Extending the Lifespan of Multicellular Organisms via Periodic and Stochastic Intercellular Competition

Resolution of the intrinsic conflict between the reproduction of single cells and the homeostasis of a multicellular organism is central to animal biology and has direct impact on aging and cancer. Intercellular competition is indispensable in multicellular organisms because it weeds out senescent cells, thereby increasing the organism’s fitness and delaying aging. In this Letter, we describe the growth dynamics of multicellular organisms in the presence of intercellular competition and show that the lifespan of organisms can be extended and the onset of cancer can be delayed if cells alternate between competition (a fair strategy) and noncompetitive growth, or cooperation (a losing strategy). This effect recapitulates the weak form of the game-theoretic Parrondo’s paradox, whereby strategies that are individually fair or losing achieve a winning outcome when alternated. We show in a population model that periodic and stochastic switching between competitive and cooperative cellular strategies substantially extends the organism lifespan and reduces cancer incidence, which cannot be achieved simply by optimizing the competitive ability of the cells. These results indicate that cells could have evolved to optimally mix competitive and cooperative strategies, and that periodic intercellular competition could potentially be exploited and tuned to delay aging.

Figure 1

Initial densities $n_{ij}(0)$ of cells in a multicellular organism, shown on a 2D lattice discretizing trait parameter space. Cellular competitive ability ${\alpha }_i$ (on $x$ axis) and cooperative ability ${\beta }_j$ (on $y$ axis) are two parameters that characterize cell traits. Color shading of the lattice demarcates functional, cancer, and senescent cell types, according to their relative positions in the trait space.

Figure 2

Fraction of different types of cells under different switching schemes. Cell fractions under (a) the periodic switching scheme with $\xi =150$ and $T=400$ and (b) the stochastic switching scheme with $\theta =200$ and $\zeta =0.375$ are shown. The average fraction of time spent with competition is identical in both schemes. ${\eta }_n>{\eta }_n^{\prime }$ in later times and ${\eta }_n+{\eta }_s>{\eta }_n^{\prime }+{\eta }_s^{\prime }$ throughout indicate an extension of the organism lifespan and delay of cancer onset, respectively. Results were averaged over ${10}^4$ realizations.

Figure 3

Lifespan $\kappa$ under different switching schemes. (a) Lifespan ${\kappa }_{\xi }$ at varying $\xi$ in the periodic switching scheme, and (b) lifespan ${\kappa }_{\zeta }$ at varying $\zeta$ in the stochastic switching scheme. Results were averaged over $5\times {10}^3$ realizations.

Figure 4

Impact of $K$ on the fraction of functional cells under different switching schemes. Functional cell fractions under (a) periodic switching scheme with $\xi =150$ and $T=400$ and (b) stochastic switching scheme with $\theta =200$ and $\zeta =0.375$. Darker line colors indicate larger values of $K$. Larger functional cell fractions ${\eta }_n$ and ${\eta }_n^{\prime }$ are sustained with increasing $K$, but smaller $K$ yield greater differences in $\max \mathrm{\Delta }{\eta }_n$ earlier, demonstrating stronger lifespan-extending effects in both switching schemes. Results were averaged over ${10}^3$ realizations.