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

背景资料：英国的老龄化人口是医疗和社会保健系统的一个既定和未来的定时炸弹，这在最近政府增加国民保险税的措施中得到了承认。健康、独立的老龄化的主要障碍之一是肌肉质量和功能的丧失，这一过程称为肌肉减少症，它与发病率和死亡率都有流行病学联系。尽管支持肌肉减少症的显著机制仍然难以捉摸，但一个确定的贡献者是“合成代谢抵抗”的发展。这种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）产生抗性。虽然我们作为一个研究小组，为发现合成代谢抗性做出了巨大贡献，但这种现象背后的生理，代谢和分子变化仍然是未知的;限制了缓解干预措施的发展。考虑到这一点，这一领域研究的主要驱动力仍然是寻求最大限度地提高老年肌肉对营养和收缩刺激的反应的方法。我们的项目将为这一议程作出重大贡献。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建设摄入的膳食蛋白质的可用性和吸收。然而，评估消化率的方法的主要问题是在人体中获得回肠样品的不可逾越的挑战（由于需要通过鼻胃超声引导插管在氨基酸吸收的远端肠部位取样）。在这里，我们提出了一个解决方案;验证和使用一种普遍的内在标记蛋白质（螺旋藻）的新方法，该方法将“报告”不同的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“增强”蛋白质来源的营养处理的影响。假设：衰老与高质量蛋白质的营养处理受损有关（即，乳清蛋白（WP））;纯化的β-乳球蛋白（BL）（来自Arla Food Ingredients（AFI））;亮氨酸含量高出约40%，必需氨基酸含量高出约20%，将在老年人中产生有利的消化率和合成代谢特征;与WP营养处理相关的肥胖减少将通过终身运动来缓解。项目计划：第1阶段-使用标记的螺旋藻（U-13 C AA，剑桥同位素实验室，MA，USA）验证微创稳定同位素示踪方法，以确定人体蛋白质消化率。第2阶段-招募老年人参加一项双臂交叉研究，以评估来自AFI的WP与BL的消化率，并确定消化率与静息时和急性阻力运动（即收缩活动）时骨骼肌收缩标志物之间的关系。 第3阶段-招募年轻人和老年人以及运动员参加一项研究，以评估消化率随年龄和体力活动的差异。预期成果和影响：与AFI的密切关系，>3篇高质量的科学论文和会议报告，针对老年人的外联活动，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.