Calorie restriction reduces biomarkers of cellular senescence in humans

Abstract

Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young-to-middle-aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Keywords: CALERIE™; aging; biomarkers; caloric restriction; inflammation; metabolism; senescence-associated secretory phenotype.

FIGURE 1

Changes in senescence‐associated biomarkers from baseline to 12‐ and 24‐month timepoints. The changes at 12 months and 24 months were evaluated by mixed effects repeated measures analysis; the symbols *, ** and *** denote p < 0.05, 0.01 and 0.001, respectively, between the ad libitum (AL) and the calorie restriction (CR) groups.

FIGURE 2

Changes in senescence‐associated biomarkers predict changes in HOMA‐IR and insulin sensitivity index at 12 and 24 months. (a, c) The relative importance of change in the top 10 biomarkers (12 months–baseline and 24 months–baseline) and of site, sex, BMI stratum (normal/overweight), intervention group (AL/CR), and baseline HOMA‐IR (base H‐IR) as determined by GBM to predict changes at 12 months and 24 months in HOMA‐IR. (b, d) The R² of the GBM models—covariates (Cov) (sex, BMI stratum, site, intervention group, and base H‐IR) alone, top 10 biomarkers alone (Bio), or covariates plus top 10 biomarkers (Cov + Bio)—for predicting change in HOMA‐IR at 12 months and 24 months. (e, g) Variable importance summaries and (f, h) the R ² of the GBM models for predicting change in the insulin sensitivity index at 12 months and at 24 months using the same covariates as above except for the use of baseline insulin sensitivity index (base IS) in place of base H‐IR. AL, ad libitum; BMI, body mass index; CR, calorie restriction; GBM, gradient boosting machine learning.

FIGURE 3

Calorie restriction reduces a senescence‐associated gene set in human adipose tissue. (a, b) GSEA plots of the SenMayo gene set comparing baseline to 12 months and baseline to 24 months using recently published RNA sequencing data derived from the adipose tissue specimens of eight CALERIE™ participants randomized to CR (Spadaro et al., 2022). (c) Heat map with expression of a subset of the genes included in SenMayo at baseline, 12 months, and 24 months. (d, e) Normalized gene expression of CDKN1A (P21) and CDKN2A (P16) at baseline, 12 months, and 24 months. CR, calorie restriction; GSEA, gene set enrichment analysis.