Abstract
Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR. 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.
Generated Summary
This research article presents the findings of a 2-year randomized controlled trial designed to assess the feasibility, safety, and effects of caloric restriction (CR) on predictors of health span and longevity in humans. The study, conducted on non-obese adults aged 21-51, involved a 2-year intervention aiming to achieve a 25% CR or an ad libitum (AL) diet. The primary outcomes were changes in resting metabolic rate (RMR) adjusted for weight change and core temperature. The study’s design included a rigorous screening process and a 2:1 randomization to the CR intervention versus an “ad libitum” (AL) control group. The study also monitored for adverse events, assessed quality of life variables, and examined various cardiometabolic risk factors, thyroid axis, and inflammation markers as secondary and exploratory outcomes. Data analysis included intention-to-treat principles, repeated measures analysis, and a hierarchical gatekeeping strategy to control for Type I error. The primary focus was on baseline, 12 months, and 24 months of the intervention to assess sustained impact. The research aimed to provide insights into the effects of CR on human survival and disease risk factors, with implications for aging-related outcomes.
Key Findings & Statistics
- Participant Demographics: The study cohort consisted of 218 participants. The cohort was predominantly female (69.7%) and Caucasian (77.1%) with ages ranging from 20.7 to 50.8 years. The mean ± standard deviation BMI was 25.1±1.7 kg/m², with normal blood pressures, fasting blood glucose, insulin, and lipids at baseline.
- Intervention Adherence and Weight Loss: Mean daily energy intake over the first 6 months of the intervention declined from baseline in CR by 480±20 kcal/d and stabilized at approximately 234±19 kcal/d below baseline. CR participants averaged 11.7±0.7% CR over 2 years. Weight loss was significant in the CR group: 7.1±0.2 kg (9.9±0.3%) at 6 months, 8.3±0.3 kg at 12 months (11.5±0.4%), and 7.6±0.3 kg at 24 months (10.4±0.4%). The decrease in lean body mass from baseline was 2.0±0.1 kg (4.2±0.2%) at 6 months, 2.0±0.1 kg at 12 months (4.3±0.3%), and 2.0±0.2 kg at 24 months (4.4±0.3%).
- Adverse Events: Incidence of at least one adverse event was similarly high among AL (96.0%) and CR (95.1%) participants. There were no deaths.
- Outcomes: In the CR group, RMR residual decreased significantly more at 12 months compared to the AL group (48±9 vs 14±12 kcal/d in AL, p = .04). TDEE decreased significantly more in CR than AL. Mean 24-hour core temperature decreased from baseline at 12 and 24 months in CR, but the small declines did not differ significantly from the change in AL.
- Thyroid Axis and Inflammation: The substantial decreases from baseline within the normal range in circulating T3 in CR (16±1.5% at month 12, 22±1.4% at 24 months) significantly exceeded changes in AL. Thyroid-stimulating hormone reductions in CR also significantly exceeded those in AL at 12 months. In both groups, TNF-α concentration decreased from baseline at 12 months, more so by 24 months (23±3.3% CR, 11±4.2% AL). The marked decreases in high-sensitivity CRP from baseline to both time points in CR significantly exceeded changes in AL.
- Cardiometabolic Risk Factors: The decreases in triglycerides and total cholesterol in CR significantly exceeded those in AL, as did decreases in low-density lipoprotein cholesterol. The increase in high-density lipoprotein cholesterol was significantly greater in CR than in AL at 24 months only. Declines in systolic and diastolic blood pressures were also significantly greater in CR than in AL (p = .001). Improvements in glucose control (HOMA-IR) in CR were significantly greater than changes in AL.
- %CR: 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).
- HOMA-IR: Improvements in glucose control (HOMA-IR) in CR were significantly greater than changes in AL (p < .001 at month 12 and month 24).
Other Important Findings
- The study found that sustained CR is feasible in nonobese humans.
- The achieved CR on correlates of human survival and disease risk factors suggests potential benefits for aging-related outcomes.
- The intervention did not significantly affect core temperature.
- The intervention achieved a degree of CR sufficient to affect some, but not all, potential modulators of longevity that have been induced by CR in laboratory animal studies.
- The degree of CR achieved in this study is tolerable and safe.
- The CR group showed substantial decreases from baseline in circulating T3 and TNF-α, exceeding changes in the AL group.
- CR broadly affected cardiometabolic risk factors, with significant improvements in triglycerides, total cholesterol, and blood pressure compared to the AL group.
- The study observed significant weight loss in the CR group.
Limitations Noted in the Document
- The study had a limited statistical power to detect rare adverse events.
- The study’s findings may not be generalizable to broader nonobese populations or those with less intensive interventions.
- The study did not achieve the full 25% CR target.
- The study’s assessment of physical activity relied on self-reported measures, which have inherent limitations in accuracy and sensitivity.
- The study was limited in its ability to determine if the intervention’s effects were due to lowered energy intake per se or weight loss.
- The study’s clinical monitoring for adverse events was limited.
Conclusion
In conclusion, the study demonstrates the feasibility and safety of sustained caloric restriction in nonobese humans, marking a significant step in exploring CR’s potential health benefits. The observed improvements in cardiometabolic risk factors and the modulation of thyroid hormones and inflammatory markers suggest that CR may influence factors associated with longevity. The significant weight loss and maintenance of weight stability are particularly noteworthy. The findings suggest that the benefits observed in the CR group, particularly in reducing cardiometabolic risk factors, could potentially translate to reduced mortality and cardiovascular disease risk. The study emphasizes the importance of clinical monitoring in individuals practicing this degree of CR, despite the absence of serious adverse events. While the findings align with the previous research on weight loss, they also suggest that a greater degree of CR might be needed to achieve more consistent effects. The study supports the potential of CR as a strategy to influence human life span and health span. The study’s success in achieving significant CR and sustained weight loss suggests a promising approach, but also underscores the need for ongoing research into the nuances of caloric restriction and the interplay of its various effects. Further studies are necessary to clarify the specific mechanisms at play and to define the optimal approach for realizing the full benefits of CR in promoting longevity and health.