A Common UDP-Glucuronosyltransferase (UGT)1A Haplotype Is Associated With Accelerated Aging in Humanized Transgenic Mice.

Abstract

Background: Aging is characterized by the progressive decline of physiological functions and is associated with an increasing risk for developing multiple age-related diseases. UDP-glucuronosyltransferase (UGT)1A enzymes detoxify a variety of endo- and xenobiotic reactive metabolites, thereby acting as indirect antioxidants. A common genetic UGT1A haplotype was shown to affect redox balance in humanized transgenic (htg) UGT1A mice. Since oxidative stress is a main activator of cellular senescence, we aimed to investigate the role of genetic UGT1A variants in the process of aging. Methods: HtgUGT1A-WT and htgUGT1A-SNP mice were harvested at the age of either 12 weeks (young) or 18 months (aged). The effect of aging was examined by analyzing UGT1A expression and activity, expression of senescence markers, and senescence-associated secretory phenotype (SASP) factors, as well as blood counts, serum parameter, and histological staining. Results: In comparison to aged htgUGT1A-WT mice, hepatic UGT1A mRNA and protein expression as well as UGT activity were significantly reduced in aged htgUGT1A-SNP mice. Moreover, elderly htgUGT1A-SNP mice exhibited increased levels of oxidative stress, senescence markers, SASP factors, and peripheral leukocyte counts compared to the respective htgUGT1A-WT mice. Consistent with these findings, we observed higher amounts of collagen and amyloid fibrils as well as an elevated senescence-associated β-galactosidase (SA-β-gal) activity in histological sections of the liver obtained from aged htgUGT1A-SNP mice. Conclusion: Our data suggest an accelerated aging process caused by a common UGT1A haplotype. Moreover, elderly individuals carrying the UGT1A haplotype might exhibit an altered metabolism of drugs, which could necessitate dose adjustments.