Epigenome-wide association study analysis of calorie restriction in humans, CALERIE™ Trial analysis

Abstract

BACKGROUND: Calorie restriction (CR) increases healthy lifespan and is accompanied by slowing or reversal of aging-associated DNA methylation (DNAm) changes in animal models. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIETM) human trial we evaluated associations of CR and changes in whole-blood DNAm. METHODS: CALERIETM randomized 220 healthy, non-obese adults in a 2:1 allocation to two years of CR or ad libitum (AL) diet. The average CR in the treatment group through 24-months of follow-up was 12%. Whole blood (baseline, 12 and 24 month) DNAm profiles were measured. Epigenome-wide association study (EWAS) analysis tested CR-induced changes from baseline to 12- and 24-months in the n=197 participants with available DNAm data. RESULTS: No CpG-site-specific changes with CR reached epigenome-wide significance (FDR<0.05). Secondary analyses of CpG sites identified in published EWAS suggest, we found that CR induced DNAm changes opposite those associated with body mass index (BMI) and smoking (p<0.003 at 12- and 24-month follow-ups). In contrast, CR altered DNAm at chronological-age associated CpG sites in the direction of older age (p<0.003 at 12- and 24-month follow-ups). CONCLUSION: Although individual CpG site DNAm changes in response to CR were not identified, analyses of sets CpGs identified in prior EWAS revealed CR-induced changes to blood DNAm. Altered CpG sets were enriched for insulin-production, glucose-tolerance, inflammation, and DNA-binding and -regulation pathways, several of which are known to be modified by CR. DNAm changes may contribute to CR effects on aging.

Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging

“…Despite this, research into age-related diseases aimed at slowing, halting and even reversing the aging process has not stopped, and extending the healthy lifespan of humans remains the focus of anti-aging research. 28,29 Researchers have been trying to find out which molecules and mechanisms are involved in the ageing process so that more corresponding drugs and sensible dietary supplements can be produced. Senescence of senescent cells or telomere attrition is an important cause of senescence, and therefore, anti-aging strategies by scavenging senescent cells and reducing the attrition of telomeres are also potential pharmacological strategies.…”