Karolinska Institute, Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Stockholm, Sweden; University of Leipzig Medical Center, Medical Department III - Endocrinology, Nephrology, Rheumatology, Leipzig, Germany.
University of Glasgow, Wolfson Wohl Cancer Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, Glasgow, UK.
Mol Aspects Med. 2022 Aug;86:101099. doi: 10.1016/j.mam.2022.101099. Epub 2022 Jun 8.
Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of ageing. Phosphorylation, acetylation, and ubiquitination cover >90% of all the reported PTMs. Several of the main PTMs are involved in normal "healthy" ageing and in different age-related diseases, for instance neurodegenerative, metabolic, cardiovascular, and bone diseases, as well as cancer and chronic kidney disease. Ultimately, data from human rare progeroid syndromes, but also from long-living animal species, imply that PTMs are critical regulators of the ageing process. Mechanistically, PTMs target epigenetic and non-epigenetic pathways during ageing. In particular, epigenetic histone modification has critical implications for the ageing process and can modulate lifespan. Therefore, PTM-based therapeutics appear to be attractive pharmaceutical candidates to reduce the burden of ageing-related diseases. Several phosphorylation and acetylation inhibitors have already been FDA-approved for the treatment of other diseases and offer a unique potential to investigate both beneficial effects and possible side-effects. As an example, the most well-studied senolytic compounds dasatinib and quercetin, which have already been tested in Phase 1 pilot studies, also act as kinase inhibitors, targeting cellular senescence and increasing lifespan. Future studies need to carefully determine the best PTM-based candidates for the treatment of the "diseasome of ageing".
翻译后修饰（PTMs）被认为是氧化应激-炎症-衰老三位一体之间的联系，从而影响衰老的几个特征。磷酸化、乙酰化和泛素化涵盖了所有已报道的PTMs的90%以上。一些主要的PTMs参与正常的“健康”衰老以及不同的年龄相关疾病，例如神经退行性疾病、代谢性疾病、心血管疾病、骨骼疾病，以及癌症和慢性肾病。最终，来自人类罕见早衰综合征以及长寿动物物种的数据表明，PTMs是衰老过程的关键调节因子。从机制上讲，PTMs在衰老过程中靶向表观遗传和非表观遗传途径。特别是，表观遗传组蛋白修饰对衰老过程具有关键影响，并可调节寿命。因此，基于PTM的疗法似乎是减轻衰老相关疾病负担的有吸引力的药物候选物。几种磷酸化和乙酰化抑制剂已获得美国食品药品监督管理局（FDA）批准用于治疗其他疾病，并为研究其有益效果和可能的副作用提供了独特的潜力。例如，研究最深入的衰老细胞溶解化合物达沙替尼和槲皮素，它们已经在1期试点研究中进行了测试，也作为激酶抑制剂，靶向细胞衰老并延长寿命。未来的研究需要仔细确定治疗“衰老相关疾病组”的最佳基于PTM的候选药物。
