Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence?

Abstract

Stem/progenitor cells ensure tissue and organism homeostasis and might represent a frequent target of transformation. Although these cells are potentially immortal, their life span is restrained by signaling pathways (p19-p53; p16-Rb) that are activated by DNA damage (telomere dysfunction, environmental stresses) and lead to senescence or apoptosis. Execution of these checkpoint programs might lead to stem cell depletion and organism aging, while their inactivation contributes to tumor formation.

Figure 1

DNA damage accumulates as the consequence of endogenous (telomere dysfunction, oxidative stress) or exogenous (oxidative stress, γ-irradiation, UV light, and others) attacks. Damaged DNA activates checkpoint responses tRb pathways and that result in apoptosis or cellular senescence. If these events occur in stem/progenitor cells, tissue homeostasis is altered — a phenomenon that might contribute to aging. If, instead, DNA mutations that inactivate these checkpoint pathways accumulate, then cancer can arise.