Weight Regain Reverses Caloric Restriction Benefits on Insulin-IGF-1 Pathway and Biological Age

This post hoc analysis of the 2-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy 2 (CALERIE-2) trial examined the consequences of weight regain on the insulin-IGF-1 nutrient-sensing pathway and biological age. The CALERIE-2 trial was a randomized controlled trial (RCT) that originally enrolled 220 participants, of whom 190 were available for this analysis. Participants were assigned to either a 25% caloric restriction (CR) intervention or a control diet. The intervention phase lasted 12 months, followed by a 12-month maintenance phase, for a total follow-up of 24 months. The setting of the trial was not reported.

During the intervention phase, weight loss ranged from 5.0 to 5.8 kg between groups at 12 months. Between months 12 and 24, most participants maintained weight (n = 112) or continued to lose weight (n = 58), whereas a smaller group regained more than 5% of baseline weight (n = 20). The primary outcome was the impact of weight regain on the insulin-IGF-1 nutrient-sensing pathway and biological age. Secondary outcomes included insulin area under the curve, ratio of insulin-like growth factor 1 (IGF-1) to insulin-like growth factor-binding protein 1, biological age, metabolic benefits, insulin resistance, and hormonal profiles linked to type 2 diabetes risk.

Results showed that weight regain reversed improvements in insulin area under the curve and the ratio of IGF-1 to IGF-binding protein 1. Sustained weight loss was associated with greater reductions in biological age. Exact effect sizes, p-values, and confidence intervals were not reported for these outcomes. The analysis was stratified by weight trajectory groups, and group differences were balanced using propensity score weighting.

Safety and tolerability data were not reported in this post hoc analysis. The study did not report adverse events, serious adverse events, or discontinuations.

Compared to prior landmark studies, the CALERIE-2 trial is one of the few long-term RCTs of caloric restriction in humans. This post hoc analysis extends findings by showing that weight regain can attenuate or reverse benefits on key regulators of the insulin-IGF-1 pathway and biological aging. However, the analysis is limited by its post hoc nature and the small number of participants who regained weight (n = 20).

Key methodological limitations include the post hoc design and the fact that participants were stratified by weight trajectory regardless of original randomization, though propensity score weighting was used to balance groups. The lack of reported p-values and confidence intervals for the main outcomes limits the ability to assess statistical significance. Additionally, the generalizability of findings to populations not in the CALERIE-2 trial is uncertain.

Clinically, these results suggest that substantial weight loss followed by weight regain can attenuate or reverse CR-induced benefits on the insulin-IGF-1 nutrient-sensing pathway and markers of biological aging. Sustained, moderate weight loss more effectively improves insulin resistance and maintains favorable hormonal profiles linked to type 2 diabetes risk and aging biology. Clinicians should emphasize the importance of sustained weight loss for long-term metabolic and aging benefits.

Several questions remain unanswered. The mechanisms by which weight regain reverses these benefits are not fully elucidated. The long-term effects beyond 2 years are unknown. Whether these findings apply to other populations, such as those with obesity or type 2 diabetes, requires further study. Additionally, the impact of different weight loss modalities (e.g., diet vs. exercise) on these pathways is not addressed.