Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis

Abstract Caloric restriction(definition) (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21–50y; BMI 22.0–27.9 kg/m 2 ), to 25% CR or ad‐libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE™ participants' blood chemistries, immunology, and epigenetic data suggest the 2‐year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere(definition) length (TL) attrition. TL was quantified in blood samples collected at baseline, 12‐, and 24‐months by quantitative PCR (absolute TL; aTL) and a published DNA‐methylation algorithm (DNAmTL). Intent‐to‐treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect‐of‐Treatment‐on‐the‐Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12‐month weight‐loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period. No differences were observed when considering TL change across the study duration from baseline to 24‐months, leaving it unclear whether CR‐related effects reflect long‐term detriments to telomere fidelity, a hormesis‐like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE™ analyses and trials.