Treating cognitive decline and other neurodegenerative conditions by selectively removing senescent cells from neurological tissue
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 eliminating senescent cells in tissues of a brain, comprising contacting senescent cells in tissues of the brain with a senolytic agent that is a Bcl-xL selective inhibitor, wherein the Bcl-xL selective senolytic agent is administered to the senescent cells in tissues of the brain intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval.
2. The method of claim 1 , wherein the Bcl-xL selective senolytic agent is a small molecule inhibitor.
3. The method of claim 1 , wherein the Bcl-xL selective senolytic agent is an antisense oligonucleotide, siRNA or shRNA.
4. The method of claim 1 , wherein the non-treatment interval is between at least about 0.5 to 12 months.
5. A method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a Bcl-xL selective senolytic agent, wherein the Bcl-xL selective senolytic agent is administered to the subject in need thereof intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval.
6. The method of claim 5 , wherein the Bcl-xL selective senolytic agent is a small molecule inhibitor.
7. The method of claim 5 , wherein the Bcl-xL selective senolytic agent is an antisense oligonucleotide, siRNA or shRNA.
8. The method of claim 5 , wherein the non-treatment interval is between at least about 0.5 to 12 months.
9. The method of claim 8 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction.
10. The method of claim 6 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction.
11. The method of claim 7 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction.
12. The method of claim 5 , wherein the administration of the pharmaceutical composition to the subject is by intracranial administration or intranasal administration.
13. The method of claim 6 , wherein the administration of the pharmaceutical composition to the subject is by intracranial administration or intranasal administration.
14. The method of claim 7 , wherein the administration of the pharmaceutical composition to the subject is by intracranial administration or intranasal administration.