The use of urinary proteomics in the assessment of suitability of mouse models for ageing.

Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions. As ageing is associated with an increased prevalence of age-related chronic disorders, understanding its underlying molecular mechanisms can pave the way for therapeutic interventions and managing complications. Animal models such as mice are commonly used in ageing research as they have a shorter lifespan in comparison to humans and are also genetically close to humans. To assess the translatability of mouse ageing to human ageing, the urinary proteome in 89 wild-type (C57BL/6) mice aged between 8-96 weeks was investigated using capillary electrophoresis coupled to mass spectrometry (CE-MS). Using age as a continuous variable, 295 peptides significantly correlated with age in mice were identified. To investigate the relevance of using mouse models in human ageing studies, a comparison was performed with a previous correlation analysis using 1227 healthy subjects. In mice and humans, a decrease in urinary excretion of fibrillar collagens and an increase of uromodulin fragments was observed with advanced age. Of the 295 peptides correlating with age, 49 had a strong homology to the respective human age-related peptides. These ortholog peptides including several collagen (N= 44) and uromodulin (N= 5) fragments were used to generate an ageing classifier that was able to discriminate the age among both wild-type mice and healthy subjects. Additionally, the ageing classifier depicted that telomerase knock-out mice were older than their chronological age. Hence, with a focus on ortholog urinary peptides mouse ageing can be translated to human ageing.

衰老是一种复杂的生物学过程，以全身性、渐进性的生物功能衰退为特征。鉴于衰老与年龄相关性慢性疾病的患病率升高密切相关，阐明其潜在分子机制可为治疗干预与并发症管理开辟路径。相较于人类，小鼠等动物模型因寿命更短且遗传背景与人类高度相似，被广泛应用于衰老研究领域。为评估小鼠衰老与人类衰老的可转化性，研究人员采用毛细管电泳-质谱联用（CE-MS）技术，对89只周龄为8至96周的野生型（C57BL/6）小鼠的尿液蛋白质组开展了分析。以年龄作为连续变量，共鉴定出295个与小鼠年龄呈显著相关的肽段。为探究小鼠模型应用于人类衰老研究的相关性，研究人员将上述分析结果与此前针对1227名健康受试者开展的相关性研究进行了对比。在小鼠与人类群体中，均观察到随着年龄增长，纤维状胶原蛋白的尿液排泄量下降，而尿调节素片段的尿液排泄量上升。在与小鼠年龄相关的295个肽段中，有49个与对应的人类年龄相关性肽段具有高度同源性。上述同源肽段（包含44个胶原蛋白片段与5个尿调节素片段）被用于构建衰老分类器，该分类器能够有效区分野生型小鼠与健康受试者的年龄。此外，该衰老分类器的分析结果显示，端粒酶敲除小鼠的生物学年龄高于其实际时序年龄。综上，通过聚焦同源尿液肽段，可实现小鼠衰老向人类衰老的转化研究。