Table 1.

Inducers of cellular senescence

Inducer	Senescence pathway
Replicative stress	Cell proliferation leads to telomere shortening, which hinders DNA copying and can activate the DNA damage response, resulting in replicative senescence.
Oncogene activation	Activation of oncogenes can directly induce the DNA damage response or activate MDM2–p53–p21 or p38AMPK–p16 signalling pathways, which lead to cellular senescence.
Loss of tumour suppressor gene	Loss of a tumour suppressor gene can induce cellular senescence via activation of Akt–mTOR–p53 signalling.
Development	Senescence markers can be observed in the limbs, nervous system, gut endoderm and mesonephros; p21 has an important role in development-associated senescence.
Epigenetic influences	Epigenetic modification of histones induces senescence by activating p16–RB signalling.
Mitochondrial dysfunction	Mitochondrial dysfunction leads to overproduction of reactive oxygen species, which cause DNA damage and activate the DNA damage response or ERK–p16–RB signalling.
Chemotherapeutic drugs or ionizing radiation	These therapies induce DNA damage and the DNA damage response, which lead to cellular senescence.