Viable yet damaged cells can accumulate during development and aging. Although eliminating those cells may benefit organ function, identification of this less fit cell population remains challenging. Previously, we identified a molecular mechanism, based on “fitness fingerprints” displayed on cell membranes, which allows direct fitness comparison among cells in Drosophila. Here, we study the physiological consequences of efficient cell selection for the whole organism. We find that fitness-based cell culling is naturally used to maintain tissue health, delay aging, and extend lifespan in Drosophila. We identify a gene, azot, which ensures the elimination of less fit cells. Lack of azot increases morphological malformations and susceptibility to random mutations and accelerates tissue degeneration. On the contrary, improving the efficiency of cell selection is beneficial for tissue health and extends lifespan.

Introduction

Moskalev et al., 2013 Moskalev A.A.

Shaposhnikov M.V.

Plyusnina E.N.

Zhavoronkov A.

Budovsky A.

Yanai H.

Fraifeld V.E. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Individual cells can suffer insults that affect their normal functioning, a situation often aggravated by exposure to external damaging agents. A fraction of damaged cells will critically lose their ability to live, but a different subset of cells may be more difficult to identify and eliminate: viable but suboptimal cells that, if unnoticed, may adversely affect the whole organism ().

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et al. Chromosome instability is common in human cleavage-stage embryos. What is the evidence that viable but damaged cells accumulate within tissues? The somatic mutation theory of aging () proposes that over time cells suffer insults that affect their fitness, for example, diminishing their proliferation and growth rates, or forming deficient structures and connections. This creates increasingly heterogeneous and dysfunctional cell populations disturbing tissue and organ function (). Once organ function falls below a critical threshold, the individual dies. The theory is supported by the experimental finding that clonal mosaicism occurs at unexpectedly high frequency in human tissues as a function of time, not only in adults due to aging (), but also in human embryos ().

Does the high prevalence of mosaicism in our tissues mean that it is impossible to recognize and eliminate cells with subtle mutations and that suboptimal cells are bound to accumulate within organs? Or, on the contrary, can animal bodies identify and get rid of unfit viable cells?

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Rhiner C. Darwin’s multicellularity: from neurotrophic theories and cell competition to fitness fingerprints. One indirect mode through which suboptimal cells could be eliminated is proposed by the “trophic theory” (), which suggested that Darwinian-like competition among cells for limiting amounts of survival-promoting factors will lead to removal of less fit cells. However, it is apparent from recent work that trophic theories are not sufficient to explain fitness-based cell selection, because there are direct mechanisms that allow cells to exchange “cell-fitness” information at the local multicellular level ().

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Moreno E. Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Lose isoforms, because they are expressed in cells marked to be eliminated by apoptosis called “Loser cells” ( Rhiner et al., 2010 Rhiner C.

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Soldini D.

Casas-Tinto S.

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Lombardía L.

Moreno E. Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Lose isoforms at the cell membrane of a particular cell does not imply that the cell will be culled, because at least two other parameters are taken into account: (1) the levels of FlowerLose isoforms in neighboring cells: if neighboring cells have similar levels of Lose isoforms, no cell will be killed ( Merino et al., 2013 Merino M.M.

Rhiner C.

Portela M.

Moreno E. ). “Fitness fingerprints” mediate physiological culling of unwanted neurons in Drosophila. Rhiner et al., 2010 Rhiner C.

López-Gay J.M.

Soldini D.

Casas-Tinto S.

Martín F.A.

Lombardía L.

Moreno E. Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Portela et al., 2010 Portela M.

Casas-Tinto S.

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Moreno E. Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition. In Drosophila, cells can compare their fitness using different isoforms of the transmembrane protein Flower. The “fitness fingerprints” are therefore defined as combinations of Flower isoforms present at the cell membrane that reveal optimal or reduced fitness (). The isoforms that indicate reduced fitness have been called Flowerisoforms, because they are expressed in cells marked to be eliminated by apoptosis called “Loser cells” (). However, the presence of Flowerisoforms at the cell membrane of a particular cell does not imply that the cell will be culled, because at least two other parameters are taken into account: (1) the levels of Flowerisoforms in neighboring cells: if neighboring cells have similar levels of Lose isoforms, no cell will be killed (); (2) the levels of a secreted protein called Sparc, the homolog of the Sparc/Osteonectin protein family, which counteracts the action of the Lose isoforms ().

Here, we aimed to clarify how cells integrate fitness information in order to identify and eliminate suboptimal cells. Subsequently, we analyzed what are the physiological consequences of efficient cell selection for the whole organism.