SIRT6 Minor Allele Genotype Is Associated with >5-Year Decrease in Lifespan in an Aged Cohort

Aging is a natural process involving complex interplay between environment, metabolism, and genes. Sirtuin genes and their downstream targets have been associated with lifespan in numerous organisms from nematodes to humans. Several target proteins of the sirtuin genes are key sensors and/or effectors of oxidative stress pathways including FOXO3, SOD3, and AKT1. To examine the relationship between single nucleotide polymorphisms (SNP) at candidate genes in these pathways and human lifespan, we performed a molecular epidemiologic study of an elderly cohort (≥65 years old.). Using age at death as a continuous outcome variable and assuming a co-dominant genetic model within the framework of multi-variable linear regression analysis, the genotype-specific adjusted mean age at death was estimated for individual SNP genotypes while controlling for age-related risk factors including smoking, body mass index, alcohol consumption and co-morbidity. Significant associations were detected between human lifespan and SNPs in genes SIRT3, SIRT5, SIRT6, FOXO3 and SOD3. Individuals with either the CC or CT genotype at rs107251 within SIRT6 displayed >5-year mean survival advantages compared to the TT genotype (5.5 and 5.9 years, respectively; q-value = 0.012). Other SNPs revealed genotype-specific mean survival advantages ranging from 0.5 to 1.6 years. Gender also modified the effect of SNPs in SIRT3, SIRT5 and AKT1 on lifespan. Our novel findings highlight the impact of sirtuins and sirtuin-related genotypes on lifespan, the importance of evaluating gender and the advantage of using age as a continuous variable in analyses to report mean age at death.

衰老是一种自然过程，涉及环境、代谢与基因之间的复杂相互作用。沉默信息调节因子（Sirtuin）基因及其下游靶点，在从线虫到人类的众多物种中均与寿命存在关联。该类沉默信息调节因子基因的多种靶点蛋白，是氧化应激通路的关键感受器与/或效应因子，涵盖FOXO3、SOD3及AKT1。为探究上述通路中候选基因的单核苷酸多态性（single nucleotide polymorphisms，SNP）与人类寿命的关联，我们针对≥65岁的老年队列开展了一项分子流行病学研究。本研究以死亡年龄作为连续结局变量，在多变量线性回归分析框架下采用共显性遗传模型，在控制吸烟、体重指数、饮酒及合并症等年龄相关危险因素的前提下，针对单个SNP基因型估算了经校正的基因型特异性平均死亡年龄。研究发现，人类寿命与SIRT3、SIRT5、SIRT6、FOXO3及SOD3基因上的SNP存在显著关联。与TT基因型携带者相比，SIRT6基因rs107251位点携带CC或CT基因型的个体平均存活年限分别高出5.5年与5.9年（q值=0.012）。其余SNP对应的基因型特异性平均存活优势介于0.5至1.6年之间。性别同样会调控SIRT3、SIRT5及AKT1基因上的SNP对寿命的影响效应。本研究的创新性发现凸显了沉默信息调节因子及其相关基因型对寿命的影响、评估性别的重要性，以及在分析中以年龄作为连续变量以报告平均死亡年龄的优势。