"A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity" (the CALERIE study), Ravussin et al 2015 http://biomedgerontology.oxfordjournals.org/content/70/9/1097.full http://biomedgerontology.oxfordjournals.org/lookup/suppl/doi:10.1093/gerona/glv057/-/DC1 (press release: http://www.nih.gov/news/health/sep2015/nia-01.htm )
"Methods. To determine CR’s feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21–51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change (“RMR residual”) and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.
Results. Body mass index averaged 25.1 (range: 21.9–28.0kg/m2). 82% percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.
Conclusions. Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.
Observational studies of persons voluntarily practicing long-term CR suggest that it favorably affects chronic disease risk factors and has several parallel effects to those in laboratory animals (5)...Although clinical trials have yielded considerable information on the effect of weight loss on obesity-related conditions, data from controlled studies in nonobese persons on CR’s effects on aging-related outcomes are sparse. In pilot trials for the present study, 6–12 months of CR in overweight but nonobese persons favorably affected risk factors for several conditions affecting health span (6–8). One (7) also provided evidence for metabolic slowing, reduced core temperature, and lowered triiodothyronine (T3), which are effects found in many laboratory animal CR studies and proposed to contribute to CR’s effects on life span.
CALERIE’s target sample size was 225, with 2:1 ratio randomization to the CR intervention versus an “ad libitum” (AL) control group who continued their habitual diet. Randomization was stratified by site, sex, and BMI dichotomized into normal weight (22.0 ≤ BMI < 25.0kg/m2) and overweight (25.0 ≤ BMI < 28.0kg/m2).
The intervention was designed to achieve 25% CR, defined as a 25% reduction from AL baseline energy intake. The target level of 25% CR was selected because this degree of CR strongly affects life span and health span in animal models, and was found to be feasible in most participants in a 6-month CALERIE pilot study (7). An intensive 2-year behavioral intervention was designed to facilitate 25% CR (11).
Baseline mean ± standard error energy intake (assessed as TDEE during weight stability) did not differ significantly between AL and CR: 2,390±45 and 2,467±34 kcal/d, respectively (p = .15). Mean daily energy intake over the first 6 months of the intervention declined from baseline (Figure 2A) in CR by 480±20 kcal/d during the first 6 months of intervention, then stabilized at approximately 234±19 kcal/d below baseline for the remainder of the trial, resulting in CR averaging 11.7±0.7% over 2 years (19.5±0.8% during the first 6 months and 9.1±0.7% on average for the remainder of the study). %CR in the AL group was 1.3±1.1% over the first 12 months and 0.4±1.1% over the second 12 months, p < .001 versus CR. Weight loss (Figure 2B) was significant in CR: 7.1±0.2kg (9.9±0.3%) at 6 months, 8.3±0.3kg at 12 months (11.5±0.4%), and 7.6±0.3kg at 24 months (10.4±0.4%), all p < .0001. The decrease in lean body mass from baseline was 2.0±0.1kg (4.2±0.2%) at 6 months, 2.0±0.1kg at 12 months (4.3±0.3%) and 2.0±0.2kg at 24 months (4.4±0.3%), all p < .001. Change in weight was predominantly due to body fat loss (74% fat at 6 months, 74% fat at 12 months, and 69% fat at 24 months).
30 participants were withdrawn or dropped from the intervention prior to completion including 4 (5.3%) in the AL control group and 26 (18.2%) in the CR group (p = .01)....
Safety and Quality of Life
There were no deaths and eight serious adverse events (seven AL, one CR), none considered to be related to the intervention. Six women (three AL, three CR) became pregnant and were permanently withdrawn according to the protocol. Eight CR participants were temporarily discontinued from the intervention for safety concerns: one for a BMI <18.5kg/m2, three for a decrease in bone mineral density ≥5% from baseline, and four for treatment-resistant anemia. Five resumed the intervention after these problems resolved. The bone mineral density deficit in one participant and anemia in two participants did not resolve and they were permanently withdrawn from the intervention. The small bone mineral density decreases (lumbar spine and femoral neck) in the CR group significantly exceeded those in the AL control group. Monitoring for eating disorders found no incident events. Adverse events are summarized in online Supplementary eTable 2. Incidence of at least one adverse event was similarly high among AL (96.0%) and CR (95.1%) participants.
We found no significant adverse effects of CR on a broad range of quality of life variables including mood, self-reported hunger, sexual function, and cognitive function, using validated measures of all constructs. These results are shown in online Supplementary eTable 3.
[ http://biomedgerontology.oxfordjournals.org/content/suppl/2015/04/07/glv057.DC1/CALERIE_JGMS_Main_Outcome_Paper_Online_Supplement_030115.docx pg8; no suspicious patterns like point-values consistently indicating harm from CR while being underpowered to give p<0.05, true, but it's hard to believe that self-reported hunger was near-identical between groups! what about the 18% lost from the CR group? you'd expect them to have had much worse side-effects, naturally - it is totally implausible that they dropped at random. still, even if you assume they were driven mad by hunger, that still implies the surviving 80% of CR subjects apparently adapted just fine to the diet, and 80% is a lot of people who could adopt CR and realize potential benefits... ]
This study addresses two long-standing issues regarding implications of CR’s extension of life span and health span in animal models: its feasibility in humans and the degree to which its human effects parallel those in animal models. CALERIE achieved significant CR and sustained weight loss over 2 years in nonobese persons, half with BMI <25kg/m2. To our knowledge, no previous study in any population, not to mention a normal weight population, has demonstrated this degree of sustained CR and weight loss for this length of time. The maintenance of weight stability in the second year of the intervention is particularly noteworthy, because it allowed assessment of CR’s effects during the phase when most CR outcomes in laboratory animal studies have been measured.
Our results indicate that the degree of CR achieved in this study is tolerable and safe, with the qualification that the study had limited statistical power to detect rare adverse events. The dropout rate of 18% in the CR group was lower than projected in our power calculations. It is nonetheless important to recognize that our study, which involved a highly motivated population and very intensive behavioral intervention, provides limited evidence regarding the feasibility of CR in broader nonobese populations or with less intensive interventions.
The fact that TDEE residual in the CR group declined more than RMR residual, and declined significantly more in CR than in AL over the 2-year intervention, suggests that the CR intervention implemented in this study produced a sustained decrease in nonresting energy expenditure more than expected for the degree of weight loss. These results are consistent with other studies in which diminution of residual TDEE during maintenance of reduced weight was comprised primarily of diminution of nonresting energy expenditure (26). The finding that changes in self-reported physical activity did not differ significantly between AL and CR groups (data not shown) suggests that CR may increase the metabolic efficiency of physical activity, which has been reported in nonhuman primates (27), and/or of other activity. However, given self-reported physical activity measures’ limitations in accuracy and sensitivity to change, additional data are needed to clarify the degrees to which CR affects physical activity levels and metabolic efficiency of physical activity.
A long-standing issue in the interpretation of CR studies has been the degree to which its effects are mediated by lowered energy intake per se or by weight loss. This issue can be addressed directly by intervention studies that include treatment arms yielding equivalent degrees of weight loss produced by CR versus increased energy expenditure from physical activity. A rodent study with such a design found that CR extended both maximum and mean life span, while increased physical activity extended only mean life span (36). A CALERIE pilot study with an analogous design found that CR and physical activity had parallel effects on a variety of metabolic outcomes (8) and on many, but not all, coronary heart disease risk factors (37), some of which were improved significantly only by CR. Although CALERIE did not include multiple treatment arms to address this issue directly, future analyses of CALERIE data on weight loss, %CR, and outcomes could provide additional insights on this point."
"Methods. To determine CR’s feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21–51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change (“RMR residual”) and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.
Results. Body mass index averaged 25.1 (range: 21.9–28.0kg/m2). 82% percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.
Conclusions. Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.
Observational studies of persons voluntarily practicing long-term CR suggest that it favorably affects chronic disease risk factors and has several parallel effects to those in laboratory animals (5)...Although clinical trials have yielded considerable information on the effect of weight loss on obesity-related conditions, data from controlled studies in nonobese persons on CR’s effects on aging-related outcomes are sparse. In pilot trials for the present study, 6–12 months of CR in overweight but nonobese persons favorably affected risk factors for several conditions affecting health span (6–8). One (7) also provided evidence for metabolic slowing, reduced core temperature, and lowered triiodothyronine (T3), which are effects found in many laboratory animal CR studies and proposed to contribute to CR’s effects on life span.
CALERIE’s target sample size was 225, with 2:1 ratio randomization to the CR intervention versus an “ad libitum” (AL) control group who continued their habitual diet. Randomization was stratified by site, sex, and BMI dichotomized into normal weight (22.0 ≤ BMI < 25.0kg/m2) and overweight (25.0 ≤ BMI < 28.0kg/m2).
The intervention was designed to achieve 25% CR, defined as a 25% reduction from AL baseline energy intake. The target level of 25% CR was selected because this degree of CR strongly affects life span and health span in animal models, and was found to be feasible in most participants in a 6-month CALERIE pilot study (7). An intensive 2-year behavioral intervention was designed to facilitate 25% CR (11).
Baseline mean ± standard error energy intake (assessed as TDEE during weight stability) did not differ significantly between AL and CR: 2,390±45 and 2,467±34 kcal/d, respectively (p = .15). Mean daily energy intake over the first 6 months of the intervention declined from baseline (Figure 2A) in CR by 480±20 kcal/d during the first 6 months of intervention, then stabilized at approximately 234±19 kcal/d below baseline for the remainder of the trial, resulting in CR averaging 11.7±0.7% over 2 years (19.5±0.8% during the first 6 months and 9.1±0.7% on average for the remainder of the study). %CR in the AL group was 1.3±1.1% over the first 12 months and 0.4±1.1% over the second 12 months, p < .001 versus CR. Weight loss (Figure 2B) was significant in CR: 7.1±0.2kg (9.9±0.3%) at 6 months, 8.3±0.3kg at 12 months (11.5±0.4%), and 7.6±0.3kg at 24 months (10.4±0.4%), all p < .0001. The decrease in lean body mass from baseline was 2.0±0.1kg (4.2±0.2%) at 6 months, 2.0±0.1kg at 12 months (4.3±0.3%) and 2.0±0.2kg at 24 months (4.4±0.3%), all p < .001. Change in weight was predominantly due to body fat loss (74% fat at 6 months, 74% fat at 12 months, and 69% fat at 24 months).
30 participants were withdrawn or dropped from the intervention prior to completion including 4 (5.3%) in the AL control group and 26 (18.2%) in the CR group (p = .01)....
Safety and Quality of Life
There were no deaths and eight serious adverse events (seven AL, one CR), none considered to be related to the intervention. Six women (three AL, three CR) became pregnant and were permanently withdrawn according to the protocol. Eight CR participants were temporarily discontinued from the intervention for safety concerns: one for a BMI <18.5kg/m2, three for a decrease in bone mineral density ≥5% from baseline, and four for treatment-resistant anemia. Five resumed the intervention after these problems resolved. The bone mineral density deficit in one participant and anemia in two participants did not resolve and they were permanently withdrawn from the intervention. The small bone mineral density decreases (lumbar spine and femoral neck) in the CR group significantly exceeded those in the AL control group. Monitoring for eating disorders found no incident events. Adverse events are summarized in online Supplementary eTable 2. Incidence of at least one adverse event was similarly high among AL (96.0%) and CR (95.1%) participants.
We found no significant adverse effects of CR on a broad range of quality of life variables including mood, self-reported hunger, sexual function, and cognitive function, using validated measures of all constructs. These results are shown in online Supplementary eTable 3.
[ http://biomedgerontology.oxfordjournals.org/content/suppl/2015/04/07/glv057.DC1/CALERIE_JGMS_Main_Outcome_Paper_Online_Supplement_030115.docx pg8; no suspicious patterns like point-values consistently indicating harm from CR while being underpowered to give p<0.05, true, but it's hard to believe that self-reported hunger was near-identical between groups! what about the 18% lost from the CR group? you'd expect them to have had much worse side-effects, naturally - it is totally implausible that they dropped at random. still, even if you assume they were driven mad by hunger, that still implies the surviving 80% of CR subjects apparently adapted just fine to the diet, and 80% is a lot of people who could adopt CR and realize potential benefits... ]
This study addresses two long-standing issues regarding implications of CR’s extension of life span and health span in animal models: its feasibility in humans and the degree to which its human effects parallel those in animal models. CALERIE achieved significant CR and sustained weight loss over 2 years in nonobese persons, half with BMI <25kg/m2. To our knowledge, no previous study in any population, not to mention a normal weight population, has demonstrated this degree of sustained CR and weight loss for this length of time. The maintenance of weight stability in the second year of the intervention is particularly noteworthy, because it allowed assessment of CR’s effects during the phase when most CR outcomes in laboratory animal studies have been measured.
Our results indicate that the degree of CR achieved in this study is tolerable and safe, with the qualification that the study had limited statistical power to detect rare adverse events. The dropout rate of 18% in the CR group was lower than projected in our power calculations. It is nonetheless important to recognize that our study, which involved a highly motivated population and very intensive behavioral intervention, provides limited evidence regarding the feasibility of CR in broader nonobese populations or with less intensive interventions.
The fact that TDEE residual in the CR group declined more than RMR residual, and declined significantly more in CR than in AL over the 2-year intervention, suggests that the CR intervention implemented in this study produced a sustained decrease in nonresting energy expenditure more than expected for the degree of weight loss. These results are consistent with other studies in which diminution of residual TDEE during maintenance of reduced weight was comprised primarily of diminution of nonresting energy expenditure (26). The finding that changes in self-reported physical activity did not differ significantly between AL and CR groups (data not shown) suggests that CR may increase the metabolic efficiency of physical activity, which has been reported in nonhuman primates (27), and/or of other activity. However, given self-reported physical activity measures’ limitations in accuracy and sensitivity to change, additional data are needed to clarify the degrees to which CR affects physical activity levels and metabolic efficiency of physical activity.
A long-standing issue in the interpretation of CR studies has been the degree to which its effects are mediated by lowered energy intake per se or by weight loss. This issue can be addressed directly by intervention studies that include treatment arms yielding equivalent degrees of weight loss produced by CR versus increased energy expenditure from physical activity. A rodent study with such a design found that CR extended both maximum and mean life span, while increased physical activity extended only mean life span (36). A CALERIE pilot study with an analogous design found that CR and physical activity had parallel effects on a variety of metabolic outcomes (8) and on many, but not all, coronary heart disease risk factors (37), some of which were improved significantly only by CR. Although CALERIE did not include multiple treatment arms to address this issue directly, future analyses of CALERIE data on weight loss, %CR, and outcomes could provide additional insights on this point."
