AGE AND CONTROL OF HUMAN SKIN BLOOD-FLOW

描述(由申请人提供)：R01 AG07004的竞争性更新继续了我们对皮肤血流温度调节控制(SkappaBF)随人类初级衰老而改变的机制及其后果的系统研究。老年皮肤对高温刺激的皮肤血管扩张(VD)和对低温刺激的皮肤血管收缩(VC)均明显减弱。前一个供资周期涉及对与老年男性和女性皮肤血管性痴呆改变相关的机制进行系统调查(在本提案的C节中作了简要概述)。下一系列拟议的研究是这一研究路线的合乎逻辑的延伸，即检查老年皮肤VC改变的机制和后果，因为(1)初级衰老与冷应激导致的核心温度更大的下降和临床低体温的发生率增加有关，(2)这些不良结果主要是相对不能收缩皮肤血管导致核心到皮肤的热传递增加的结果，(3)在传出VC控制通路中存在几个看似合理的与年龄相关的变化部位，但尚未在体内进行测试。此外，由于VC减少和核心-皮肤热阻降低的综合影响，体重和肌肉质量较低的老年男性和女性发生体温过低的风险更大。具体目标1-3分别在交感神经传递、神经递质/受体和终末器官反应水平上研究老年皮肤中Vc反射减弱的基本传出机制。这些研究使用了新的和最近改进的技术，允许在体内检查与年龄相关的人类皮肤变化。具体目标1量化老年和年轻男性和女性在进行性皮肤降温过程中的皮肤交感神经活动(SSNA)及其与VC的关系。具体目标2解决了青年和老年受试者中去甲肾上腺素和非去甲肾上腺素能机制在反射性VC中的相对贡献。描述了后续实验，以确定神经肽Y在这种特定年龄的VC反应中的潜在作用。具体目标3将检查去甲肾上腺素的剂量反应特性，以评估老年皮肤血管对去甲肾上腺素的反应。最后，具体目标4涉及一系列全身室内实验，旨在确定和模拟改变的VC对核心到皮肤热传递的阻力的影响，即在完全血管收缩状态下的组织阻力(绝缘性)。对热损失的抵抗力既是生理调节(VC)的函数，也是被动系统特性(如肌肉质量)的函数。由于人类衰老的一个常见后遗症是肌肉质量的进行性丧失(骨质疏松症)，骨质疏松症的老年男性和女性可能面临更大的体温过低和与体温过低相关的问题。因此，在具体目标4下拟议的研究将包括不同年龄组之间的肌肉质量差异。

DESCRIPTION (provided by applicant): This competitive renewal of R01 AG07004 continues our systematic investigations into mechanisms underlying altered thermoregulatory control of skin blood flow (SkappaBF) with primary human aging, and the consequences thereof. Both cutaneous vasodilation (VD) in response to hyperthermic stimuli and cutaneous vasoconstriction (VC) in response to hypothermic stimuliare significantlyattenuated in aged skin. The previous funding cycle involved a systematic investigation of the mechanisms related to altered cutaneous VD in older men and women (briefly summarized in Section C of this proposal). The next sequence of proposed studies is the logical extension of this line of investigation, i.e., examining the mechanisms and consequences of altered cutaneous VC in aged skin, since (1) primary aging is associated with both a larger decrease in core temperature with cold stress and an increased incidence of clinical hypothermia, (2) these untoward outcomes are primarily the result of a relative inability to vasoconstrict the skin vasculature leading to an increased core-to-skin heat transfer, (3) several plausible sites of age-related changes exist in the efferent VC control pathway which have not been tested in vivo. Furthermore, older men and women with a low body mass and lean muscle mass are at ever) greater risk of hypothermia because of the combined effects of reduced VC and decreased core-to-skin thermal resistance. Specific Aims 1-3 examine basic efferent mechanisms of attenuated reflex VC in aged skin at the sympathetic nerve transmission, neurotransmitter/receptor, and end-organ response levels, respectively. These studies make use of new and recently refined techniques that allow for the in vivo examination of age-related changes in human skin. Specific Aim 1 quantifies the skin sympathetic nerve activity (SSNA) during progressive skin cooling in older vs. young men and women and its relation to VC. Specific Aim 2 addresses the relative contributionsof noradrenergic and nonnoradrenergic mechanisms in reflexVC inyoung and older subjects. Follow-up experiments are described that will determine the potential role of neuropeptide Y in this age-specific VC response. Specific Aim 3 will examine the dose response characteristics of noradrenergicVC to assess the responsiveness of the aged cutaneous vasculature to norepinephrine. Finally, Specific Aim 4 involves a series of whole-body chamber experiments designed to determine and model the effects of altered VC on the resistance to core-to-skin heat transfer, i.e., tissue resistance (insulation) in the fully vasoconstricted state. Resistance to heat loss is a function of both physiological adjustments (VC) and characteristics of the passive system (e.g., muscle mass). Because a common sequelae of human aging is a progressive loss of muscle mass (sarcopenia), sarcopenic elderly men and women may be at even greater risk of hypothermia and hypothermia-related problems. Therefore, the proposed studies under Specific Aim 4 will include differences in muscle mass within age groups.