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量（SkappaBF）与原发性人类衰老的温度调节控制改变的机制及其后果的系统研究。老化皮肤对高温刺激的皮肤血管舒张（VD）和对低温刺激的皮肤血管收缩（VC）均显著减弱。之前的资助周期涉及对老年男性和女性皮肤VD改变相关机制的系统调查（在本提案的C部分简要总结）。下一个研究序列是这一研究的逻辑延伸，即检查衰老皮肤中皮肤VC改变的机制和后果，因为(1)原发性衰老与冷应激导致的核心温度大幅下降和临床低体温发生率增加有关；(2)这些不利的结果主要是由于血管收缩皮肤血管系统的相对无能导致核心到皮肤的热传递增加；(3)在输出VC控制途径中存在几个看似与年龄相关的变化位点，但尚未在体内进行测试。此外，由于VC减少和核心-皮肤热阻降低的共同作用，低体重和瘦肌肉质量的老年男性和女性体温过低的风险更高。具体目的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衰老皮肤中反射VC减弱的基本传出机制。这些研究利用了新的和最近改进的技术，允许对人体皮肤中与年龄相关的变化进行体内检查。特异性目的1量化老年、青年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探讨了去甲肾上腺素能和非去甲肾上腺素能机制在年轻和老年受试者反射性vc中的相对作用。后续实验将确定神经肽Y在这种年龄特异性VC反应中的潜在作用。特异性目的3将检查去甲肾上腺素能vc的剂量反应特征，以评估老年皮肤血管对去甲肾上腺素的反应性。最后，Specific Aim 4涉及一系列全身腔室实验，旨在确定和模拟VC改变对核心到皮肤传热阻力的影响，即血管完全收缩状态下的组织阻力（绝缘）。对热损失的抵抗是生理调节（VC）和被动系统特性（如肌肉质量）的功能。由于人类衰老的一个常见后遗症是肌肉量的逐渐减少（肌肉减少症），肌肉减少的老年男性和女性可能面临更大的低体温和低体温相关问题的风险。因此，在具体目标4下提出的研究将包括年龄组内肌肉质量的差异。

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.