ABSTRACT
Caloric restriction in non-obese humans improves metabolic efficiency and reduces oxidative damage markers which may decrease cancer incidence and progression.
Keywords: Caloric restriction, Oxidative stress, Metabolism, Aging, Obesity, Biology of malignant cells, Tumor metabolism
Context
The global burden of cancer is significant. In 2015, there were approximately 17.5 million cancer cases, 8.7 million deaths, and 208.3 million disability-adjusted life-years with half of all cancers in people aged 66 and older.1 The 21st century is plagued by an obesogenic environment where calorie rich diets and sedentary behaviors are driving a reduction in lifespan and an increase in cancer incidence and mortality. Nutrition interventions such as calorie restriction (CR) which have shown to preserve human health and prolong lifespan in numerous animal species since the 1930’s, are gaining momentum. Two of the largest longitudinal studies in Rhesus monkeys agree that CR reduces incidence of age-related conditions and diseases such as cancer, diabetes, and cardiovascular disease, but disagree that young-onset CR reduced all-cause mortality and age-related death.2 Differences in diet composition and animal husbandry are two debated reasons for the conflicting results on lifespan in addition to a slight CR in the control animals and age at time of CR initiation. Thus, the benefit of CR interventions for human health span and biomarkers of aging is the subject of clinical trials.
Methods
In 53 (34 CR and 19 ad libitum control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a 25% reduction in caloric intake over 2 years. Year 1 was active weight loss while year 2 was weight loss maintenance. Adherence to the caloric restriction with multivitamin supplementation was fostered through an intense behavioral intervention which included a mathematically predicted weight loss trajectory, meal provisions, structured curriculum, and regular meetings with a behavioral intervention team. Clinical outcomes were assessed at 1 and 2 years of the CR intervention. Body weight was measured fasting, and body composition (% fat) was measured by dual X-ray absorptiometry. Total daily energy expenditure was measured during 14-day assessment periods by doubly labeled water. Energy expenditure was measured over 24-hours and during sleep (sleep EE) in a room calorimeter. Physical activity including spontaneous physical activity and activity-related energy expenditure was measured with indirect calorimetry (metabolic chamber) and stable isotopes (doubly labeled water). Urinary 2,3 – dinor – iPF(2α) – III and four F2 – isoprostane isomers were measured to assess systemic oxidative damage. Biomarkers of aging including fasting glucose, insulin, dehydroepiandrosterone and core body temperature (telemetry) were measured. Biomarkers of metabolism including circulating hormones such as thyroid stimulating hormone, triiodothyronine (T3), thyroxine, reverse T3 and leptin were measured in fasting blood. Nitrogen, creatinine, norephinephrine, and epinephrine were measured in a 24-hour urine collection.3
Findings
The behavioral intervention achieved a 14.9% CR across the 2-year intervention. While the control group maintained body weight over 2 years, the CR group decreased body weight by −9.4 ± 0.4 kg at year 1 which was maintained at year 2 (−8.7 ± 0.4 kg). Approximately 70% of the weight loss constituted a reduction in fat mass. After accounting for expected changes in sleep EE due to body mass changes, sleep EE was reduced approximately 7% indicating a metabolic adaptation in comparison with the control group. Numerous biomarkers of aging have been identified in rodents and primates, including body temperature and hormones. Leptin, T3, insulin, and night-time core body temperature were significantly reduced in the CR group at year 1 and 2. In addition, decreased systemic oxidative stress was observed in the CR group as indicated by reduced urinary F2-isoprostane and the three additional isomers. Positive effects on health related quality of life in the parent study were observed.4
Commentary
This study demonstrates caloric restriction, even in non-obese humans, has health benefits through metabolic mechanisms related to the rate of living theory (improved metabolic efficiency) and oxidative damage theory (decreased production of reactive oxygen species). These two theories also relate to cancer incidence and pathogenesis. Endogenous reactive oxygen species produced during cellular respiration play an important role in the initiation and progression of carcinogenesis as they may cause damage to DNA which can lead to mutations and genomic instability. In addition, excess adipose tissue dysregulates lipids, estrogens, androgens, insulin, insulin-like growth factor-1 (IGF-1), and adipokine-related inflammatory factors. Dysregulation of these signaling molecules, such as in overweight and obesity stimulate cell proliferation, growth, and survival via several interrelated mechanisms including the stimulation of anabolic pathways (growth hormone/IGF-1). CR has been shown to decrease signaling through anabolic pathways which may lead to decreased cell proliferation and increased apoptosis which may in turn reduce cancer incidence and recurrence.5 Indeed, drastic weight loss in women who have had bariatric surgery have reduced rates of cancer later in life.6 The role of CR in slowing cancer progression by decreasing growth factor-regulated cell proliferation and apoptosis and IGF-1 growth and cell cycle regulation is evident in various preclinical animal models. However, chronic moderate CR is difficult to employ and maintain in cancer patients and improvement in treatment outcomes vary. Therefore there is growing interest in CR and similar dietary interventions including short-term fasting, intermittent fasting, ketogenic diets, and caloric mimetics (i.e. metformin and methionine restriction).7 Clinical research is needed to better understand the effects these interventions may have on cancer progression and recurrence both independently and in complement to standard of care.
Competing interests
This is an auto-commentary written in part by Dr. Leanne Redman who is the first author of the manuscript reviewed here.
References
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