The VETSA Longitudinal Twin Study of Cortisol and Aging

描述（由研究者提供）：压力和暴露于糖皮质激素（GC）水平升高导致下丘脑-垂体-肾上腺（HPA）轴的变化，影响认知和适应性衰老。对压力的生理反应，包括皮质醇的升高，也会受到心理社会和其他生物因素的个体差异的调节。确定与衰老有关的风险和保护因素是公共卫生的优先事项。为此，我们将在大量中年双胞胎样本的纵向评估中，通过唾液皮质醇测量来检验HPA对急性和持续压力源的反应，以及它与慢性压力源的关系。关于皮质醇的认知研究主要集中在海马功能障碍和情景记忆方面。然而，在前额皮质和相关的执行功能中存在不成比例的年龄相关异常，前额皮质中存在高浓度的GC受体。我们认为皮质醇相关的认知功能障碍与执行功能和情景记忆缺陷有关。我们还将测量睾酮，脱氢表雄酮和GRK3基因型。睾酮和脱氢表雄酮随着年龄的增长而下降，而皮质醇则趋于上升；即使皮质醇不随年龄增长而增加，高皮质醇血症的症状仍可能表现出来。因此，皮质醇与脱氢表雄酮或睾酮的比值（而不是皮质醇的绝对水平）可能是功能升高的有用指标

DESCRIPTION (provided by investigator): Stress and exposure to elevated glucocorticoid (GC) levels cause changes in the hypothalamic-pituitary-adrenal (HPA) axis that affect cognitive and adaptive aging. Physiological responses to stress-including elevations in cortisol-are also moderated by individual differences in psychosocial and other biological factors. Identification of risk and protective factors associated with aging is a public health priority. Toward that end, we will examine HPA response to acute and sustained stressors, and its association with chronic stressors via salivary cortisol measures in the longitudinal assessment of a large sample of middle aged twins. Cognitive research on cortisol has focused on hippocampal dysfunction and episodic memory. However, there are disproportionate age-related abnormalities in prefrontal cortex and associated executive functions, and high concentrations of GC receptors in prefrontal cortex. We propose that cortisol-related cognitive dysfunction in aging will be associated with executive function as well as episodic memory deficits. We will also measure testosterone, DHEA, and genotype the GRK3 gene. Testosterone and DHEA decrease with age whereas cortisol tends to increase; even when cortisol does not increase with age, symptoms of hypercortisolemia may still be manifested. Thus, the ratio of cortisol to DHEA or testosterone (rather than absolute level of cortisol) may be a useful index of functionally elevated cortisol. GRK3 plays a role in regulating the CRF receptor; we will examine whether the P-5 variant of GRK3 is, associated with GC hypersecretion during stress and a lower threshold for stress-induced responses. The proposed study builds on our NIA-funded study, which we refer to as the Vietnam Era Twin Study of Aging (VETSA). The VETSA is assessing 720 twin pairs from the Vietnam Era Twin Registry (360 pairs at age 51+/-1; 360 pairs at age 56+/-1) with planned follow-up every 5 years. An extensive, daylong assessment includes neurocognitive, personality/psychosocial and health/medical measures, and blood samples for genotyping. Key advantages are beginning in midlife (before substantial age-related declines), and having only 2 large, narrow age cohorts to maximize power to detect within-person change over time. This study will begin in VETSA year 3 and include 480 VETSA twin pairs. We will compare at-home and in-lab cortisol, testosterone, and DHEA measures, thereby employing a relatively novel approach to provide comparison to typical (at-home) basal levels. Using multivariate twin analytic approaches, we will determine the extent of genetic, and shared and unique environmental factors influencing cortisol in midlife as well as their association with other key measures.