Compositions for the elimination of senescent cells
The invention relates to a composition comprising one or more inhibitors capable of inhibiting at least two of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and lipoxygenase or a composition comprising one or more inhibitors capable of inhibiting an enzyme with arachidonate-Co A ligase activity, specifically long-chain-fatty-acid-Co A ligase (ACSL) 1, ACSL3, ACSL4, ACSL5, ACSL6, SLC27A2 or ACSBG2, or a combination thereof for use in selectively eliminating senescent cells. The invention further relates to an in vitro method of identifying senescent cells in a subject and to a method of identifying candidate compounds for the selective elimination of senescent cells.
1 . A method of selectively eliminating senescent skin fibroblasts, senescent lung fibroblasts, senescent umbilical vein endothelial cells, and senescent renal proximal tubule endothelial cells comprising administering a composition comprising an inhibitor of long-chain-fatty-acid-CoA ligase (ACSL) 4 to treat idiopathic pulmonary fibrosis, osteoarthritis, skin wounds, and skin aging in a patient, wherein the ACSL4 inhibitor is triacsin C, and wherein senescent cells are characterized by an increased intracellular level of lysophosphatidylcholine, arachidonic acid and/or phospholipase A2 activity compared to a non-senescent cell of the same type or age.
2 . The method of claim 1 , wherein the composition further comprises at least one inhibitor of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) or lipoxygenase selected from the group consisting of diclofenac, MK886, licofelone.
3 . The method of claim 2 , wherein the inhibitor of COX-1, COX-2, or lipoxygenase is diclofenac.
4 . The method of claim 2 , wherein the inhibitor of COX-1, COX-2, or lipoxygenase is MK886.
5 . The method of claim 2 , wherein the inhibitor of COX-1, COX-2, or lipoxygenase is licofelone.
6 . The method of claim 1 , wherein the composition further comprises a compound capable of inhibiting intracellular conversion of arachidonic acid, wherein said compound is cycloate.
7 . The method of claim 1 , wherein the composition further comprises a compound capable of manipulating intracellular ATP levels, wherein said compound is oligomycin.
8 . The method of claim 1 , wherein the patient has idiopathic pulmonary fibrosis.
9 . The method of claim 1 , wherein the patient has osteoarthritis.
10 . The method of claim 1 , wherein the patient has a skin wound.
11 . The method of claim 1 , wherein skin aging is treated.