obese, and 17% of US children are overweight. In the authors' analysis of NHANES data from 1999-2004, they found an increasing prevalence of overweight in children (ages 2-19 years) and an increasing prevalence of obesity in men, but not women; however, women had nearly double the rate of severe obesity compared with men. Excessive adiposity is a serious problem, and is associated with insulin resistance, dyslipidemia, low-grade inflammation, and changes in levels of growth factor and other hormones that play a role in the development of diabetes, atherosclerosis, and some types of cancer.2-3 Furthermore, evidence is accumulating that adiposity is associated with accelerated aging.2-4

A number of studies have demonstrated that decreasing caloric intake by 30% or more in young or middle-aged laboratory animals prevents or retards age-related chronic diseases and significantly prolongs maximal life span.5-6 The mechanisms through which this effect is mediated are not known, but may include reductions in metabolic rate, oxidative stress and inflammation, improved insulin sensitivity, and changes in neuroendocrine and sympathetic nervous system function.7-12

Whether long-term calorie restriction with adequate nutrition slows aging in humans is not yet known. Maximal life span, defined as the mean life span of the longest-lived decile of the cohort, or roughly, the life span at which 95% of the population has already died, is the gold standard for determining whether an intervention slows aging. It is improbable that information regarding the effect of calorie restriction on maximal life span in humans will become available in the foreseeable future. However, as an alternative to measuring maximal longevity, it is possible to determine if calorie restriction induces some of the same metabolic, hormonal, and gene expression adaptations in humans that are thought to be involved in the slowing of aging in calorie-restricted lower organisms.

Studies of volunteers in Biosphere 2, who experienced severe food restrictions for much of the 2-year investigation,13 and of highly motivated individuals who have self-selected a calorie-restricted, optimal nutrition diet for an average of 6 years,14 have demonstrated significant decreases in cardiovascular risk factors, blood pressure, inflammatory markers, and fasting insulin and glucose levels associated with calorie restriction. In addition, Meyer et al have recently shown that long-term calorie restriction in humans has cardiac-specific effects, which ameliorate aging-associated changes in diastolic function, a well-accepted marker of primary aging.15

In this issue of JAMA, Heilbronn et al16 report results from phase 1 of the Comprehensive Assessment of the Long Term Effects of Reducing Intake of Energy (CALERIE) Trial, a randomized clinical trial funded by the National Institute on Aging, that evaluated the effects of 6-month calorie restriction on surrogate biomarkers of longevity,17 and importantly, on body temperature, thyroid function, and oxidative stress in nonobese humans. Forty-eight healthy men and women were randomly assigned to a control group that received a diet supplying 100% of energy requirements, a 25% calorie-restricted diet, a 12.5% calorie-restricted diet plus a prescribed exercise program to achieve a 12.5% increase in energy expenditure, or a very low-calorie diet (890 kcal/d) until achieving a 15% reduction in body weight followed by a weight maintenance diet.

The work of Heilbronn and colleagues adds considerable information to current understanding of the effects of calorie restriction in humans. All 3 calorie-restricted interventions produced significant body weight reduction and fat loss over the 6-month study period. Other significant changes at 6 months included decreases in serum insulin level, sedentary energy expenditure, body temperature, triiodothyronine (T3) level, and DNA damage. Levels of fasting glucose and dehydroepiandrosterone sulfate (DHEAS), protein carbonyl concentration, spontaneous physical activity, and thermic effect of food (expressed as percentage of energy intake) were not changed from baseline; whether the lack of effect on these outcomes was related to the short study duration remains to be determined.

The most important contributions from this study for enhancing current understanding of the effects of calorie restriction on aging relate to the calorie restriction–mediated reductions in core body temperature, serum T3 levels, and oxidative damage to DNA, as reflected by a reduction in DNA fragmentation. The oxidative stress hypothesis of aging is currently one of the most accepted explanations for how aging occurs at the biochemical and cellular level. Evidence supporting this hypothesis comes from several recent studies that demonstrated strong correlations between accelerated aging and the accumulation of oxidative damage to cellular macromolecules, and reduced oxidative damage in longer-surviving, calorie-restricted rodents.7, 18 In particular, the calorie restriction–mediated reduction in circulating T3 levels in rodents and monkeys is thought to play a key role in reducing core body temperature, cell metabolism, and free radical production.19-22 In mice, it has been shown that calorie restriction down-regulates the expression of several DNA damage–inducible transcripts, consistent with reduced endogenous DNA damage.23 The study by Heilbronn et al is the first to report a significant decline in DNA damage in response to calorie restriction in humans.

Several limitations in the CALERIE study design, some of which the authors note, deserve mention. The study was of insufficient duration to detect changes in biomarkers of longevity such as serum DHEAS and glucose concentrations and involved a relatively small number of participants per group. Longer-term studies, with a larger number of calorie-restricted individuals who reach and maintain a new body weight and total body fat plateau, are needed to determine whether the hormonal, metabolic, and gene expression adaptations are maintained and are similar to those observed in long-term calorie-restricted rodents.

It is anticipated that the study by Heilbronn et al will stimulate additional investigation of the effects of calorie restriction in humans. Measuring tissue-specific effects of calorie restriction using genomic, proteomic, and metabolomic techniques will foster the development of an understanding of the complex biological processes involved in the antiaging effects of calorie restriction.

Although is it not likely that many individuals would adopt a calorie-restricted diet, the value of these studies is that they suggest possible mechanisms of aging in humans and points of intervention to modify the effects of aging. Further elucidating the mechanisms that control longevity will be a major step in understanding the age dependency of a range of chronic human diseases and will help to improve the quality of life in old age.


AUTHOR INFORMATION

Corresponding Author: Luigi Fontana, MD, PhD, Washington University School of Medicine, 4566 Scott Ave, Campus Box 8113, St Louis, MO 63110 (lfontana@im.wustl.edu).

Financial Disclosures: None reported.

Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.

Author Affiliations: Division of Geriatrics and Nutritional Sciences and Center for Human Nutrition, Washington University School of Medicine, St Louis, Mo, and the Division of Food Science, Human Nutrition and Health, Istituto Superiore di Sanitá, Rome, Italy.


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