Intercellular competition and the inevitability of multicellular aging

Paul Nelson and Joanna Masel
PNAS December 5, 2017 114 (49) 12982-12987; published ahead of print October 30, 2017 https://doi.org/10.1073/pnas.1618854114

  1. Edited by Raghavendra Gadagkar, Indian Institute of Science, Bangalore, India, and approved October 6, 2017 (received for review November 14, 2016)

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Figures

  • Fig. 1.
    Fig. 1.

    Illustrative example of a {f,z}→{v,c} mapping, showing contour lines of equal v in black and equal c in gray, with arrows showing the direction of positive change. A degradation event of average size, and affecting only v or only c, moves a genotype down by exactly one contour line. Robustness to senescence and cancer is illustrated by lines that are more closely spaced at the beginning of the degradation process than at the end. Robustness to cancer is also illustrated by curvature in the contour lines showing changing c with constant v. Our argument assumes that mutations tend to affect only v or only c, and the map is constructed in such a way as to maximize the extent to which this is true. We also assume the absence of strong positive degradational covariance. From the genotype shown with a dot, degradation events in the gray region contribute to such covariance (as do those in the sector above, in which far fewer mutations are found).

  • Fig. 2.
    Fig. 2.

    Intercellular competition prevents accumulation of senescent cells at the cost of allowing cancerous cells to proliferate. (A and B) Cellular changes causing senescence (μv = 10−3, μc = 0) cause senescent cells (gray) to accumulate without intercellular competition (α = 0, top row), depleting functional cells (black), but are purged when cells compete (α = 0.002, bottom row). Cellular changes causing cancer (μv = 0, μc = 10−5) lead to a small population of cancerous cells (black diagonal stripes) that are prevented from proliferating without intercellular competition (C) but can spread when cells compete (D). When cells are subject to both senescence- and cancer-causing changes, senescent cells accumulate without intercellular competition (E) and cancerous cells proliferate when cells compete (F). In F, a portion of cancerous cells acquire senescent changes, resulting in a class of cells that are both cancerous and senescent (gray with diagonal stripes). The white dashed line in F indicates functional cells from E to illustrate the extent to which intercellular competition delays (but does not prevent) the loss of functional cells.

  • Fig. 3.
    Fig. 3.

    (A) Robustness to somatic changes delays, but does not halt, loss of functional cells. (B) Failure to halt aging is a result of negative covariance between cellular cancer (can.) c and senescence (sen.) v, and is negative under all conditions. While the magnitude of negative covariance decreases later in life, this decrease is due to a depletion of total variance of cell types (most cells are either senescent or cancerous) and occurs long after a multicellular organism would have died (fraction of functional cells ∼0.1). α = 0.002 throughout.

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Inevitability of multicellular aging
Paul Nelson, Joanna Masel
Proceedings of the National Academy of Sciences Dec 2017, 114 (49) 12982-12987; DOI: 10.1073/pnas.1618854114
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