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 (CALERIE TM) human trial we evaluated associations of CR and changes in whole-blood DNAm. Methods CALERIE TM 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 CR treatment was not associated with epigenome-wide significant (FDR<0.05) DNAm changes at the individual-CpG-site level. Secondary analysis of sets of CpG sites identified in published EWAS revealed that CR induced DNAm changes opposite to those associated with higher body mass index and cigarette 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.

中文翻译：

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人类热量限制的全表观基因组关联研究分析，CALERIE TM 试验分析

背景 热量限制 (CR) 可以延长动物模型中的健康寿命，并减缓或逆转与衰老相关的 DNA 甲基化 (DNAm) 变化。在减少能量摄入长期影响综合评估 (CALERIE TM) 人体试验中，我们评估了 CR 与全血 DNAm 变化的关联。方法 CALERIE TM 将 220 名健康、非肥胖成年人按 2:1 随机分配，接受为期两年的 CR 或随意 (AL) 饮食。24 个月随访期间，治疗组的平均 CR 率为 12%。测量全血（基线、12 和 24 个月）DNAm 谱。表观基因组范围关联研究 (EWAS) 分析测试了 n=197 名具有可用 DNAm 数据的参与者中 CR 引起的从基线到 12 个月和 24 个月的变化。结果CR治疗与个体CpG位点水平的全表观基因组显着(FDR＜0.05)DNAm变化无关。对已发表的 EWAS 中确定的 CpG 位点组进行的二次分析表明，CR 诱导的 DNAm 变化与与较高体重指数和吸烟相关的变化相反（12 个月和 24 个月随访时 p<0.003）。相反，CR在与实际年龄相关的CpG位点处向老年方向改变了DNAm(在12个月和24个月的随访中p＜0.003)。结论 虽然尚未确定响应 CR 的单个 CpG 位点 DNAm 变化，但对先前 EWAS 中确定的 CpG 组的分析揭示了 CR 诱导的血液 DNAm 变化。改变的 CpG 组在胰岛素产生、葡萄糖耐量、炎症以及 DNA 结合和调节途径方面得到丰富，其中一些已知会被 CR 修饰。DNAm 的变化可能会导致 CR 对衰老的影响。