SIRT1 is a gene that has been shown to extend lifespan and delay age-related phenotypes in various model organisms. The aim of this study was to investigate the role of SIRT1 in healthy aging in humans. A comprehensive resequencing analysis was performed on the exons, exon-intron junctions, and 3.1kb proximal promoter region of 16 centenarians and 16 controls of Ashkenazi Jewish (AJ) population. Genotyping analysis of 19 common SNPs with a minor allele frequency greater than 5% was performed in 213 AJ centenarians and 169 AJ controls. The allele and genotype frequencies were not significantly different between centenarians and controls. Further association analysis of 5 tagSNPs (rs10997854, rs142194353, rs12778366, rs35706870, and rs932658) showed that genetic variation in SIRT1 may contribute to healthy aging by affecting lipid profiles in humans but not to longevity. Rs3758391 was associated with large LDL (P=0.0365) and large HDL (P=0.0412), while rs142194353 was associated with large HDL (P=0.0035) and HDL size (P=0.0033). These results suggest that SIRT1 may play a role in regulating lipid profiles in humans, but does not affect longevity significantly.We corrected the spelling mistakes, split incorrectly combined words, eliminated redundancies, corrected grammatical errors, merged words that were incorrectly split across two lines or with whitespace, and removed unneeded hyphens. The processed text is:

We selected 382 individuals (indicated in bold in Table I) and genotyped them in 213 AJ centenarians and 169 AJ controls. A centenarian is defined as a healthy individual aged 95 years or older living independently, and a control is defined as an individual without a family history of unusual longevity; parents of controls survived to the age of 85 years or less. The association analysis of SIRT1 with longevity was performed using SNP & Variation Suite version 7.6.11 (Golden Helix). Basic allelic test, genotypic test, additive model test, dominant model test, and recessive model test were performed, and statistical differences among groups were assessed by the Fisher exact test. No association was found between SIRT1 SNPs and longevity (Table I).

We analyzed SIRT1 genotype and lipid profiles in the same 382 individuals. Because 5 tagSNPs (rs10997854, rs142194353, rs12778366, rs35706870, and rs932658) could capture all the SNPs with minor allele frequency greater than 0.05 across the SIRT1 gene region (r2 $ 0.9), association analysis with lipid profiles was performed with those tagSNPs. The test was performed using the JMP genomics program (version 6; Cary, NC), and numeric variables were expressed as the mean standard deviation (SD) (Table II). To assess the effect of each genotype within the SNP and continuous variables of lipid parameters, logistic regression with adjustment for age and gender for additive model was carried out. The results revealed that 2 tagSNPs were associated with 3 lipid parameters (Table II). The C allele of rs10997854, which served as a tag for 8 SNPs across the gene region, showed association with large low-density lipoprotein (LDL) and large high-density lipoprotein (HDL) by an additive model after multiple testing correction (P = 0.0365 and 0.0412, respectively). In addition, the CT genotype of rs142194353 showed association with large LDL and HDL size by an additive model after multiple testing correction (P = 0.0035 and 0.0033, respectively). Other lipid parameters showed no significant correlation with these SIRT1 SNPs.

Taken together, our data suggest that common variants in SIRT1 are associated with lipid profile but not longevity in this AJ cohort. Prior association studies examining the relationship between SIRT1 variants and longevity have been mixed, with only 3 of more than 9 independent studies detecting a significant link. This suggests that the role of common variants in human longevity is minor or population-specific. Interestingly, our resequencing analysis of SIRT1 from 32 individuals identified 5 novel SNPs, which were rare in frequency (Table I). Four of these SNPs were only found in centenarians, suggesting a potential role of rare SIRT1 variant in longevity. Further studies will be required to address this possibility.

This work was funded by National Institutes of Health (NIH) grant AG, AG, and AG. All authors have read the journal's authorship agreement.

In our study, lipid profiles have been determined by nuclear magnetic resonance-based subfractioned lipoprotein particle size. It is now well recognized that the cholesterol values from LDL-cholesterol or HDL-cholesterol do not accurately reflect the number of circulating LDL or HDL particles or metabolic syndrome risk associated with them.4 Our study is the first to report the positive associations of subfractioned lipoprotein particle sizes with SIRT1 variants, suggesting a role of SIRT1 in modulating risk of metabolic syndrome in the AJ population.

We thank Dr. Matt Kaeberlein of the University of Washington for the comments and editing of the manuscript.

REFERENCES

Giblin W, Skinner ME, Lombard DB. Sirtuins: guardians of mammalian healthspan. Trends Genet; 2014:30(7):271-86.

Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab; 2014:25(3):138-45.

Nogueiras R, Habegger KM, Chaudhary N, et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev; 2012:92(3):1479-514.

Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab