Poster #095, Stanford University
Loss of TET1 Results in Phenotypic Changes Linked with Healthier Aging
Mentors: Bhavneet Kaur, PhD and Nidhi Bhutani, PhD
Epigenetic changes are chemical modifications to the DNA that regulate gene expression and play a key role in aging. In particular, DNA methylation is crucial to gene expression as the methylation of the cytosine bases in DNA inhibits expression. The ten-eleven translocation (TET) enzymes are involved in the demethylation of DNA. TET1 oxidizes the methylated form of cytosine, 5-methylcytosine (5mC), to 5-hydroxylmethylcytosine (5hmC). However, the effects of TET1 on the dynamic equilibrium of DNA methylation and demethylation, and ultimately aging, are poorly understood. Previous research from our laboratory identified an association between abnormal TET1 activity and osteoarthritis. Since osteoarthritis is an age-related disease, we hypothesized that TET1 could also play a key role in aging. To investigate its influence on aging, we utilized cohorts of control and TET1 knockout mice of varying ages (6, 12, and 24-month-old mice; n = 4 or 5 per age group in each cohort). After genotyping tail samples from each mouse, we used dual-energy X-ray absorptiometry (DEXA) scans to compare lean and fat mass, and micro-CT scans on knee samples to identify differences in trabecular and cortical bone thickness as indicators of bone health. In contrast to control mice, TET1 knockout mice showed several notable age-related trends: (1) 12% lower fat mass and 13-gram lower body mass; (2) 1.14-fold higher trabecular and cortical bone thickness; and (3) 1.11-fold greater bone volume fraction. Importantly, the results indicated healthier aging in TET1 knockout mice relative to control mice. However, the underlying mechanisms are not yet fully understood. Specific changes in the 5hmC levels have not yet been determined, and further molecular-level research is required to fully understand the downstream effects of the epigenetic modifications and their relationship with aging.