Intercellular competition and the inevitability of multicellular aging

Abstract

Current theories attribute aging to a failure of selection, due to either pleiotropic constraints or declining strength of selection after the onset of reproduction. These theories implicitly leave open the possibility that if senescence-causing alleles could be identified, or if antagonistic pleiotropy could be broken, the effects of aging might be ameliorated or delayed indefinitely. These theories are built on models of selection between multicellular organisms, but a full understanding of aging also requires examining the role of somatic selection within an organism. Selection between somatic cells (i.e., intercellular competition) can delay aging by purging nonfunctioning cells. However, the fitness of a multicellular organism depends not just on how functional its individual cells are but also on how well cells work together. While intercellular competition weeds out nonfunctional cells, it may also select for cells that do not cooperate. Thus, intercellular competition creates an inescapable double bind that makes aging inevitable in multicellular organisms.

Keywords: cancer; cellular degradation; cellular robustness; cooperation; negligible senescence.

Fig. 1.

Illustrative example of a $\left\{f,z\right\}\to \left\{v,c\right\}$ 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.

Intercellular competition prevents accumulation of senescent cells at the cost of allowing cancerous cells to proliferate. (A and B) Cellular changes causing senescence (μ_v = 10⁻³, μ_c = 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 (μ_v = 0, μ_c = 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.

(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.