Michael Rera

selected publications

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

   Cansell, Céline, Goepp, Vivien, Bain, Fanny, Todd, Nicolas, Douard, Veronique, Monnoye, Magali, Zane, Flaminia, Sanchez, Clara, Pietrancosta, Nicolas, Rovere, Carole, Denis, Raphaël GP, Luquet, Serge, and Rera, Michael

   BMC Biology 2025

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   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" is a central tool for picking this complex "lock of biology", that one of ageing. 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 allowed us to discover that ageing is made up of two successive phases : a first phase where individuals are healthy and have no risk of mortality, but show an age-dependent and increasing risk of entering a second phase, characterized by the so-called hallmarks of ageing and a high 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 characterized the high risk of imminent death and would extend its implications to a broader range of species for ageing research.Competing Interest StatementThe authors have declared no competing interest.Agence Nationale de la Recherche, https://ror.org/00rbzpz17, ANR-20-CE44-0010CNRS, ATIP

2. Ageing as a two-phase process: theoretical framework

   Zane, Flaminia, MacMurray, Claire, Guillermain, Clémence, Cansell, Céline, Todd, Nicolas, and Rera, Michael

   Front. Aging 2024

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   Human ageing, along with the ageing of conventional model organisms, is depicted as a continuous and progressive decline of biological capabilities accompanied by an exponentially increasing mortality risk. However, not all organisms experience ageing identically and our understanding of the phenomenon is coloured by human-centric views. Ageing is multifaceted and influences a diverse range of species in varying ways. Some undergo swift declines post-reproduction, while others exhibit insubstantial changes throughout their existence. This vast array renders defining universally applicable “ageing attributes” a daunting task. It is nonetheless essential to recognize that not all ageing features are organism-specific. These common attributes have paved the way for identifying “hallmarks of ageing,” processes that are intertwined with age, amplified during accelerated ageing, and manipulations of which can potentially modulate or even reverse the ageing process. Yet, a glaring observation is that individuals within a single population age at varying rates. To address this, demographers have coined the term ‘frailty’. Concurrently, scientific advancements have ushered in the era of molecular clocks. These innovations enable a distinction between an individual’s chronological age (time since birth) and biological age (physiological status and mortality risk). In 2011, the “Smurf” phenotype was unveiled in Drosophila, delineating an age-linked escalation in intestinal permeability that presages imminent mortality. It not only acts as a predictor of natural death but identifies individuals exhibiting traits normally described as age-related. Subsequent studies have revealed the phenotype in organisms like nematodes, zebrafish, and mice, invariably acting as a death predictor. Collectively, these findings have steered our conception of ageing towards a framework where ageing is not linear and continuous but marked by two distinct, necessary phases, discernible in vivo, courtesy of the Smurf phenotype. This framework includes a mathematical enunciation of longevity trends based on three experimentally measurable parameters. It facilitates a fresh perspective on the evolution of ageing as a function. In this article, we aim to delineate and explore the foundational principles of this innovative framework, emphasising its potential to reshape our understanding of ageing, challenge its conventional definitions, and recalibrate our comprehension of its evolutionary trajectory.

3. A scenario for an evolutionary selection of ageing

   Roget, Tristan, MacMurray, Claire, Jolivet, Pierre, Méléard, Sylvie, and Rera, Michael

   eLife 2024

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   Signs of ageing become apparent only late in life, after organismal development is finalized. Ageing, most notably, decreases an individual’s fitness. As such, it is most commonly perceived as a non-adaptive force of evolution and considered a by-product of natural selection. Building upon the evolutionarily conserved age-related Smurf phenotype, we propose a simple mathematical life-history trait model in which an organism is characterized by two core abilities: reproduction and homeostasis. Through the simulation of this model, we observe (1) the convergence of fertility’s end with the onset of senescence, (2) the relative success of ageing populations, as compared to non-ageing populations, and (3) the enhanced evolvability (i.e. the generation of genetic variability) of ageing populations. In addition, we formally demonstrate the mathematical convergence observed in (1). We thus theorize that mechanisms that link the timing of fertility and ageing have been selected and fixed over evolutionary history, which, in turn, explains why ageing populations are more evolvable and therefore more successful. Broadly speaking, our work suggests that ageing is an adaptive force of evolution.

4. Ethical and social implications of approaching death prediction in humans-when the biology of ageing meets existential issues

   Gaille, Marie, Araneda, Marco, Dubost, Clément, Guillermain, Clémence, Kaakai, Sarah, Ricadat, Elise, Todd, Nicolas, and Rera, Michael

   BMC Medical Ethics 2020
5. Two phases of aging separated by the Smurf transition as a public path to death

   Dambroise, Emilie, Monnier, Lea, Ruisheng, Lu, Aguilaniu, Hugo, Joly, J-S, Tricoire, Herve, and Rera, Michael

   Scientific reports 2016
6. A new, discontinuous 2 phases of aging model: Lessons from Drosophila melanogaster

   Tricoire, Hervé, and Rera, Michael

   PloS one 2015
7. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila

   Rera, Michael, Clark, Rebecca I, and Walker, David W

   Proceedings of the National Academy of Sciences 2012