Targeting mechanisms of ageing with geroprotectors to maintain musculoskeletal health

使用老年保护剂针对衰老机制以维持肌肉骨骼健康

• 批准号: BB/R001510/1
• 负责人: Ilaria Bellantuono
• 金额: $ 33.62万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR001510%2F1
• 关键词: Targeting; mechanisms; ageing; geroprotectors; maintain

As we get older, the quality of our bones and joints deteriorates. These changes make it more likely that we will develop osteoporosis and osteoarthritis. In osteoporosis, patients lose significant amounts of bone tissue, leaving their bones less dense and at a much greater risk of fracturing. When an older patient suffers a bone fracture, recovery is difficult and they often lose mobility and independence. Patients with osteoarthritis suffer from pain and stiffness in their joints, which also reduces their mobility. Osteoporosis and osteoarthritis are often linked. A patient with osteoarthritis, for example, may also show signs of bone loss in the affected limb. Together those two diseases are a major cause of visits to GP surgeries and cost over £5 billion per year to the NHS. Each disease is often treated separately, with patients required to take many drugs. Not only is the administration of multiple drugs costly, but patients can also suffer more side effects. In addition, drugs sometimes work less well when they are given in combination with other medicines that are unrelated.A new way of treating multiple diseases related to ageing, such as osteoporosis and osteoarthritis, is now emerging. It is based on the idea that ageing per se plays a major part in the development of these diseases and that drugs designed to delay the onset of ageing may also be able to delay the onset of age-related diseases. The reasoning is that cells in the body's tissues work less well as we age because the cells are ageing too - accumulating damage to their DNA and protein 'building blocks', for example. The tissues consequently deteriorate in quality and become more prone to disease. Researchers now have good evidence that if we keep our cells in a youthful state by interfering with the factors that cause cells to age, the cells will work better. This has been shown in studies using mice. When drugs that are known to keep cells in their youthful state were given to mice, the mice lived longer than animals which were not given the drugs. Tissues such as the heart and muscle were also kept healthier and in better working order. At the moment, we don't know whether these drugs can keep bones and joints in a youthful and healthier state as well. This is what we plan to investigate in this study. We will collaborate with the US-based National Institute of Ageing Intervention Testing Programme, a group that is renowned for their success with this type of work. The US researchers are continuing to test these drugs on mice, so they can determine how much longer the mice live. We are collecting bones and joints from these same mice following their treatment with three different drugs (rapamycin, 17alphaestradiol and acarbose). We will assess whether the joints and bones of these mice are any healthier. Our laboratory has an excellent track record in the analysis of bone and joints and we have access to all the techniques required. If this work shows that drugs which delay ageing can also promote the health of the skeletal system we will then seek more funding for a follow-on study. This would use animal models again, and examine specifically whether these drugs prevent the onset of osteoporosis and osteoarthritis and improve the function of the skeletal system. Such findings would also pave the way for new ways of thinking about how to identify new treatments for age-related diseases.

随着年龄的增长，我们的骨骼和关节的质量会恶化。这些变化使我们更有可能患上骨质疏松症和骨关节炎。在骨质疏松症中，患者失去了大量的骨组织，使他们的骨骼密度降低，骨折的风险更大。当老年患者遭受骨折时，恢复是困难的，并且他们经常失去移动性和独立性。骨关节炎患者的关节疼痛和僵硬，这也降低了他们的活动能力。骨质疏松症和骨关节炎往往是联系在一起的。例如，患有骨关节炎的患者也可能在受影响的肢体中显示出骨丢失的迹象。这两种疾病是全科医生手术的主要原因，每年花费超过50亿英镑。每种疾病通常都是单独治疗的，患者需要服用多种药物。多种药物的管理不仅成本高昂，而且患者还可能遭受更多的副作用。此外，当药物与其他无关的药物联合使用时，效果有时会较差。一种治疗骨质疏松症和骨关节炎等多种与衰老有关的疾病的新方法正在出现。它基于这样一种想法，即衰老本身在这些疾病的发展中起着重要作用，旨在延缓衰老的药物也可能能够延缓与年龄有关的疾病的发病。其原因是，随着我们年龄的增长，身体组织中的细胞工作得不那么好，因为细胞也在老化-例如，对它们的DNA和蛋白质“构建模块”的损害不断积累。因此，这些组织的质量下降，更容易患病。研究人员现在有很好的证据表明，如果我们通过干扰导致细胞衰老的因素来保持细胞处于年轻状态，细胞就会更好地工作。这一点已经在使用小鼠的研究中得到证实。当给小鼠服用已知能使细胞保持年轻状态的药物时，小鼠比没有服用药物的动物活得更长。心脏和肌肉等组织也保持更健康，工作状态更好。目前，我们还不知道这些药物是否能使骨骼和关节保持年轻和健康的状态。这就是我们在这项研究中计划调查的内容。我们将与美国国家老龄化干预测试计划研究所合作，该研究所以成功开展此类工作而闻名。美国研究人员正在继续在小鼠身上测试这些药物，以便他们能够确定小鼠的寿命还有多长。我们收集了这些小鼠在接受三种不同药物（雷帕霉素、17 α雌二醇和阿卡波糖）治疗后的骨骼和关节。我们将评估这些小鼠的关节和骨骼是否更健康。我们的实验室在骨和关节分析方面有着出色的记录，我们可以获得所需的所有技术。如果这项工作表明延缓衰老的药物也能促进骨骼系统的健康，我们将为后续研究寻求更多的资金。这将再次使用动物模型，并特别检查这些药物是否能预防骨质疏松症和骨关节炎的发作，并改善骨骼系统的功能。这些发现还将为如何确定与年龄有关的疾病的新疗法的新思维方式铺平道路。

项目成果

Geroprotectors and Skeletal Health: Beyond the Headlines.

• DOI: 10.3389/fcell.2022.682045
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Rayson A;Boudiffa M;Naveed M;Griffin J;Dall'Ara E;Bellantuono I
• 通讯作者: Bellantuono I