A minimally invasive stable-isotope approach to determine nutrient handling across the life-course.

背景：英国人口老龄化是医疗和社会护理体系的一个既定和未来的定时炸弹，这一点在政府最近增加国民保险税的措施中得到了承认。健康、独立衰老的主要障碍之一是肌肉质量和功能的丧失，这一过程被称为骨质疏松症，这种疾病在流行病学上与发病率和死亡率都有联系。尽管石棺减少的显著机制仍然难以捉摸，但一个已确定的因素是“合成代谢抵抗”的发展。这一现象表现在骨骼肌细胞对调节肌肉维持的关键环境线索，即收缩活动和食物(蛋白质)摄入产生抵抗力。虽然我们作为一个研究小组，对合成代谢抵抗的发现做出了巨大贡献，但这种现象背后的生理、代谢和分子变化仍然未知，限制了缓解干预措施的发展。考虑到这一点，这一领域研究的一个主要驱动力仍然是寻找最大化老年肌肉对营养和收缩刺激的反应的方法。我们的项目将对这一议程做出重大贡献。一个新出现的命题是，随着年龄的增长，消化和肠道功能的变化可能会限制骨骼肌形成所摄取的膳食蛋白质的可用性和摄取量。然而，评估消化率的方法的主要问题是在获取人类回肠样本方面存在难以克服的挑战(因为需要在通过鼻胃超声引导的插管吸收氨基酸的远端肠道部位采样)。在这里，我们提出了一个解决方案；验证和使用一种普遍固有标记的蛋白质(螺旋藻)的新方法，该方法将“报告”不同蛋白质来源是如何被消化的。该项目将对健康生物科学和营养产品开发产生重大影响。目的：验证一种评估蛋白质消化率的微创方法，并确定年龄和体力活动对标准和强化蛋白质来源的营养处理的影响。假设：衰老与对优质蛋白质(即乳清蛋白)的营养处理受损有关；纯化的β-乳球蛋白(来自Arla食品配料(AFI))；产生的亮氨酸含量增加约40%，必需氨基酸含量增加约20%，将在老年人中引发有利的消化和合成代谢特征；终身锻炼将缓解与年龄相关的处理乳清蛋白的营养减少。项目计划：第一阶段-使用标记螺旋藻(U-13C AA，剑桥同位素实验室，美国马萨诸塞州)验证一种微创稳定同位素示踪方法，以确定人类的蛋白质消化率。第二阶段-招募老年人参加一项双臂交叉研究，以评估AFI对WP和BL的消化率，并确定消化率与骨骼肌合成代谢指标之间的关系，无论是在静止状态下还是在急性阻力运动(即收缩活动)反应中。阶段3-招募年轻人和老年人，并掌握运动员参与一项研究，以评估消化率作为年龄和体力活动的函数的差异。预期成果和影响：与AFI建立牢固的关系，3篇高质量的科学论文和会议报告，老年人的外联活动，对营养政策建议的影响。

Background: The UK's ageing population is an established and future timebomb for health and social care systems, recognised in recent government measures to increase national insurance taxation. One of the major road-blocks to healthy, independent ageing is the loss of muscle mass and function, in a process called sarcopenia, which has established epidemiological links to both morbidity and mortality. Despite the salient mechanisms underpinning sarcopenia remaining elusive, an established contributor is the development of "anabolic resistance". This phenomenon manifests in skeletal muscle cells becoming resistant to key environmental cues regulating muscle maintenance i.e. contractile activity and food (protein) intake. While we, as a research group, have contributed greatly to the discovery of anabolic resistance, the physiological, metabolic and molecular changes that underlie this phenomenon are still unknown; limiting the development of mitigating interventions. Reflecting this, a major driver of research in this area remains to seek means by which to maximise older muscle responses to nutritional and contractile stimuli. Our project will contribute significantly to this agenda. One emerging proposition is that changes in digestion and gut function with ageing may limit the availability and uptake of ingested dietary proteins for skeletal muscle building. However, the main issue with methods to assess digestibility are the insurmountable challenges in obtaining ileal samples in humans (due to the need to sample at the distal intestinal site of amino acid absorption via nasogastric ultrasound guided cannulae). Herein, we propose a solution; to validate and use a novel approach of a universally intrinsically labelled protein (Spirulina) that will "report" how different protein sources are digested. This project will have a significant impact on both health biosciences and nutrition product development. Aim: To validate a minimally-invasive method to assess protein digestibility, and to determine the impact of age and physical activity on nutrient handling of standard and 'enhanced' protein sources. Hypotheses: Ageing is associated with impaired nutrient handling of high-quality protein (i.e., whey protein (WP)); Purified beta-lactoglobulin (BL) (from Arla Food Ingredients (AFI)); yielding ~40% higher leucine content and ~20% higher essential amino acid content, will elicit favourable digestibility and anabolic profiles in older people; Age-associated reductions in nutrient handling of WP will be mitigated by life-long exercise. Project Plan: Phase 1 - To validate a minimally-invasive stable-isotope tracer methodology using labelled Spirulina (U-13C AA, Cambridge Isotope Laboratories, MA, USA), to determine protein digestibility in humans. Phase 2 - To recruit older adults to participate in a 2-arm cross over study to assess the digestibility of WP versus BL from AFI, and to determine the relationship between digestibility and markers of skeletal muscle anabolism both at rest and in response to acute resistance exercise (i.e. contractile activity). Phase 3 - To recruit young and older adults, and masters athletes to participate in a study to assess differences in digestibility as a function of age and physical activity. Expected outcomes & impact: A strong relationship with AFI, >3 high-quality scientific papers and conference presentations, outreach activities for older adults, implications for nutritional policy recommendations.