747B Poster - 12. Physiology, metabolism and aging
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Celine Cansell ¹; Fanny Bain ¹; Vivien Goepp ²; Nicolas Todd ³; Veronique Douard ⁴; Flaminia Zane ¹; Clara Sanchez ⁵; Nicolas Pietrancosta ^6,7; Carole Rovere ⁵; Raphael GP Denis ^8,9; Serge Luquet ⁹; Michael Rera ¹

Affiliations:
1) Center for Research and Interdisciplinarity (CRI), Inserm U1284, Université de Paris, F-75006 Paris, France; 2) MinesParisTech, CBIO – Centre for Computational Biology, PSL Research University, 75006, Paris, France & Institut Curie, PSL Research University, 75005, Paris, France & Inserm, U900, Paris; 3) Centre Roland Mousnier, CNRS, Sorbonne Université, 75005 Paris, France & Laboratory of Population Health, Max Planck Institute for Demographic Research, 18057 Rostock, Germany; 4) Université Paris-Saclay, INRAE, AgroParisTech, MICALIS Institute, 78350 Jouy-en-Josas, France; 5) Université Côte d’Azur, IPMC-CNRS UMR 7275, F-06560 Valbonne, France; 6) Laboratoire des Biomolécules, LBM, Département de chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, Paris 75005, France; 7) Neuroscience Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS) INSERM, CNRS, Sorbonne Université, Paris 75005, France; 8) Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France; 9) Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France

Keywords:
b. metabolism; i. lifespan

The “Smurf” model of ageing, first described in Drosophila, is characterized by two successive and necessary phases. A first phase A where individuals have no risk of mortality but an age-dependent increasing risk of entering phase B. A second phase B where individuals show a high risk of impending death from natural causes. Individuals in phase B show typical hallmarks of ageing such as decreased energy storage, locomotor activity and fertility, a deregulation of insulin signaling, and a strong increase in systemic inflammation. The discovery of this model was made possible by a singular characteristic of phase B, its increased intestinal permeability. To assess intestinal permeability in Drosophila, a non-absorbable and non-toxic blue food dye is added to the medium of adult individuals. In contrast to phase A, for individuals in phase B, the dye crosses the intestinal epithelium and reaches the hemolymph turning individuals blue. According to their color, blue individuals were hence dubbed "Smurfs".
We propose here for the first time that the two phases of ageing separated by the “Smurf” transition are relevant to mice, thanks to a longitudinal longevity study using two different mouse strains, in both males and females. By integrating physiological, metabolic and molecular measurements with the life history, we assessed the predictive power of the model concerning the high risk of impending death in this model organism. This allows us to answer three research questions:
(1) As described in Drosophila, is the end of life in mammals characterized by an increase in intestinal permeability?
(2) Is there a specific physiological signature of the end of life in mammals?
(3) Do identified biomarkers allow us to discriminate between two subpopulations characterized by different mortality risk at any chronological age?
The characterization of this “Smurf” two-phase ageing model in mammals is essential to study and to better understand ageing because it allows a primordial thing currently still impossible: to evaluate the physiological age of individuals. It also allows a better understanding of the underlying mechanisms of ageing by offering the possibility to exclude individuals presenting the classically accepted hallmarks of ageing in order to define the causes of the appearance of these hallmarks. Finally, it is a putative game changer in the domain of personalized medicine paving the way for a unifying and truly public model of ageing, while extending the Drosophila model to mammals.