In the present study, we have investigated possible associations between longevity and 41 SNPs in 20 candidate genes involved in bitter taste perception. Our intensive SNP tagging approach along with the analyses of haplotypes provides a close to exhaustive analysis of the possible associations of longevity with the known common polymorphic variants at these bitter taste receptor loci.
We found that five polymorphisms were associated with longevity: three in the TAS2R16
gene (rs6466849, rs860170 and rs978739), one in the TAS2R4
gene (rs2233998) and two in the TAS2R5
(rs2227264). rs6466849 and rs978739 share a modest degree of LD (r2
0.52) indicating that they might not be statistically independent findings, while rs2233998 and rs2227264 are in complete LD (r2
0.99) and therefore represent the same association. Two haplotypes, (rs1357949–rs6466849–rs860170–rs978739: T_A_A_G) of the TAS2R16
gene and rs2588350 (TAS2R7
): G_G_T showed a suggestive association with longevity. After correction for multiple testing only one polymorphism, rs978739 showed a statistically significant association with longevity (p
0.001). In particular, the frequency of homozygotes A/A increases gradually from 35% in the subjects aged 20 to 70 up to 55% in centenarians. A distribution of the genotypes through various age strata is given in .
Bar chart of age by genotypes showing the association between the polymorphism of TAS2R16 rs 978739 and longevity.
gene is one of the most studied genes in the bitter taste receptor family and interestingly it has been shown that it underwent recent selective pressure 
. 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 
. 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 
. 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 
although its real effect on cancer remains controversial 
. 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 
. The bark and leaf of willow species contain the prodrug salicin; following absorption salicin is metabolized into various salicylate derivatives 
. Salicin has effects similar to aspirin (acetylsalicylic acid) on analgesia and as an anti-inflammatory agent 
. 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.
Polymorphic variants in TAS2R16 confer differential response in vitro
via functional changes in the receptor 
and have been suggested to influence the sensations, liking, or intake of common beverages that contain phytochemicals and other pharmacologically active ingredients linked to chronic diseases 
. Moreover the functional polymorphism K172N (rs846664) appears to be a risk factor for alcohol intake 
and dependence 
. 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 
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 harmful compounds are recognized by the receptor throughout the life span and that this could, in the long term, modify the chances to reach very old ages. However there is also another possible, even though highly speculative, explanation of the involvement of TAS2R16 genetic variability in healthy aging. Numerous recent reports investigated non-gustatory actions of taste receptors. They have been shown to be expressed in a plethora of tissues such as the respiratory system where they affect respiratory functions in response to noxious stimuli 
, and the gastrointestinal tract where they are suspected to regulate the activation of metabolic and digestive functions 
. Recently it has been shown that taste receptors are expressed also in the testis in mouse, where they can be involved in spermatogenesis 
. The emerging picture is therefore that taste receptors could behave as pleiotropic genes, whose products are used by various cells, or have signaling function on various targets not linked one to the other. Probably the bitter sensing is just one of the functions performed by this cluster of genes, which could have a central role in the homeostasis of the organisms. Therefore their genetic variations can affect profoundly various traits, including longevity, in a way that we are just beginning to understand