Center on Aging, University of Connecticut School of Medicine, Farmington, USA.
Department of Neuroscience, University of Connecticut School of Medicine, Farmington, USA.
J Gerontol A Biol Sci Med Sci. 2021 Jun 14;76(7):1153-1160. doi: 10.1093/gerona/glab070.
A geroscience-informed approach to the increasing prevalence of bladder control problems in older adults requires understanding the impact of aging on dynamic mechanisms that ensure resilience in response to stressors challenging asymptomatic voluntary control over urine storage and voiding. Bladder control is predicated on sensory neural information about bladder volume. Modulation of volume-induced bladder wall tensions by autonomic and mucosal factors controls neural sensitivity to bladder volume. We hypothesized that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels integrate these factors and thereby mediate adrenergic detrusor tension control. Furthermore, loss of HCN expression compromises that integration and could result in loss of precision of detrusor control. Using a life-span mouse model, reverse transcription quantitative real-time PCR and pharmacologic studies in pretensioned intact and mucosa-denuded bladder strips were made. The dominant hcn1 expression declines with maturation and aging; however, aging is also associated with increased variance around mean values. In strips from Mature animals, isoproterenol had less effect in denuded muscle strips than in intact strips, and HCN blockade diminished isoproterenol responsiveness. With aging, variances about mean response values significantly increased, paralleling hcn1 expression. Our findings support a role for HCN in providing neuroendocrine/paracrine integration and suggest an association of increased heterogeneity of HCN expression in aging with reductions in response precision to neuroendocrine control. The functional implication is an increased risk of dysfunction of brainstem/bladder regulation of neuronal sensitivity to bladder volume. This supports the clinical model of the aging bladder phenotype as an expression of loss of resilience, and not as emerging bladder pathology with aging.
衰老科学启示我们，要了解导致老年人膀胱控制问题日益普遍的原因，就必须认识到衰老对确保应对挑战无症状尿液储存和排空自主控制的应激源的弹性的动态机制的影响。膀胱控制依赖于有关膀胱容量的感觉神经信息。自主和黏膜因素对容量引起的膀胱壁张力的调节控制着对膀胱容量的神经敏感性。我们假设超极化激活环核苷酸门控（HCN）通道整合了这些因素，从而介导肾上腺素能逼尿肌张力控制。此外，HCN 表达的丧失会损害这种整合，可能导致逼尿肌控制精度的丧失。使用寿命期小鼠模型，进行了逆转录定量实时 PCR 和预先紧张完整和黏膜去黏膜膀胱条带的药理学研究。主导的 hcn1 表达随着成熟和衰老而下降；然而，衰老也与平均值周围方差的增加有关。在来自成熟动物的条带中，去黏膜肌肉条带中的异丙肾上腺素的作用小于完整条带中的作用，并且 HCN 阻断减弱了异丙肾上腺素的反应性。随着衰老，平均响应值的方差显著增加，与 hcn1 表达平行。我们的发现支持 HCN 在提供神经内分泌/旁分泌整合中的作用，并表明衰老时 HCN 表达异质性增加与对神经内分泌控制的响应精度降低有关。其功能意义是大脑/膀胱对神经元对膀胱容量敏感性调节的功能障碍风险增加。这支持了衰老膀胱表型作为弹性丧失的表现，而不是随着衰老出现的膀胱病理学的临床模型。
