taste receptor family and interestingly it has been shown that it underwent recent selective pressure [75]. It mediates the detection of salicin and other naturally occurring bitter compounds such as diphenidol, sodium benzoate, amygdalin, arbutin, helicin, D- salicin, sinigrin, and phenyl beta-D-glucopyranoside [76,77]. Several of these compounds have been reported to have a pharmacologic effect and to be present in human food. For example, arbutin is present in pears, bearberries and wheat, and has been reported to be a strong inhibitor of bladder cancer proliferation [78]. Amygdalin, also known as Vitamin B17, is found in several fruit seeds and has been reported to have both apoptotic activity and to inhibit cell cycle genes [79] although its real effect on cancer remains controversial [80]. Sinigrin is found in plants of the Brassicaceae family such as broccoli, brussels sprouts, and the seeds of black mustard. It has been proposed to have a preventive effect on colorectal cancer and to inhibit bladder cancer [81]. The bark and leaf of willow species contain the prodrug salicin; following absorption salicin is metabolized into various salicylate derivatives [82]. Salicin has effects similar to aspirin (acetylsalicylic acid) on analgesia and as an anti-inflam- matory agent [82]. These reports point to a role for the TAS2R16 receptor in recognizing beneficial molecules with which the organism interacts during life. One can speculate that an impaired function of the receptor might affect the efficacy of the various compounds and that this could lead on the long term to a disadvantage for the organism.

Supporting Information

Table S1 Table S1 Shows the genes and SNPs selected in the study, the Hardy-Weinberg equilibrium (HWE) values observed for each SNP in the study, their position in the genome, in the gene, and the amino acidic change specified.

Table S2 Logistic regression analysis for taste SNPs in long lived subjects.

Table S4 Logistic regression analysis for haplotypes T2R3-T2R4-T2R5-genes in long lived subjects.

Table S5 Logistic regression analysis for haplotypes of TAS2R16 gene in long lived subjects.

Table S6 Logistic regression analysis for haplotypes of T2R38 gene in long lived subjects.

Polymorphic variants in TAS2R16 confer differential response in vitro via functional changes in the receptor [83] and have been suggested to influence the sensations, liking, or intake of common beverages that contain phytochemicals and other pharmacologi- cally active ingredients linked to chronic diseases [84]. Moreover the functional polymorphism K172N (rs846664) appears to be a risk factor for alcohol intake [85] and dependence [86]. This variant is very rare in Caucasian populations and therefore its genotyping was not attempted in this sample set. TAS2R16 genetic variants have also been associated with the development of nicotine dependence in African Americans [67].

Table S7 Logistic regression analysis for haplotypes T2R40 gene in long lived subjects.

Table S8 Logistic regression analysis for haplotypes of T2R41 in long lived subjects.

Table S9 Logistic regression analysis for haplotypes of T2R7 -T2R9 genes in long lived subjects.

Table S10 Logistic regression analysis for haplotypes T2R14-T2R50-T2R20 genes in long lived subjects.

These observations point to a role of variation in the TAS2R16 receptor in recognizing and therefore modulating the effect of both beneficial and harmful molecules with which the organism interacts during life. It is possible that the fine tuning of the receptor function due to the genetic polymorphisms along with the environment may modulate how many beneficial and how many

Table S11 Logistic regression analysis for haplotypes of T2R19-T2R31-T2R46-T2R30 genes in long lived subjects.

Author Contributions

Acknowledgments

Conceived and designed the experiments: DC RB. Performed the experiments: MC PC CR DC. Analyzed the data: FDR AM. Wrote the paper: FC GR DC GP.

We would like to thank Prof. Dennis Drayna for his precious help and support.

References

nutritional epidemiology: applications, needs and new horizons. Hum Genet

:

–

Kushi LH, Doyle C, M

ullough M, Rock CL, Demark-Wahnefried W, et al. (

) American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin

:

–

Lumeng JC, Cardinal TM, Sitto JR, Kannan S (

) Ability to taste

-n- propylthiouracil and BMI in low-income preschool-aged children. Obesity (Silver Spring)

:

–

Mattson MP (

) Dietary factors, hormesis and health. Ageing Res Rev

:

–

Micha R, Kalantarian S, Wirojratana P, Byers T, Danaei G, et al. (

) Estimating the global and regional burden of suboptimal nutrition on chronic disease: methods and inputs to the analysis. Eur J Clin Nutr

:

–

Solfrizzi V, D’Introno A, Colacicco AM, Capurso C, Del Parigi A, et al. (

) Dietary fatty acids intake: possible role in cognitive decline and dementia. Exp Gerontol

:

–

Solfrizzi V, Panza F, Frisardi V, Seripa D, Logroscino G, et al. (

) Diet and Alzheimer’s disease risk factors or prevention: the current evidence. Expert Rev Neurother

:

–

Buckland G, Agudo A, Travier N, Huerta JM, Cirera L, et al. (

) Adherence to the Mediterranean diet reduces mortality in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). Br J Nutr

:

–

Tognon G, Rothenberg E, Eiben G, Sundh V, Winkvist A, et al. (

) Does the Mediterranean diet predict longevity in the elderly? A Swedish perspective. Age (Dordr)

:

–

Bell KI, Tepper BJ (

) Short-term vegetable intake by young children classified by

-n-propylthoiuracil bitter-taste phenotype. Am J Clin Nutr

:

–

Garcia-Bailo B, Toguri C, Eny KM, El-Sohemy A (

) Genetic variation in taste and its influence on food selection. Omics

:

–

Keller KL (