Introduction: Obesity increases the risk of Type 2 diabetes, cardiovascular disease, several types of cancer, and other age-related disorders. Among older adults, obesity is also related to epigenetic age, typically measured with DNA methylation (DNAm). Because less is known about obesity and epigenetic aging earlier in the lifespan, this study examined the relationship between obesity and DNAm in young adulthood and whether these relationships vary by sex. Methods: A cross-sectional community sample of 290 healthy young adults (mean age 27.39 years, 60% female; 80% African American, 18% White) had their BMI and waist circumference measured. Four epigenetic age estimators were derived from salivary DNA: Hannum DNAm, Horvath DNAm, Phenoage DNAm, and GrimAge DNAm. Sociodemographic covariates included age, sex, race, parental education, and income-to-needs ratio. Results: After adjusting for covariates, higher BMI and waist were associated with higher DNAm PhenoAge in both sexes, with a stronger effect on BMI in males (β = 0.35, p < .001) compared to females (β = 0.13, p = .002). Higher waist, but not BMI, was associated with higher Horvath DNA methylation age. Both BMI and waist circumference were associated with higher Hannum DNAm age in men but not in women. Neither BMI nor waist circumference were related to GrimAge. Discussion: This study extends prior research by linking obesity with accelerated epigenetic aging in young adulthood, replicating the associations across two measures of obesity and four indices of salivary epigenetic aging. The results add to evidence that higher BMI accelerates aging early in the lifespan.

The role of adrenal hexose-6-phosphate dehydrogenase in providing reducing equivalents to P450 cytochrome steroidogenic enzymes in the endoplasmic reticulum is uncertain. Hexose-6-phosphate dehydrogenase resides in the endoplasmic reticulum lumen and co-localizes with the bidirectional enzyme 11β-hydroxysteroid dehydrogenase 1. Hexose-6-phosphate dehydrogenase likely provides 11β-hydroxysteroid dehydrogenase 1 with NADPH electrons via channeling. Intracellularly, two compartmentalized reactions generate NADPH upon oxidation of glucose-6-phosphate: cytosolic glucose-6-phosphate dehydrogenase and microsomal hexose-6-phosphate dehydrogenase. Because some endoplasmic reticulum enzymes require an electron donor (NADPH), it is conceivable that hexose-6-phosphate dehydrogenase serves in this capacity for these pathways. Besides 11β-hydroxysteroid dehydrogenase 1, we examined whether hexose-6-phosphate dehydrogenase generates reduced pyridine nucleotide for pivotal adrenal microsomal P450 enzymes. 21-hydroxylase activity was increased with glucose-6-phosphate and, also, glucose and glucosamine-6-phosphate. The latter two substrates are only metabolized by hexose-6-phosphate dehydrogenase, indicating that requisite NADPH for 21-hydroxylase activity was not via glucose-6-phosphate dehydrogenase. Moreover, dihydroepiandrostenedione, a non-competitive inhibitor of glucose-6-phosphate dehydrogenase, but not hexose-6-phosphate dehydrogenase, did not curtail activation by glucose-6-phosphate. Finally, the most compelling observation was that the microsomal glucose-6-phosphate transport inhibitor, chlorogenic acid, blunted the activation by glucose-6-phosphate of both 21-hydroxylase and 17-hydroxylase indicating that luminal hexose-6-phosphate dehydrogenase can supply NADPH for these enzymes. Analogous kinetic observations were found with microsomal 17-hydroxylase. These findings indicate that hexose-6-phosphate dehydrogenase can be a source, but not exclusively so, of NADPH for several adrenal P450 enzymes in the steroid pathway. Although the reduced pyridine nucleotides are produced intra-luminally, these compounds may also slowly transverse the endoplasmic reticulum membrane by unknown mechanisms.