Fight Aging!

Researchers consider that the state of late life health in humans, and the mechanisms involved, are a balance between risk of death by cancer and risk of death by loss of tissue function. Cancer risk is increased by the activity of damaged cells, particularly stem cells, in a dysfunctional tissue environment, while loss of tissue function is accelerated by suppressing that activity. Tissue must be maintained, such as via a supply of new cells to replace losses, and cells must be active in order for that maintenance to occur.

Cellular senescence is a part of this balance of benefit and harm. Cellular senescence is a cancer suppression mechanism, halting the replication of cells at risk of becoming cancerous, as well as attracting the attention of the immune system to the local area via inflammatory signaling. Too much cellular senescence, and a lasting burden of cellular senescence when senescent cells are not efficiently destroyed by the immune system, disrupts tissue function and accelerates degenerative aging via that very same inflammatory signaling, however.

The advent of senolytic therapies to selectively destroy senescent cells will allow us to have our cake and eat it. If senescent cells are only periodically removed by treatment, then the short-term benefit of cellular senescence in suppression of immediate cancer risk resulting from cell damage will be retained, while the long-term downside of lingering senescent cells will be eliminated.

Modeling of senescent cell dynamics predicts a late-life decrease in cancer incidence

Current oncogenic theories state that tumors arise from cell lineages that sequentially accumulate (epi)mutations, progressively turning healthy cells into carcinogenic ones. While those models found some empirical support, they are little predictive of intraspecies age-specific cancer incidence and of interspecies cancer prevalence. Notably, in humans and lab rodents, a deceleration (and sometimes decline) of cancer incidence rate has been found at old ages. Additionally, dominant theoretical models of oncogenesis predict that cancer risk should increase in large and/or long-lived species, which is not supported by empirical data.

Here, we explore the hypothesis that cellular senescence could explain those incongruent empirical patterns. More precisely, we hypothesize that there is a trade-off between dying of cancer versus dying of other ageing-related causes. This trade-off between organismal mortality components would be mediated, at the cellular scale, by the accumulation of senescent cells. In this framework, damaged cells can either undergo apoptosis or enter senescence. Apoptotic cells lead to compensatory proliferation, associated with an excess risk of cancer, whereas senescent cell accumulation leads to ageing-related mortality.

To test our framework, we build a deterministic model that first describes how cells get damaged, undergo apoptosis, or enter senescence. We then translate those cellular dynamics into a compound organismal survival metric also integrating life-history traits. We address four different questions linked to our framework: can cellular senescence be adaptive, do the predictions of our model reflect epidemiological patterns observed among mammal species, what is the effect of species sizes on those answers, and what happens when senescent cells are removed? Importantly, we find that cellular senescence can optimize lifetime reproductive success. Moreover, we find that life-history traits play an important role in shaping the cellular trade-offs.