Stress induced telomere shortening: longer life with less mutations?

Abstract

Background: Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging agents. However the implications of this mechanism are not fully understood.

Results: With the help of in silico model we investigate the effect of genotoxic stress on telomere attrition and apoptosis in a population of non-identical replicating cells. When comparing the populations of cells with constant vs. stress-induced rate of telomere shortening we find that stress induced telomere shortening (SITS) increases longevity while reducing mutation rate. Interestingly, however, the effect takes place only when genotoxic stresses (e.g. reactive oxygen species due to metabolic activity) are distributed non-equally among cells.

Conclusions: Our results for the first time show how non-equal distribution of metabolic load (and associated genotoxic stresses) combined with stress induced telomere shortening can delay aging and minimize mutations.

Figure 1

Schematic diagram picturing the inter-relations between DNA damage, cellular aging and cancer. As a result of DNA damage (D), induced by genotoxic stresses, mutations accumulate in individual cells (M). Cells exposed to larger amounts of stress have higher probability to accumulate more mutations. The replication of these potential mutators (i.e. tumor originating cells), is limited by the two distinct aging mechanisms: a) replicative senescence mediated by telomere attrition and b) p53 mediated cell cycle arrest and apoptosis. While the effect of p53 is rapid (can happen within several hours after the insult), the effect of telomeres is slow.

Figure 2

Stress-Induced Telomere Shortening (SITS) (left, A-C) allows for delayed aging when compared to the constant rate of Telomere Shortening (TS) (right, D-F). A) and D) show how the number of cells capable of replication change in time. In both cases, as cells divide, the average telomere length, <T>, decreases (B) and E)) and the number of accumulated mutations, <M> increases (C and F)). In B) and E) The colorcoded are the distribution of telomere lengths in the population, the average is shown by dotted line. Observe that in C) (but not in F) the rate of increase in M, dM/dt is slowing down at later time points. The results are shown for DNA damage <D> =0.25 and the cell-to-cell variation in DNA damage, $\frac{{\sigma }_D}{<D>}=1.5$. For TS case the constant rate of telomere shortening Const=0.25.

Figure 3

The SITS mediated gain (combined decrease in mutation rate and increase in longevity) is maximal at intermediate levels of DNA damage. The time average of the mutation rate, $\langle \frac{\mathit{\text{dM}}}{\mathit{\text{dt}}}\rangle$(A) and longevity, L(B) are shown as function of DNA damage, 〈D〉. Each point represents an average of 100 simulation runs. To scan across increasing average DNA damage, 〈D〉, we altered the mean of the gaussian distribution, μ_D. The red(orange) lines and corresponding errorbars represent SITS (TS). Cell-to-cell variation in DNA damage, $\frac{{\sigma }_D}{\langle D\rangle }=1.5$.

Figure 4

Cell-to-cell variability is required for the beneficial effect of SITS. The colorcoded are the ratios between the average SITS and TS mutation rates, R_M, (A) and longevities, R_L(B). The ratios are shown as function of average level of DNA damage, <D> and cell-to-cell variability in DNA damage, σ_D/<D>. The slice at σ_D/<D>=1.5 would correspond to the ratios of the red and orange lines in Figure 3.