SIRT6 minor allele genotype is associated with >5-year decrease in lifespan in an aged cohort

Abstract

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.

Figure 1. AKT1 rs3803304 location and adjusted mean age at death and genotype frequency distribution stratified by gender.

A. SIRT6 is located on chromosome 19p13.3, 8491 bp in length with 8 exons . rs107251, indicated by a blue dash and blue arrows, is an intron variant located after exon 4. It is not located in a mammalian conserved region indicating it is not likely a causal variant for lifespan. Several SNPs are located in SIRT6; rs107251 is thought to capture all of this information. SNPs denoted by a red dash are missense variants; a green dash denotes a synonymous variant. B. CC genotypes and CT genotypes have a >5-year adjusted mean survival advantage over the TT genotype. Data were calculated by multivariable linear regression with adjustment for BMI, smoking, alcohol consumption and comorbidities. There is a significant genotype distribution difference between the 65+RHS and HapMap-CEU populations (p<0.01).

Figure 2. SIRT3 from chromosomal to base pair level demonstrating the location and characteristics of the two SIRT3 SNPs significantly associated with adjusted mean age at death.

A. SIRT3 is located on chromosome 11p15.5, 21332 bp in length with 5 exons. Of 12 SIRT3 SNPs genotyped, two were significantly associated with age at death, rs511744 and rs4758633, denoted by the blue arrows. These two SNPs are approximately 450 base pairs apart, located just after exon 1. Even though very close in physical location, there was a significant gender × rs4758633 interaction effect (p = 0.08) but not rs511744 (p = 0.49). These two SNPs are not in mammalian conserved regions (MCR) indicating they are likely not causal but in LD with the functional variant. SNPs denoted by a red dash are missense variants; a green dash denotes a synonymous variant. B. Adjusted mean age at death for males and females for rs511744. Data were calculated by multivariable linear regression with adjustment for BMI, smoking, alcohol consumption and comorbidities. Genotype frequency distribution did not differ between males and females for rs511744 (p = 0.86) C. Adjusted mean age at death for males and females for rs4758633. Genotype frequency distribution did differ for rs4758633 (p<0.01).D. rs511744 and rs4758633 are in moderate LD (r² value between 0.5-0.8) for both males and females.

Figure 3. SIRT5 from chromosomal to kilobase level to show the location and characteristics of two SIRT5 SNPs significantly associated with the adjusted mean age at death.

A. SIRT5 is located on chromosome 6p23, 37,647 bp long with 8 exons. Blue arrows denote the three SNP genotypes within SIRT5. SNP rs2841505 is an upstream variant in a mammalian conserved region (MCR) and rs4712047 is an intron variant, not in a mammalian conserved region. SNPs denoted by a red dash are missense variants; a green dash denotes a synonymous variant. B. The gender interaction effect with rs2841505 was not significant (p = 0.55). The genotype frequency distribution did not differ between males and females (p = 0.54). C. The gender interaction effect with rs4712047 was significant (p = 0.06). The genotype frequency distribution does not differ between males and females (p = 0.47). D. Pairwise LD estimates suggest rs2841505 and rs4712047 are in low LD.

Figure 4. AKT1 rs3803304 location and adjusted mean age at death and genotype frequency distribution stratified by gender.

AKT1 is located on chromosome 14q32.33. The gender interaction effect with rs3803304 was significant (p = 0.04). There is no difference in genotype distribution between males and females (p = 0.85).