Tier 3 — preclinical

Association of SIRT6 Gene Polymorphisms with Human Longevity

Li Y, Qin J, Wei X, Liang G, Shi L, Jiang M, Xia T, Liang X, He M, Zhang Z
Iranian Journal of Public Health 2016 Volume 45, issue 11, pages 1420–1426

Bibliography

DOI
No DOI available
PubMed
PMID 28032059
PubMed Central
PMC5182250
Funding
National Natural Science Foundation of China (NSFC-81260423, NSFC-61161009) awarded to Dr Zh. Zhang.
Competing interests
The authors declare that there is no conflict of interest.

Study snapshot

DesignCase-control genetic association study using TaqMan SNP genotyping.
ModelRural Chinese population in Bama County (Hongshuihe River Basin, Guangxi), a region known for exceptional longevity.
Sample503 total participants across three groups — longevity group n=169 (43 men, 126 women, aged 90–110); internal control n=158 (aged 26–82, same region); external control n=176 (aged 20–82, Nandan County ~160 km away).
InterventionNone — observational genotyping study. rs350846 C/G genotype determined via TaqMan SNP Genotyping Assay.
DurationCross-sectional single time-point genotyping and biometric measurement.
Endpointsrs350846 C/G genotype frequency by group; Hardy-Weinberg equilibrium test; Minor allele frequency of the C allele; Multinomial logistic regression of longevity against genotype + BMI + waist circumference + SBP + DBP + FBG + TC + TG + HDL-c + LDL-c + sex

What the study showed, in plain terms

This is the first published human genetic study looking specifically at a common SIRT6 variant and longevity. Researchers at Guangxi Medical University genotyped 503 rural Chinese adults for a single-nucleotide polymorphism in the SIRT6 gene (rs350846) — a C-versus-G change in the DNA sequence. The participants came from Bama County, a region well known for exceptional longevity, plus two control groups.

The headline finding — reported in the paper's abstract and conclusion — is that the C allele of rs350846 was more common in the geographically distant external control group than in the long-lived group or its local controls. Superficially this sounds like the C allele is protective against longevity, or that the G allele favours it.

The more careful reading is different. When the authors ran the multinomial logistic regression — the model that asks whether the SIRT6 SNP is an independent predictor of longevity after accounting for confounders like BMI, blood pressure, and cholesterol — the SIRT6 genotype effect washed out. BMI, systolic blood pressure, and HDL cholesterol remained significant. The SNP did not.

Read honestly, this is a hypothesis-generating result. It shows a difference in SIRT6 genotype frequency across three Chinese populations, but does not demonstrate an independent SIRT6 effect on human longevity once lifestyle and cardiometabolic factors are controlled for.

Key findings

  • Long-lived Bama residents (n=169, aged 90–110) had significantly lower BMI and triglycerides but higher SBP, DBP, HDL-c, and LDL-c than either control group — the anticipated cardiometabolic profile of an exceptionally long-lived rural cohort.
  • The dominant SIRT6 rs350846 genotype in the longevity group was GG (52.7%), similar to the internal Bama control (54.4%). The external control group (Nandan County, 160 km away) had a different distribution, with CG dominant (50.0%) and only 36.4% GG.
  • The minor allele-C frequency was 0.287 in the longevity group and 0.386 in the external control group — a significant difference on chi-square testing (P=0.006).
  • In the multinomial logistic regression model adjusting for BMI, waist circumference, SBP, DBP, FBG, TC, TG, HDL-c, LDL-c, and sex, no rs350846 genotype was an independent predictor of longevity in either comparison. Significant independent predictors were BMI (protective for longevity), SBP (protective at lower values), HDL-c (variable direction across comparisons), and sex.
  • Genotype frequencies satisfied Hardy-Weinberg equilibrium in all three groups.

What this study can and cannot tell us

This is a single-site case-control study with a modest sample size (503 total participants) in a specific Chinese rural population. The findings cannot be generalised to other ethnicities or geographies without replication. A subsequent larger study in a Hainan Island Chinese population (n=1,462) examined five different SIRT6 SNPs and found no association with longevity — highlighting how population-specific these signals can be.

The paper's conclusion — that "the C allele of rs350846 in the SIRT6 gene, CC and CG genotypes, as well as BMI, systolic pressure, and HDL-c are associated with longevity" — overstates what the regression analysis actually shows. The genotype effect washed out in the adjusted model. Only the cardiometabolic covariates were independent predictors. Readers relying on the abstract alone will come away with a stronger SIRT6 conclusion than the data support.

The external control group came from a different county (Nandan) with different lifestyle, diet, and possibly environmental exposures. Some of the between-group difference in allele frequencies may reflect geographic population structure rather than a longevity-selection signal.

rs350846 is only one of many common SIRT6 variants. This study cannot rule out an effect from other SNPs, from rare variants like the enhanced-function centenarian variant later described by Simon and colleagues, or from epigenetic regulation of SIRT6 expression.

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