Nine of the 10 asthma subjects who began the ADCR regimen complied with the diet, as indicated by progressive weight loss, and completed the study. All 9 subjects exhibited improved asthma symptoms, control and quality of life, demonstrating a clinical benefit of the ADCR diet. An improvement of ACQ or mini AQLQ score of 0.5 is considered clinically important and has been repeatedly shown to be useful in research and management of individual asthma patients. In a recent clinical study of 1414 asthma patients newly started on either fluticosone proprionate or montelucast an improvement in ACQ and mini-AQLQ scores of >1 unit or 47% and 25% respectively was observed38
. Our ADCR study recorded a 54% improvement in ACQ and 61% improvement in mini- AQLQ in patients already on baseline controller therapy. Although medical and surgical induced weight loss is also associated with similar degrees of quality of life improvement (SF-36) our patients also demonstrated improvement in asthma specific control (ACQ) and symptoms (ACUI ) score. Our study demonstrated a 0.25 improvement in ASUI within 3–4 weeks, when weight loss was only 4%. In studies using the ASUI a change of >0.25–0.3 is associated with a clinically detectable difference in asthma severity classification Although all these scoring systems could be linked simply to weight loss the rapid change associated with change in inflammatory markers are consistent with improvement in asthma burden. The improvement in PEF of 44.6 L/min+-3.8 in our study is consistent with the improvement usually observed after “optimizing” controller medications in mild/moderate asthmatics. Although major weight loss (13%) is known to result in some improvement in pulmonary function, our PEF improvement occurred within 3–4 weeks when weight loss was 4%; PEF thereafter remained constant, whereas continued through 8 weeks, suggesting that the change in pulmonary function in response to the ADCR diet was not due solely to weight loss.
The significant increase in the FEV1 after albuterol in the subjects during the ADCR diet compared to baseline suggests an effect of the ADCR diet on airway smooth muscle responsiveness, consistent with an anti-inflammatory effect. In a study of 58 obese women losing >13% of body weight over six months, there was no change in response to metacholine challenge5
, suggesting that the changes were independent of airway reactivity. Although we did not evaluate methacholine responsiveness, the improved airway response to bronchodilators should not be caused by weight loss per se and is consistent with an anti-inflammatory response from the ADCR diet.
Particularly striking were the reductions in levels of TNFα, BDNF and markers of oxidative stress (protein carbonyls, nitrotyrosine and 8-isoprostane) in the serum of the asthma patients during the course of the ADCR diet period. Levels of these markers of inflammation and oxidative stress were decreased on both ad libitum and CR days, indicating a sustained effect of the ADCR diet that did not fluctuate in response to the level of energy intake on the day prior to blood sampling. The decreased levels of TNFα and BDNF suggest that ADCR suppresses inflammation, which may contribute to the beneficial effects of ADCR on asthma symptoms and hyperresponsiveness. Indeed, studies of asthma patients and animal models of asthma have provided evidence that TNFα10, 12
and BDNF16, 39
are important mediators of airway inflammation and associated symptoms. It was previously reported that levels of protein carbonyls, nitrites and nitrates, and lipid peroxidation products were increased in plasma from patients with bronchial asthma compared to control subjects40
. The consistent and progressive decrease in levels of oxidative stress in our subjects may therefore be a marker of, or to have contributed to, the improvement in symptoms on the ADCR diet. The striking reduction in markers of oxidative damage which we observed have not been described in daily calorie restriction studies. Other authors have reported modest or non-significant changes in levels of protein carbonyls with various CR regimes41, 42, 43
. Similarly, in a previous weight loss study nitrotyrosine levels declined 23% in the Caucasian women and remained unchanged in African American women44
, suggesting that different groups of subjects exhibit differential reductions in oxidative stress in response to weight loss.
The mechanism(s) by which ADCR reduces oxidative stress and inflammation in asthmatic subjects remains to be established. However, based upon previous studies of the effects of alternate day fasting on cellular physiology in rodents, two general mechanisms are likely. First, because subjects on ADCR exhibit a reduction in overall energy intake and lose weight, there is likely a reduction in cellular oxygen free radical production24, 41, 42
. The latter effect of ADCR would be associated with lower levels of oxidatively modified proteins and lipid peroxidation products in the blood. Second, ADCR may impose a mild beneficial stress, to which cells respond adaptively by up-regulating the expression of antioxidant systems. Such increased cellular stress resistance has been shown occur in rodents on an alternate day energy restriction regimen, resulting in increased disease resistance24
. It will be of considerable interest to determine the effects of ADCR on gene expression in tissue involved in the pathogenesis of asthma.
We found that serum leptin levels were lower in subjects on CR compared to AL days throughout the 8 week study period, and that leptin levels on AL days decreased progressively during the 8-week study period. Leptin has been shown to exert pro-inflammatory actions45
, and it is therefore possible that the reduction in leptin levels contribute to the anti-inflammatory effects of the ADCR diet. On the other hand, the ADCR diet did not significantly affect circulating levels of this hormone, a result consistent with our evidence that the ADCR does not result in a sustained overactivation of the hunger response.
Humans are unable to consistently comply with a long-term daily caloric reduction of 40% (consuming 60% of maintenance), as has been used in most animals studies to date. The authors of a recent three week trial in which 16 volunteers alternated eating ad lib for 24 hours and nothing the next 24 hours concluded that, due to persistent hunger and irritability, it was unlikely subjects would stay on the regime for extended periods of time46
. We designed the ADCR pattern of eating intended as an accommodation to human needs and adaptation to human meal pattern of the alternate day total fasting pattern used in rodent studies. When rats or mice are maintained on an alternate day fasting regimen they maintain body weights 10–25% lower than ad libitum fed control animals, live up to 30% longer and exhibit improvement in a range of health indicators47
. A regimen which allows ad libitum feeding on one day and reduced food/caloric intake on the next day (for longer periods of time), whereby a stable weight is maintained, may prolong lifespan and healthspan in humans48
. Low levels of oxidative stress may be necessary to reach very old age; at least two studies have shown lower oxidative stress in centenarians than in 70 year olds49, 50
In our study, the ADCR pattern of eating consisted of repeating cycles of a (approximately) 36 hour period of very low calorie intake and a 12 hour period of AL eating was tolerable and efficacious in treating asthma symptoms, at least in obese subjects. Larger studies that include a control group or a cross-over design with measures of airway reactivity and inflammation will be required to further elucidate the full impact of ADCR diets on obese asthma patients. Further studies to improve asthma outcome are desirable since current therapies do not seem to modify the underlying process or factors that determine disease progression. It will also be important to determine if such diets benefit patients with other disorders that involve inflammation and oxidative stress such as atherosclerotic heart disease51