ABSTRACT

Sirtuin 6 (SIRT6) exerts a protective effect on health and extends the lives of model organisms. We, therefore, aimed to clarify whether age-related epigenetic drift is responsible for differences in SIRT6 expression in peripheral blood mononuclear cells (PBMCs) of healthy young (n = 55, mean age 27.5 ± 4.4 years), middle-aged (n = 51, 65.4 ± 3.3 years), and long-lived (n = 51, 93.9 ± 3.6 years) humans. In silico analysis was performed using the STRING network. No age-related differences were observed in the percentage of SIRT6 CpG island methylation. However, the age affected the expression of miR-34a-5p, miR-125a-5p, miR-186-5p, miR-342-5p and miR-766-3p (all p < 0.0001), miR-181-2-3p and Let-7c (both p = 0.0003), and miR-103a-3p (p = 0.0069). A negative association was observed between SIRT6 mRNA and miR-186-5p (r_s = −0.25, p = 0.026), and a positive association was observed with miR-34a-5p (r_s = 0.31, p = 0.0055) and miR-181a-2-3p (r_s = 0.39, p = 0.0002). SIRT6 mRNA also negatively correlated with the expression of TP53 (r_s = −0.41, p = 0.0126) and MYC (r_s = −0.35, p = 0.0448). Notably, the expression of several miRNAs and genes was similar in young and long-lived groups but different from the middle-aged group. We conclude that age-related epigenetic changes can affect the expression of SIRT6 in PBMCs and, in this way, possibly influence immunosenescence. Moreover, molecular events could differentiate ‘normal’ ageing from that of long-lived individuals.

摘要

Sirtuin 6（SIRT6）对健康具有保护作用，并延长了模型生物的寿命。因此，我们旨在阐明与年龄相关的表观遗传漂移是否是造成健康中青年（n = 55，平均年龄27.5±4.4岁）的外周血单个核细胞（PBMC）SIRT6表达差异的原因。51岁，65.4±3.3岁）和寿命长（n = 51、93.9±3.6岁）的人。使用STRING网络进行计算机分析。SIRT6的百分比未发现与年龄相关的差异CpG岛甲基化。但是，年龄影响了miR-34a-5p，miR-125a-5p，miR-186-5p，miR-342-5p和miR-766-3p的表达（所有p <0.0001），miR-181-2- 3p和Let-7c（p = 0.0003）和miR-103a-3p（p = 0.0069）。之间观察到负相关SIRT6的mRNA和miR-186-5p（R_小号 = -0.25，p值= 0.026），和一个正相关用的miR-34A-5P（R观察到_小号 = 0.31，P = 0.0055）和miR -181a-2-3p（r _s  = 0.39，p = 0.0002）。SIRT6 mRNA也与TP53（r _s  = -0.41，p = 0.0126）和MYC（r _s）的表达呈负相关_。 = -0.35，p = 0.0448）。值得注意的是，一些miRNA和基因的表达在年轻和长寿组中相似，但与中年组不同。我们得出结论，与年龄相关的表观遗传变化可能会影响PBMC中SIRT6的表达，并以此方式可能影响免疫衰老。此外，分子事件可以将“正常”衰老与长寿个体的衰老区分开。