Enzymes of Xenobiotic Metabolism and Variation in Human Longevity

How much might varying competence in managing foreign compounds and biological substances, xenobiotics such as those resulting from infection or environmental toxins, determine the observed variations in human longevity? Researchers here look for variations in the genes encoding for xenobiotic metabolizing enzymes involved in dealing with these invading substances, and find a modest association with longevity in humans. While interesting, it is worth remembering that this sort of genetic study tends to fail in replication. It is rare for any association between genetic variants and longevity to reliably show up in more than one study population.

Aging is a complex phenotype responding to a plethora of drivers in which genetic, behavioral, and environmental factors interact with each other. This can be conceptualized in terms of exposome - that is, the totality of exposures to which an individual is subjected throughout a lifetime and how those exposures affect health. The exposome basically includes a wide variety of toxic or potentially harmful compounds of exogenous (environmental pollutants, dietary compounds, drugs) or endogenous (metabolic by-products such as those resulting from inflammation or lipid peroxidation, oxidative stress, infections, gut flora) origin and related biological responses during the life course.

The individual ability to properly cope with xenobiotic stress can influence susceptibility to diseases and, thus, the quality and the rate of aging, phenotypes that certainly result from the cumulative experiences over lifespan. Additionally, in all the different theories proposed to explain the aging process, a common denominator remains the progressive decline of the capacity to deal with environmental stressors to which the human body is constantly exposed.

In this scenario, a crucial role can be played by the coordinated activity of cellular mechanisms evolved for reducing the toxicity of endogenous and xenobiotic compounds to which humans are exposed. These mechanisms comprehend a broad range of reactions of detoxification that make harmful compounds less toxic, more hydrophilic, and easier to be excreted. The main effectors of these mechanisms are a large number of enzymes and transporters, collectively referred to as xenobiotic-metabolizing enzymes (XMEs) or drug metabolizing enzymes (DMEs).

With aging, there is a decline in the ability to mount a robust response to xenobiotic insults. This is somewhat attributed to the age-related reduction in liver mass, which can result in reduced metabolism rates and in the decreased kidney and liver blood flows, which can result in reduced excretion and elimination of xenobiotic and its metabolites. In addition, a reduction in the activity of XMEs and DMEs and the consequent fall in biotransformation capacity have been reported in both old animals and humans.

We reasoned that genetic variants of XME genes might affect the chance to live a long life. In order to test this hypothesis, we screened a set of 35 SNPs in 23 XME genes and their association with aging and survival in a cohort of 1112 individuals aged 20-108 years. Four variants in different genes differently impacted the longevity phenotype. In particular, the highest impact was observed in the age group 65-89 years, known to have the highest incidence of age-related diseases. In fact, genetic variability of these genes we found to account for 7.7% of the chance to survive beyond the age of 89 years. Results presented herein confirm that XME genes, by mediating the dynamic and the complex gene-environment interactions, can affect the possibility to reach advanced ages, pointing to them as novel genes for future studies on genetic determinants for age-related traits.

Link: https://doi.org/10.3390/genes10050403


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