A Common <i>UDP-Glucuronosyltransferase</i> ( <i>UGT</i> ) <i>1A</i> Haplotype Is Associated With Accelerated Aging in Humanized Transgenic Mice

<b>Background:</b> 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 <i>UGT1A</i> haplotype was shown to affect redox balance in humanized transgenic (htg) <i>UGT1A</i> mice. Since oxidative stress is a main activator of cellular senescence, we aimed to investigate the role of genetic <i>UGT1A</i> variants in the process of aging. <b>Methods:</b> Htg<i>UGT1A</i>-WT <i>and</i> htg<i>UGT1A</i>-SNP mice were harvested at the age of either 12 weeks (young) or 18 months (aged). The effect of aging was examined by analyzing <i>UGT1A</i> expression and activity, expression of senescence markers, and senescence-associated secretory phenotype (SASP) factors, as well as blood counts, serum parameter, and histological staining. <b>Results:</b> In comparison to aged htg<i>UGT1A</i>-WT mice, hepatic <i>UGT1A</i> mRNA and protein expression as well as UGT activity were significantly reduced in aged htg<i>UGT1A</i>-SNP mice. Moreover, elderly htg<i>UGT1A</i>-SNP mice exhibited increased levels of oxidative stress, senescence markers, SASP factors, and peripheral leukocyte counts compared to the respective htg<i>UGT1A</i>-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 htg<i>UGT1A</i>-SNP mice. <b>Conclusion:</b> Our data suggest an accelerated aging process caused by a common <i>UGT1A</i> haplotype. Moreover, elderly individuals carrying the <i>UGT1A</i> haplotype might exhibit an altered metabolism of drugs, which could necessitate dose adjustments.