Abstract
Xenobiotic-metabolizing enzymes (XME) mediate the body’s response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact the ability to cope with xenobiotics and, consequently, disease predisposition. We hypothesized that the variability of these genes influencing the interaction with the exposome could affect the individual chance of becoming long-lived. We tested this hypothesis by screening a cohort of 1112 individuals aged 20–108 years for 35 variants in 23 XME genes. Four variants in different genes (CYP2B6/rs3745274-G/T, CYP3A5/rs776746-G/A, COMT/rs4680-G/A and ABCC2/rs2273697-G/A) 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.
Highlights
Aging is a complex phenotype responding to a plethora of drivers in which genetic, behavioral, and environmental factors interact with each other
Since the weight of genetic factors increases starting from 65 years of age, we investigated the association of the above variants with biomarkers of age-associated changes in physical (HG and activities of daily living (ADL)) and cognitive (MMSE and Geriatric Depression Scale (GDS)) abilities
The present study—the first to our knowledge to investigate the association between SNPs in Xenobiotic-metabolizing enzymes (XME) genes and human longevity—found that their variability conditions the chance to reach very old age by affecting survival in an age-specific way. This is a novel finding considering that the variability of XME genes has been extensively investigated in relation to drug metabolism and response to treatment
Summary
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 [1]. Genes 2019, 10, 403 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. 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)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
