Two-phase model of ageing in mice for improved identification of age-related and late life metabolic decline.

Living animals reach their end-of-life through a stereotypic set of fascinating but poorly understood processes. The discovery, first in flies and later in nematodes and zebrafish, of the "Smurf phenotype" has provided a valuable tool to investigate ageing and its associated physiological changes. Using the Smurfs, we have shown an evolutionarily conserved end-of-life transition across Drosophilids, nematodes, and zebrafish. This tool has been key to identify the discontinuous nature of ageing and predict impending death from natural causes as well as from environmental stresses. This phenotype led us to propose a two-phase perspective of ageing: a first phase where individuals are apparently healthy and have low risk of mortality, but show an age-dependent and increasing risk of entering a second phase, marked by more pronounced hallmarks of ageing and a markedly increased risk of death. Here, we test whether these two consecutive phases of ageing separated by the Smurf transition are a conserved feature of ageing in the mammals using Mus musculus as a model. We performed a longitudinal longevity study using both males and females from two different mouse genetic backgrounds and by integrating physiological, metabolic, and molecular measurements with the life history of approximately 150 mice. We show the existence of a phenotypic signature typical of the last phase of life, observable at any chronological age. Validating the two-phase ageing model in a mammalian organism allows better characterization of the high risk of imminent death and would extend its implications to a broader range of species for ageing research. The Stage 1 version of this Registered Report was submitted on 19th January 2022.