Abstract
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.
Highlights
During a lifetime, a number of molecular and cellular insults accumulate and lead to ageing [1]
To identify peptides associated with ageing, the urinary proteome profiles of a cohort of 89 C57BL/6 wild-type mice were analysed by coupled to mass spectrometry (CE-MS) (Fig 1)
Non collagen peptides were predominantly positively correlated with age and included fragments of kidney androgen-regulated protein, pro-epidermal growth factor, alpha-1-antitrypsin, major urinary protein, meprin A subunit alpha, complement factor D, uromodulin and serine protease inhibitor A3K whereas collagen fragments were predominantly negatively correlated with age and included collagen alpha-1(I) chain, collagen alpha-1(III) chain and collagen alpha-2(I) chain (S1 Table, see rho factor)
Summary
A number of molecular and cellular insults accumulate and lead to ageing [1]. Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions, leading to impaired tissue function increasing the likelihood of death. The burden caused by age-related diseases is prominent and prone to increase over the years. As life expectancy increases, improving health in the elderly population will be pivotal in dealing with subsequent enormous socio-economic challenges as a consequence of this improved longevity [2]. There is an urgency to develop intervention strategies that will improve management of co-morbidities associated with ageing. Management of complications associated with ageing can firstly be accomplished by understanding molecular mechanisms associated with healthy ageing
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