Table 1.

A representative list of stimuli and inducers responsible for cellular senescence

Stimulus or inducer	Treatment example or induction route	In vivo consequence
Telomeric attrition	Suppressors of telomerase activity (e.g., SYUIQ‐5,3′‐azido‐3′‐deoxythymidine, pyridostatin)	Aging; cancer[ 123 , 124 ]
Genotoxic agents	Inducers of DNA replication stress (e.g., bromodeoxyuridine, hydroxyurea); Genotoxic drugs including DNA topoisomerase inhibitors (e.g., etoposide, doxorubicin, mitoxantrone), DNA crosslinkers (e.g., mitomycin C, cisplatin) and drugs with complex effects (e.g., actinomycin D, methotrexate bleomycin)	Cancer regression accompanied by off‐target or side effects[ 32 , 110 , 125 , 126 ]
Deregulated nutrient sensing	Perception of intracellular and/or extracellular nutrient signals (amino acids, glucose, NAD+) by signaling mediated by insulin IGF1, mTOR, or AMPK	Aging‐associated changes[ 127 , 128 ]
Ionizing irradiation	X‐ray, γ‐radiation, UV light	Cancer regression accompanied by side effects[ 125 , 126 ]
Oncogene activation	HRas, KRas, NRas, BRAF	Cancer progression or suppression[ 129 , 130 , 131 ]
Loss of tumor suppressors	p53, PTEN	Tumor inhibition; cancer progression[ 132 , 133 ]
Oxidative stress	Inducers of reactive oxygen species (e.g., paraquat, hydrogen peroxide)	Aging[ 134 ]
Mitochondrial dysfunction	Decline of mitochondrial malix enzyme 1 (ME1) and malix enzyme 2 (ME2), reduced NAD+ level or decreased NAD+/NADH ratio	Aging[ 135 , 136 ]
Loss of proteostasis	ER stress, mTOR activation, UPR events	Aging[ 137 , 138 , 139 ]
Suppression by cyclin‐dependent kinase inhibitors	Upregulation of CDKIs such as p16INK4a /p19ARF/p21CIP1 (downstream of p53) (e.g., nutlin 3a); senescence‐inducing drugs (e.g., abemaciclib, palbociclib, ribociclib)	Tumor suppression; cancer progression[ 140 , 141 ]
Cytokines	TGF‐β and analogs	Aging[ 142 , 143 ]
Activators of protein kinase C	PEP005, PEP008, TPA/PMA,	Aging[ 144 ]
Epigenetic modifications	DNA methyltransferase suppressors (e.g., 5‐aza‐2‐deoxycytidine); Histone deacetylases inhibitors (e.g., sodium butyrate, trichostatin A); Histone acetyltransferase antagonists (e.g., C646, curcumin); Histone methyltransferases suppressors (e.g., BRD4770)	Aging; cancer[ 145 , 146 ]
High‐fat diet	Suppression of SIRT1/Beclin‐1/autophagy axis; Accumulation of senescent glial cells in proximity to the lateral ventricle	Diet; insulin resistance; type 2 diabetes; hyperlipidemia; neuropsychiatric disorders (e.g., anxiety‐related behavior)[ 70 , 147 , 148 ]
d‐Galactose treatment	Cardiac and mitochondrial dysfunction	Development of obese insulin‐resistance; aging; neuron damage[ 149 , 150 ]
Autophagy impairment	Loss of specific autophagic programs (e.g., those mediated by p62/SQSTM1)	Aging features and/or age‐related pathological conditions[ 136 , 137 ]
Lamin B1 reduction	Dysregulation of mTOR and mitochondrial integrity, decrease of DiGeorge syndrome critical region 8 (DGCR8)	Chronic obstructive pulmonary disease (COPD), aging, osteoarthritis, Hutchinson‐Gilford progeria syndrome (HGPS)[ 151 , 152 ]