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Genetic and epigenetic Muller’s ratchet as a mechanism of frailty and morbidity during aging: a demographic genetic model

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Abstract

Mutation accumulation has been proposed as a cause of senescence. During this process, age-related genetic and epigenetic mutations steadily accumulate. Cascading deleterious effects of mutations might initiate a steady “accumulation of deficits” in cells, despite the existence of repair mechanisms, leading to cellular senescence and functional decline of tissues and organs, which ultimately manifest as frailty and disease. Here, we investigate several of these aspects in differentiating cell populations through modeling and simulation using the Moran birth–death (demographic) process, under several scenarios of mutation accumulation. Deleterious mutations seem to rapidly accumulate particularly early in the course of life, during which the rate of cell division is high, thereby exerting a greater effect on subsequent cellular senescence. Our results are compatible with the principle of the Muller’s ratchet taking place in asexually reproducing organisms. The ratchet speed in a given tissue depends on the size of the cell population, mutation rate and the impact of such mutations on cell phenotypes. It varies substantially among cells in different tissues and organs due to heterogeneity in relation to cell and organ-specific demographic features. Ratchet accelerates particularly after middle age, resulting in a synergistic fitness decay at the level of cell populations. We extend Fisher’s average excess concept and rank order scale to interpret differential phenotypic effects of the increase of the mutation load among cell populations within a given tissue. We postulate that classical evolutionary genetic models can explain, at least in part, the origins of frailty, subclinical conditions, morbidity and the health consequences of senescence.

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Acknowledgements

We dedicate this paper to Richard Lewontin and Tomoko Ohta and for their prescient ideas on units of selection and mutational effects, respectively. We thank the referees for helpful comments. DRG thanks Peter Ellison, David Haig, Nir Barzilai, Jan Vijg for support, and Drs. Caleb Finch, Robert Perlman, Annapurna Poduri, Sri Raj and Alan Templeton, for suggestions.

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Authors and Affiliations

  1. Graduate University for Advanced Studies, Hayama, Kanagawa, 240-0193, Japan

    Hideki Innan

  2. Institute Jacques Monod, Paris, France

    Reiner Veitia

  3. Universite Paris Diderot, Paris, France

    Reiner Veitia

  4. Museum of Comparative Zoology, Harvard University, Cambridge, MA, 02138, USA

    Diddahally R. Govindaraju

  5. The Institute of Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10460, USA

    Diddahally R. Govindaraju

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  1. Hideki Innan
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  2. Reiner Veitia
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DRG, HI, and RV designed study, performed research, contributed new analytical tools, analyzed data and wrote the paper.

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Correspondence to Hideki Innan or Diddahally R. Govindaraju.

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Innan, H., Veitia, R. & Govindaraju, D.R. Genetic and epigenetic Muller’s ratchet as a mechanism of frailty and morbidity during aging: a demographic genetic model. Hum Genet 139, 409–420 (2020). https://doi.org/10.1007/s00439-019-02067-9

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