Variants of a Bitter Taste Receptor Gene are More Prevalent in Centenarians

This paper is chiefly interesting for the discussion on possible mechanisms by which variants in a taste receptor gene might be modestly influencing the odds of living a longer, healthier life. Calorie restriction, practiced to even a lesser degree, has such as a strong effect on aging in comparison to most other factors that one has to consider whether alterations in mechanisms of taste can be influential on aging via consequent alterations in dietary preferences.

Yet taste is complicated, and these genes also have other functions that seem clearly relevant to health over the long term. As this paper illustrates, even when provided with a very specific taste-related mechanism to discuss, and data on its prevalence in centenarians versus the rest of the population, it is far from straightforward to arrive at a robust conclusion. Of course it remains the case that, even given that robust conclusion, the size of this effect would not be large enough to care about in a world in which rejuvenation therapies are presently under development.

Bitter taste receptors play crucial roles in detecting bitter compounds not only in the oral cavity, but also in other tissues where they are involved in a variety of non-tasting physiological processes. Disorders or modifications in the sensitivity or expression of these receptors can affect physiological functions. Here we evaluated the role of the bitter receptor TAS2R38 in attainment of longevity, since it has been widely associated with individual differences in taste perception, food preferences, diet, nutrition, immune responses and pathophysiological mechanisms.

Our results show that the genetically homogeneous cohort of subjects ranging in age from 90 to 105 years of an area recognised as one of the world's longevity hot spots, differed based on the genotype distribution and haplotype frequencies of TAS2R38 gene from the two genetically heterogeneous cohorts from the South of Sardinia where the longevity level is distinctly lower. Results show in the centenarian cohort an increased frequency of subjects carrying the homozygous genotype for the functional variant of TAS2R38 (PAV/PAV) and a decreased frequency of those having homozygous genotype for the non-functional form (AVI/AVI), as compared to those determined in the two control cohorts.

A number of studies on human nutrition have suggested that the TAS2R38 variants and the related 6-n-propylthioural (PROP) phenotype may influence dietary behaviour and nutritional status. The possible association between PROP responsiveness and perception and intake of fats has been extensively studied, but with controversial results. The widely accepted hypothesis is that PROP non-tasters, compared to PROP super-tasters, show a reduced ability to perceive dietary fat which could lead them to increase the consumption of high-fat foods to compensate the reduced perception. In agreement with this assumption, the high frequency of the tasting homozygous genotype (PAV/PAV) and the low frequency of the non-tasting one (AVI/AVI), that we found in centenarian subjects, suggest that these individuals may have reached an exceptional longevity because of their genetic predisposition to a low-fat diet.

On the other hand, the extreme bitterness intensity of PROP super-tasters has been shown to be the primary reason for avoiding bitter-tasting fruits and vegetables. Since many bitter-tasting compounds in foods (e.g., flavonoids, phenols, glucosinolates) have benefit effects for health, our results in the centenarian cohort seem to be in contrast with the possibility that TAS2R38 genotype is a genetic factor that favour an adequate intake of fruits and vegetables or other bitter foods recommended for a healthy life. However, only a few studies have investigated the relationship between TAS2R38 variants and vegetable intake obtaining controversial results. The notion that TAS2R38 might serve to govern food intake is interesting, but eating behaviour is a complex phenomenon influenced by a broad range of environmental factors.

In addition, it is known that TAS2R38 receptor serves other genotype-dependent roles which are relevant for health, with the PAV form associated with an efficient immune response, a favourable body composition, as well as with physiological processes. On the contrary, the AVI group is associated with a higher risk to develop many dysfunctions and diseases. Therefore, it is not surprising that we find in the centenarian cohort an increased frequency of homozygous subjects for the functional variant of TAS2R38 (PAV) and above all a decreased frequency of those having homozygous genotype for the non-functional form (AVI).



Interesting article, particularly the final sentence of the third paragraph. People who eat a low fat diet, whether by genetic predisposition or by sheer willpower, tend to live longer. This idea jumped out at me far more than the discussion about taste preferences. Having just passed my 73rd birthday in perfect health, I have found that a forceful 3-day food consumption plan (I hate the word diet) of avoiding fatty foods - including fighting off the headaches in the first day or two - gets me to a high level of energy and clearheadedness. Highly recommended: copious amounts of low-calorie beer as needed. It really helps during those three days. Once you get to the other side, it's smooth sailing from then on.

Posted by: Tony Scott at December 16th, 2019 12:40 PM

I'm wondering if it has to do with the capacity to stimulate the vagus nerve. There is a lot of discussion about using bitters as a means to increase vagal tone. Considering that stress is at the core the majority of illness, and aging is a form of illness(or even the entire umbrella), then anything that fortifies the body, and calms the system, allowing for a better stress response, and greater heart rate variability, could have something to do with the equation.

More bitter receptors could mean more spatial area by which the vagus nerve is stimulated by any given variety of food preferences containing bitter substances. It could even be akin to androgen receptors and capacity for muscle growth, rather than just the amount of circulating androgens themselves - only in this case, it is more about adaptive physiological response, courtesy of the reparative state elicited by increased parasympathetic/ventral vagal tone, rather than more of an isolated, musculoskeletal hormonal response provided for by greater androgen receptor sites.

Bitters are often used for digestion - and in kind, proper vagal tone lends way to the "rest and digest" state needed to properly breakdown, digest, assimilate, detoxify and excrete what is ingested. Much of the immune system is also in the gut, such as the galt-associated lymphoid tissue, so the downstream effect is rather self-defining in nature as well. Less stress on the GALT, less stress on the immune system. Bitters are also said to increase liver detoxification - and if so, then that is yet another core organ whose function improves, thus assisting the organism as a whole.

So if the body is in a relaxed state, providing increased HRV, decreased stress, better balance of hormones and immunity, increased digestion, detoxification, elimination and excretion, and bitters can trigger the nerve responsible for this neurological/autonomic cascade, then theoretically, the number and density of bitter receptors could greatly facilitate the efficiency of this process, and due to such efficiency, could assist in sustaining life for a greater period of time due to the systemic neuro-autonomic effect.

HRV is often said to be one of the greatest markers of longevity. If bitters stimulate the ventral vagal state of the parasympathetic nervous system, then by default, vagal tone will increase, which will allow the heart rate to be able to come back down efficiently after rising, and will correspondingly assisting in improving HRV, and thus, delayed risk of mortality.

It's very interesting to read about bitter receptor density in centenarian populations. I'm curious to see what comes of this. I often sense aging to be as much of a systemic issue as a cellular one. Cells make up the whole, but systems, such as the autonomics, influence vast arrays of functions despite the health or integrity of individual cells - and likewise, cells which are healthy or unhealthy, especially in terms of mitochondrial function, determine whether greater sympathetic activity is needed for survival and stress hormone production when mitochondrial function or number is too miniscule to power the body on clean energy alone. One way is a deprivation state, where energy is used on credit, and debt is paid by physiological decline or disrepair, and the other, is where clean, efficient energy is produced, and thus takes the body out of the backup emergency, sympathetic state, and back into a ventral vagal state, where cellular energy can thus be more efficiently recycled. I'm fascinated by the autonomic nervous system, so this was a really cool study(and concept) to look at.

Posted by: Adam at December 16th, 2019 5:14 PM

I'm much more interested in the other physiological roles of bitter taste receptors than their gustatory function. Perhaps variation in these receptors do influence individuals' diet choices, but this needs to be demonstrated first before speculating further. Some foods that don't taste bitter upon digestion yield substances that are quite bitter; for example gelatin yields proline, which is quite bitter (though it may be broken down only to prolyl hydroxyproline and I don't know what that tastes like). Many common medications are that taken in pill form are also bitter (e.g., colace) and it would be interesting to know if interaction with bitter taste receptors accounts for some of their known activities and perhaps activities that have not yet been examined. Further, probably the most bitter substances, bile acids, are released upon ingestion (in healthy people) of fats.

Posted by: CD at December 17th, 2019 10:08 AM

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