METHODS AND COMPOSITIONS FOR KILLING SENESCENT CELLS AND FOR TREATING SENESCENCE-ASSOCIATED DISEASES AND DISORDERS
Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.
1 . A method of selectively killing a senescent cell, comprising:
contacting the senescent cell with a compound that selectively inhibits E3 ubiquitin-protein ligase (MDM2),
wherein the senescent cell is characterized as a non-cancerous cell that expresses the senescent cell-associated polypeptide p16.
2 . The method of claim 1 , wherein the senescent cell expresses the senescence-associated secretory phenotype (SASP) factors interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3).
3 . The method of claim 1 , wherein the senescent cell produces senescence-associated β-galactosidase (SA-β-GAL).
4 . The method of claim 1 , wherein the inhibitor is an imidazoline compound.
5 . The method of claim 4 , wherein the imidazoline compound is selected from nutlin-1, nutlin-2, nutlin-3, and RG 7112.
6 . The method of claim 5 , wherein the imidazoline compound has the following structure:
or a pharmaceutically effective salt thereof,
wherein X is halide, R 1 is alkyl, R 2 is —H or heteroalkyl, and R 3 is —H or ═O.
7 . The method of claim 6 , wherein the imidazoline compound is nutlin-3.
8 . The method of claim 6 , wherein the imidazoline compound is 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-2-piperazinone or a pharmaceutically acceptable salt thereof.
9 . The method of claim 1 , wherein the senescent cell is contacted with the compound in vitro.
10 . The method of claim 1 , wherein the senescent cell is in an osteoarthritic joint.
11 . The method of claim 1 , wherein the senescent cell is in an atherosclerotic plaque.
12 . The method of claim 1 , wherein the senescent cell is in pulmonary tissue.