FOXO3, Telemere Dynamics and Healthy Brain Aging

项目摘要/摘要 长寿似乎受到遗传和细胞因素的强烈影响。FOX03基因编码 转录因子叉头盒O-3(FOX03)一直被认为与延长人类寿命有关。 衰老通常伴随着逐渐的脑萎缩和神经认知能力下降，但细胞 衰老过程背后的机制仍不清楚。 这项拟议的研究试图了解端粒在细胞水平上如何衰老 端粒酶活性的缩短和改变，与长寿和大脑老化有关。我们假设 保护性FOX03基因变异与减速大脑衰老有关，并表明较慢的 大脑老化也与外周血白细胞端粒酶活性和端粒长度增加有关 (PBL)。大脑体积和功能将通过结构磁共振成像进行横断面评估 100名男性和女性Kuakini的MRI和静息状态功能连接(RSFC)MRI 檀香山心脏计划(Kuakini HHP)后代研究参与者。局灶性脑萎缩和脑功能紊乱 RSFC将作为大脑老化的指标，并将被检查与FOXO_3基因和 PBL端粒酶活性和端粒长度。此外，我们将调查RSFC中的差异 与FOXO_3基因、端粒酶活性或端粒长度、8-oxo-DG(DNA断裂的一种指标)有关 频率)，或血液中抗炎细胞因子水平与正常情况下认知过程受损有关 衰老。这项研究的结果可能为深入了解保护性FOXO_3变异体对 脑老化，并可能阐明衰老的生物学机制，并最终确定增加干预措施 健康生活的年数。

Project Summary/Abstract Longevity appears to be strongly affected by genetic and cellular factors. The FOXO3 gene that encodes the transcription factor forkhead box O-3 (FOXO3) has been consistently linked to increased human lifespan. Aging is typically accompanied by gradual brain atrophy and neurocognitive decline, but the cellular mechanisms underlying the aging process are still unclear. The proposed study seeks to understand how aging at the cellular level, as characterized by telomere shortening and altered telomerase activity, is related to longevity and brain aging. We hypothesize that the protective FOXO3 gene variant is associated with decelerated brain aging, and suggest that a slower rate of brain aging is also linked to greater telomerase activity and telomere length in peripheral blood leukocytes (PBL). Brain volume and function will be cross-sectionally assessed by structural magnetic resonance imaging (MRI) and resting-state functional connectivity (RSFC) MRI, respectively, in 100 male and female Kuakini Honolulu Heart Program (Kuakini HHP) Offspring study participants. Regional brain atrophy and disrupted RSFC will serve as indices of brain aging and will be examined for associations with FOXO3 genotype and PBL telomerase activity and telomere length. Additionally, we will investigate whether differences in RSFC associated with FOXO3 genotype, telomerase activity or telomere length, 8-oxo-dG (a measure of DNA break frequency), or anti-inflammatory cytokine levels in the blood relate to cognitive processes impaired in normal aging. Results from this study may provide insight into effects of the protective FOXO3 variant on the rate of brain aging, and may elucidate biological mechanisms of aging and eventually identify interventions to increase the number of years of healthy living.