rs350845 — SIRT6
Intronic eQTL in SIRT6 where the rare A allele upregulates SIRT6 expression across 18 tissue types and is enriched in Ashkenazi Jewish centenarians, linking higher SIRT6 activity to improved genomic stability and longevity
Details
- Gene
- SIRT6
- Chromosome
- 19
- Risk allele
- G
- Consequence
- Regulatory
- Inheritance
- Additive
- Clinical
- Protective
- Evidence
- Moderate
- Chip coverage
- v3 v4 v5
Population Frequency
Ancestry Frequencies
Related SNPs
Category
Longevity & AgingSee your personal result for SIRT6
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SIRT6 rs350845 — The Longevity Guardian Variant That Shapes Your Genomic Defense System
Your cells wage a continuous war against entropy. Every day, ultraviolet radiation, reactive oxygen species, replication errors, and jumping genetic elements called retrotransposons threaten the integrity of your DNA. SIRT6 — a NAD+-dependent enzyme — sits at the center of this defense, coordinating DNA double-strand break repair, telomere maintenance, retrotransposon silencing, and metabolic regulation. How well your cells wage this war is partly determined by how much SIRT6 your genome produces, and rs350845 is one of the key regulatory switches.
The Mechanism
rs350845 lies within an intron of the SIRT6 gene on chromosome 19p13.3. Although it does not change the
SIRT6 protein sequence, it functions as a cis-acting expression quantitative trait locus (eQTL)11 cis-acting expression quantitative trait locus (eQTL)
a
genetic variant that influences how much of a nearby gene is transcribed into mRNA
— specifically, the A allele increases SIRT6 transcription across at least 18 tissue types. Carriers of
one or two A alleles produce measurably more SIRT6 protein than GG individuals.
SIRT6 requires NAD+22 NAD+
nicotinamide adenine dinucleotide, a coenzyme that declines with age and is the
substrate that powers all sirtuin activity as a cofactor to
perform two distinct enzymatic reactions: histone deacetylation (removing acetyl marks from histones H3K9
and H3K56 to compact chromatin at DNA break sites and telomeres) and mono-ADP ribosylation (chemically
tagging proteins like PARP1 and KAP1 to recruit repair machinery and silence retrotransposons).
When SIRT6 levels are high — as in A-allele carriers — these two functions operate more robustly:
- DNA double-strand break repair: SIRT6 stabilizes DNA-PK and recruits repair factors within seconds of a break occurring. Higher expression means more rapid response to genotoxic insults.
- LINE1 retrotransposon silencing: SIRT6 mono-ADP ribosylates KAP1, which in turn recruits HP1α to package LINE1 elements into condensed, transcriptionally silent heterochromatin (Van Meter et al., Nature Communications 2014)33 (Van Meter et al., Nature Communications 2014). During aging, SIRT6 becomes depleted from these loci and LINE1s reactivate — driving inflammation and genomic instability. GG individuals, producing less baseline SIRT6, may reach this depletion threshold earlier.
- Telomere maintenance: SIRT6 deacetylates H3K9 at telomeric chromatin, stabilizing the protective cap structure. Insufficient SIRT6 causes telomere uncapping and chromosomal end-joining.
The Evidence
The primary human evidence for rs350845 comes from a 2022 study of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ controls (Simon et al., EMBO Journal 2022)44 (Simon et al., EMBO Journal 2022). The A allele was present in 17.2% of centenarian chromosomes compared to 12.6% in controls (p = 0.009), a nominally significant enrichment replicated against gnomAD reference frequencies (p = 0.007). The same study noted that rs350845 is in near-perfect linkage disequilibrium (r² > 0.98) with rs350843 and rs350846, which also upregulate SIRT6 — all three eQTLs are effectively measuring the same longevity signal.
The causal link between higher SIRT6 and longer life is robustly supported by animal models. SIRT6 transgenic male mice showed 14.5% mean lifespan extension with reduced IGF1 signaling (Kanfi et al., Nature 2012)55 (Kanfi et al., Nature 2012). A later study achieved lifespan extension in both sexes by restoring energy homeostasis in aged animals, with SIRT6 overexpression enhancing hepatic NAD+ synthesis and maintaining glucose output through improved gluconeogenic substrate utilization (Roichman et al., Nature Communications 2021)66 (Roichman et al., Nature Communications 2021). Across mammalian species, SIRT6 DNA double-strand break repair efficiency correlates strongly with maximum lifespan — longer-lived species simply have more active SIRT6.
A separate rs350845 association was reported for Parkinson's disease risk in a Hungarian cohort (Torok et al., Scientific Reports 2021)77 (Torok et al., Scientific Reports 2021), but the finding was not significant after false discovery rate correction and should be considered exploratory.
The evidence level for rs350845 is moderate: the longevity association is nominally significant in one well-designed cohort and is mechanistically coherent, but replication in non-Ashkenazi populations and larger genome-wide studies is needed to establish it at the strong level.
Practical Implications
The core implication of this SNP is about NAD+ sufficiency and DNA-damage avoidance. SIRT6 is NAD+-dependent, and NAD+ declines ~50% by age 60 in humans. GG individuals, who already produce less baseline SIRT6, are more exposed to the functional consequences of this decline. Supporting NAD+ levels with precursors and protecting against unnecessary DNA damage (ionizing radiation, genotoxic chemicals, tobacco carcinogens) become especially relevant for GG carriers.
For AG and AA carriers, the A allele provides partial to full upregulation of SIRT6 expression — but this benefit still depends on adequate NAD+ availability to keep the enzyme active. All genotypes benefit from NAD+ support, but the priority is highest for GG.
Interactions
rs350845 is in high LD with rs350843 and rs350846, which tag the same SIRT6-upregulating haplotype. These are not independent signals.
rs107251 is a separate SIRT6 intronic variant (not in LD with rs350845) associated with >5-year mean survival advantage for CC and CT carriers vs TT in an Iowa aging cohort (TenNapel et al., PLOS ONE 2014)88 (TenNapel et al., PLOS ONE 2014). Individuals who carry the protective allele at both rs350845 (A) and rs107251 (C) likely enjoy additive SIRT6-related genomic stability benefits, though formal compound analysis has not been published.
rs12696304 (TERC) influences telomere length through the telomerase RNA component. Since SIRT6 also regulates telomere chromatin stability, GG carriers at rs350845 who also carry G alleles at rs12696304 face a double burden of reduced telomere protection: less SIRT6-mediated heterochromatin at telomere ends AND shorter baseline telomere length from reduced telomerase activity. Both variants are in the longevity category and their interaction is mechanistically plausible, though specific compound data are lacking.
For the supervisor: a compound action covering rs350845 GG + rs12696304 GG would target individuals with dual telomere vulnerability — reduced SIRT6-mediated telomere chromatin stability AND reduced telomerase RNA activity. Combined recommendation: prioritize NAD+ precursor supplementation to maximize SIRT6 activity and emphasize high-MUFA dietary patterns (CORDIOPREV evidence) plus monitoring telomere-associated biomarkers. Evidence level: emerging (mechanistically coherent, no published compound study).
Nutrient Interactions
Genotype Interpretations
What each possible genotype means for this variant:
Common genotype with baseline SIRT6 genomic defense capacity
You have two copies of the G allele at rs350845 — the most common genotype, found in approximately 78% of people globally. This is the reference genotype: your SIRT6 gene is regulated at its typical baseline level, without the additional transcriptional boost associated with the A allele.
This does not indicate disease. It simply means you do not carry the longevity-associated eQTL variant identified in Ashkenazi centenarians. Your SIRT6 genomic stability functions are intact but not enhanced beyond the population baseline.
One protective A allele provides partial upregulation of SIRT6 across multiple tissues
The centenarian study by Simon et al. (EMBO Journal 2022) identified rs350845 A as a cis-eQTL that upregulates SIRT6 across 18 tissue types. Higher SIRT6 is consistent with extended lifespan in mouse models (14.5% mean lifespan extension in males; both sexes in the energy homeostasis study).
The key enzymatic functions you get more of with the A allele are NAD+-dependent: SIRT6 deacetylates H3K9 and H3K56 at DNA break sites to compact chromatin and recruit repair machinery, and mono-ADP ribosylates KAP1 to silence LINE1 retrotransposons. Since these reactions all require NAD+, the benefit of carrying the A allele depends on maintaining adequate cellular NAD+ levels — something that declines approximately 50% by the sixth decade of life.
Two copies of the protective A allele drive highest SIRT6 expression and maximal genomic stability benefit
The functional benefit of the AA genotype is additive at the expression level — both alleles independently upregulate SIRT6 transcription. In model organisms, SIRT6 overexpression extends lifespan by 14.5% (males, Kanfi et al. Nature 2012) to ~30% in more recent studies, operating through reduced IGF1/IIS signaling, preserved energy homeostasis via hepatic NAD+ synthesis, and DNA damage suppression.
Critically, the benefit is NAD+-dependent. SIRT6 cannot deacetylate histones or ribosylate repair factors without adequate NAD+ as cofactor. The AA genotype produces more SIRT6 enzyme — but if cellular NAD+ is depleted (as occurs with aging, excess alcohol, or chronic inflammation), the extra enzyme has no substrate. The practical implication: AA individuals have more to gain from NAD+ supplementation than GG individuals, because they have more SIRT6 enzyme waiting to be activated.
The centenarian study also identified two rare SIRT6 missense variants (N308K/A313S) that further enhance SIRT6 mADPr activity, LINE1 suppression, and DSB repair beyond the eQTL effect. These are separate from rs350845, but together they suggest that the longevity-promoting haplotype involves both more SIRT6 (eQTL effect at rs350845) and better SIRT6 (functional improvement from the missense alleles).
Key References
Simon et al. EMBO Journal 2022 — Ashkenazi centenarian cohort (450 centenarians, 550 controls) identifying rs350845 A allele enriched in centenarians (17.2% vs 12.6%, p=0.009) as an eQTL upregulating SIRT6 across 18 tissues
Kanfi et al. Nature 2012 — SIRT6 transgenic male mice showed 14.5% mean lifespan extension via IGF1/IIS pathway suppression, first sirtuin shown to regulate mammalian lifespan
Roichman et al. Nature Communications 2021 — SIRT6 overexpression extends healthy lifespan in both male and female mice by restoring energy homeostasis through enhanced NAD+ synthesis and gluconeogenic substrate utilization
Van Meter et al. Nature Communications 2014 — SIRT6 represses LINE1 retrotransposons by ribosylating KAP1, and this repression fails with stress and aging, allowing retrotransposon reactivation
Mao et al. Science 2011 — SIRT6 promotes DNA repair under stress by activating PARP1 at double-strand breaks; mono-ADP-ribosylation of PARP1 K521 is the key activation mechanism
Torok et al. Scientific Reports 2021 — SIRT6 rs350845 shows weak nominal association with Parkinson's disease risk in a Hungarian cohort (not significant after FDR correction)