RESUMO
Hepatic xenobiotic metabolism and transport decline with age, while intact xenobiotic metabolism is associated with longevity. However, few studies have examined the genome-wide impact of epigenetic aging on these processes. We used reduced representation bisulfite sequencing (RRBS) to map DNA methylation changes in liver DNA from mice ages 4 and 24 months. We identified several thousand age-associated differentially methylated sites (a-DMS), many of which overlapped genes encoding Phase I and Phase II drug metabolizing enzymes, in addition to ABC and SLC classes of transporters. Notable genes harboring a-DMS were Cyp1a2, Cyp2d9, and Abcc2 that encode orthologs of the human drug metabolizing enzymes CYP1A2 and CYP2D6, and the multidrug resistance protein 2 (MRP2) transporter. Cyp2d9 hypermethylation with age was significantly associated with reduced gene expression, while Abcc2 expression was unchanged with age. Cyp1a2 lost methylation with age while, counterintuitively, its expression also reduced with age. We hypothesized that age-related dysregulation of the hepatic transcriptional machinery caused down-regulation of genes despite age-related hypomethylation. Bioinformatic analysis of hypomethylated a-DMS in our sample found them to be highly enriched for hepatic nuclear factor 4 alpha (HNF4α) binding sites. HNF4α promotes Cyp1a2 expression and is downregulated with age, which could explain the reduction in Cyp1a2 expression. Overall, our study supports the broad impact of epigenetic aging on xenobiotic metabolism and transport. Future work should evaluate the interplay between hepatic nuclear receptor function and epigenetic aging. These results may have implications for studies of longevity and healthy aging.
RESUMO
The growing prevalence of cardiovascular diseases in the United States (US) has disproportionately affected minority populations more than their white counterparts. A population that is often overlooked is the Asian American population, particularly Southeastern Asian immigrants. Despite having relatively favorable socioeconomic indicators compared to the general US population, Asian Americans, specifically Southeast Asian individuals, face a significant burden of traditional cardiovascular risk factors and are considered a high cardiovascular disease risk group. In addition, most studies have aggregated Asian populations into one major racial group rather than analyzing the different ethnicities among the Asian categorization. While some studies suggest that the acculturation process has some degree of impact on cardiovascular health, there has not been a widely-used tool to measure or ascertain the totality of acculturation. Instead, multiple proxies have been used to measure acculturation, and prior studies have argued for more culturally-tailored acculturation proxies. This paper aims to assess the implications of different acculturation measures on cardiovascular health among Asian Americans, particularly Southeastern Asian immigrants. The following proxies were expanded on in this paper: English spoken at home, length of stay in the US, religiosity and spirituality, and admixed family structures. Previous studies showed that as the length of stay in the US increases, the burden of cardiovascular risk factors increases. However, the impact of English spoken at home, religiosity, and admixed family structure are still inconclusive given the extent of current studies. While most studies suggest that an increase in acculturation increases the risk of cardiovascular disease, it is critical to note that acculturation is a multifaceted process. Therefore, more studies are necessary to appropriately examine the implications of various acculturation processes on cardiovascular risk factors in Asians, specifically Southeastern Asian individuals in the US.
