Method of optimizing conditions for selectively removing a plurality of senescent cells from a tissue or a mixed cell population
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 for treating a subject to relieve or delay progression of symptoms of a disease or disorder by selectively removing p16 positive senescent cells that are not cancer cells from a target tissue in the subject,
wherein the method comprising the following steps:
(a) performing a physical examination of the subject to determine a target tissue in the subject from which it is desirable to remove senescent cells that are not cancer cells;
(b) identifying a small molecule compound that is capable of selectively removing senescent cells from the target tissue;
(c) determining a course of treatment that includes a dosage, a formulation, and a route of administration of the small molecule compound that selectively kills senescent cells in the target tissue, compared with non-senescent cells;
(d) administering the small molecule compound identified in step (b) to the subject in accordance with the course of treatment determined in step (c); and
(e) withholding treatment of the subject with the small molecule during a non-treatment interval of at least two weeks that immediately follows the administering in step (d);
whereby at least some of the senescent cells are selectively removed from the target tissue consequent to step (d), resulting in relief or delayed progression of at least one of the symptoms of the disease or disorder during the non-treatment interval of step (e).
2. The method of claim 1 , wherein the senescent cells removed from the target tissue are further characterized as expressing the SASP factors IL-6 and MMP3.
3. The method of claim 1 , wherein the small molecule compound identified in step (b) is an MDM2 inhibitor which is administered in step (d) as a monotherapy.
4. The method of claim 1 , wherein the small molecule compound identified in step (b) is a cis-imidazoline compound.
5. The method of claim 1 , wherein the small molecule compound identified in step (b) is an inhibitor of Bcl-2, Bcl-xL, or Akt.
6. The method of claim 1 , wherein
the small molecule compound identified in step (b) is administered to the subject in step (d) as a single dose, followed by the non-treatment interval of at least two weeks.
7. The method of claim 1 , wherein
the small molecule compound identified in step (b) is administered to the subject in step (d) in a plurality of cycles, followed by the non-treatment interval.
8. The method of claim 1 , wherein the non-treatment interval in step (e) is at least one month.
9. The method of claim 1 , wherein the target tissue comprises human lung fibroblasts.
10. The method of claim 1 , wherein the target tissue comprises pre-adipocytes.
11. The method of claim 1 , wherein the target tissue is lung tissue.
12. The method of claim 1 , further comprising measuring whether p16 positive senescent cells have been removed from the target tissue in the subject.
13. The method of claim 1 , further comprising examining the subject to determine whether at least one of the symptoms of the disease or disorder have been relieved or delayed in progression, consequent to removing the p16 positive senescent cells from the target tissue.