EP-4735120-A2 - CHEMICALLY INDUCED REPROGRAMMING TO REVERSE AGING

Abstract

Provided herein are methods of rejuvenating, restoring cellular function to, decreasing the biological age of, decreasing the apparent chronological age of, and reprogramming cells, organs, and tissues, using chemical cocktails comprising two or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Also provided herein are methods of treating a disease, methods of monitoring cellular aging, and pharmaceutical compositions and kits using two or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Inventors

• SINCLAIR, DAVID A.
• YANG, JAE-HYUN
• PETTY, Christopher
• DIXON-MCDOUGALL Thomas

Assignees

• President and Fellows of Harvard College

Dates

Publication Date

20260506

Application Date

20240628

Claims (1)

1. CLAIMS What is claimed is: 1. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 210/240 12591029. H0824.70430WO00 2. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 3. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 211/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 4. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 212/240 12591029. H0824.70430WO00 valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 5. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 213/240 12591029. H0824.70430WO00 forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 6. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 214/240 12591029. H0824.70430WO00 arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 7. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 215/240 12591029. H0824.70430WO00 smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 8. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 216/240 12591029. H0824.70430WO00 9. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 10. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 217/240 12591029. H0824.70430WO00 ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 11. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 218/240 12591029. H0824.70430WO00 forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 12. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 219/240 12591029. H0824.70430WO00 Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 13. The method of any one of claims 1-12, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof three or more compounds selected from the group. 14. The method of any one of claims 1-13, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof four or more compounds selected from the group. 15. The method of any one of claims 1-14, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof five or more compounds selected from the group. 16. The method of any one of claims 1-15, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof six or more compounds selected from the group. 17. The method of any one of claims 1-16, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 18. The method of any one of claims 1-17, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 220/240 12591029. H0824.70430WO00 tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 19. The method of any one of claims 1-18, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 20. The method of any one of claims 1-19, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 221/240 12591029. H0824.70430WO00 21. The method of any one of claims 1-20, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 22. The method of any one of claims 1-21, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 23. The method of any one of claims 1-22, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 222/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 24. The method of any one of claims 1-23, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 25. The method of any one of claims 1-24, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate. 26. The method of any one of claims 1-25, wherein the ascorbic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is ascorbic acid, lithium ascorbate, Ester-C, ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate. 27. The method of any one of claims 1-6 and 13-16, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof. 28. The method of any one of claims 1-6, 13-16, and 27, wherein the lithium salt is selected from lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, and lithium citrate. 223/240 12591029. H0824.70430WO00 29. The method of any one of claims 1-6, 13-16, 27, and 28, wherein the lithium salt is lithium chloride. 30. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 31. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 32. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 33. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 34. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate. 35. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof lithium ascorbate. 36. The method of any one of claims 1-5 and 7-34, wherein the cell is a senescent cell. 37. The method of claim 36, wherein the senescent cell is within the tissue or organ. 38. The method of any one of claims 1-5, 7-34, 36, and 37 , wherein the cell, tissue, or organ is within a subject. 39. The method of any one of claims 1-38, further comprising: increasing cellular respiration, reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, or a combination thereof, ex vivo or in vitro. 40. The method of any one of claims 1-5, 7-11, 13-34, and 36-39, wherein the cell or tissue is from eye, ear, nose, mouth including gum and roots of teeth, bone, lung, breast, udder, pancreas, stomach, esophagus, muscle including cardiac muscle, liver, blood vessel, skin including hair, heart, brain, nerve tissue, kidney, testis, prostate, penis, cloaca, fin, ovary, or intestine, optionally wherein 224/240 12591029. H0824.70430WO00 the tissue is damaged or the tissue may be considered healthy but suboptimal for performance or survival in current or future conditions. 41. The method of any one of claims 5, 11, 13-29, 34, and 36-40, wherein the method reduces expression of the at least one gene associated with aging. 42. The method of any one of claims 5, 11, 13-29, 34, and 36-40, wherein the method increases expression of the at least one gene associated with aging. 43. The method of any one of claims 5, 11, 13-29, 34, and 36-42, wherein the at least one gene associated with aging is associated with: inflammation, mitochondrial metabolism, lysosomal function, apoptosis, p53, growth signaling, or a combination thereof, ex vivo or in vitro. 44. The method of any one of claims 1-5, 7-11, 13-34, and 36-43, further comprising activating an enhancer of reprogramming in the cell, tissue, or organ. 45. The method of claim 44, wherein the enhancer of reprogramming is a class I histone deacetylase (HDAC1-3). 46. The method of any one of claims 1-5, 7-11, 13-34, and 36-45, comprising restoring epigenetic information in the cell, tissue, or organ. 47. The method of claim 46, wherein the epigenetic information is lost due to aging, injury, disease, or a combination thereof in the cell, tissue, or organ. 48. The method of any one of claims 1-5, 7-11, 13-34, and 36-47, comprising reestablishing an epigenetic status of the cell, tissue, or organ that is similar to the status formed soon after final differentiation. 49. The method of any one of claims 1-5, 7-11, 13-34, and 36-48, wherein the cell, tissue, or organ is not reprogrammed to a pluripotent state. 50. The method of any one of claims 1-49, wherein the method rejuvenates an epigenetic clock of a cell, tissue, organ, subject, or a combination thereof. 51. The method of any one of claims 4, 10, 13-29, 33, 36-40, and 44-50, wherein the apparent chronological age of the cell, organ, or tissue is reduced by about three years. 225/240 12591029. H0824.70430WO00 52. The method of any one of claims 1-5, 7-11, 13-34, and 36-51, wherein the cell, tissue, or organ is treated for about four days. 53. The method of any one of claims 1-29 and 36-52, wherein the laduviglusib (CHIR99021), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 54. The method of any one of claims 1-29 and 36-53, wherein the RepSox (E-616452), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 55. The method of any one of claims 1-29 and 36-54, wherein the ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 10 µg/mL to about 100 µg/mL. 56. The method of any one of claims 1-29 and 36-55, wherein the valproic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 400 µM. 57. The method of any one of claims 1-29 and 36-56, wherein the tranylcypromine, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 2.5 µM to about 7.5 µM. 58. The method of any one of claims 1-29 and 36-57, wherein the forskolin, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 25 µM to about 75 µM. 59. The method of any one of claims 1-29 and 36-58, wherein the butyric acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 300 µM. 226/240 12591029. H0824.70430WO00 60. The method of any one of claims 1-29 and 36-59, wherein the basic fibroblast growth factor (bFGF), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 50 µg/mL to about 150 µg/mL. 61. The method of any one of claims 1-29 and 36-60, wherein the arotinoid acid (TTNPB), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 62. The method of any one of claims 1-29 and 36-61, wherein the Y-27632, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 63. The method of any one of claims 1-29 and 36-62, wherein the smoothened agonist (SAG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.25 µM to about 0.75 µM. 64. The method of any one of claims 1-29 and 36-63, wherein the linifanib (ABT-869), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.5 µM to about 1.5 µM. 65. The method of any one of claims 1-29 and 36-64, wherein the alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 250 µM to about 750 µM. 66. The method of any one of claims 1-6, 13-29, and 36-65, wherein the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM. 67. The method of any one of claims 30-52, wherein the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM. 227/240 12591029. H0824.70430WO00 68. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-67, wherein the subject is a human. 69. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-68, wherein the subject is a pediatric subject. 70. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-68, wherein the subject is an adult subject. 71. The method of claim 70, wherein the adult subject is a senior adult subject. 72. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-71, wherein the subject is healthy. 73. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-71, wherein the subject has, is suspected of having, or is at risk for an age-related disease. 74. The method of claim 73, wherein the age-related disease is a neurological disease. 75. The method of claim 74, wherein the neurological disease is a neurodegenerative disease. 76. The method of claim 75, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). 77. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-76, wherein the administration comprises systemic administration to the subject. 78. A method of monitoring cellular aging, the method comprising: (a) providing a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; (b) contacting the cell with at least one test agent; (c) measuring a first signal from a first protein produced by the first reporter gene; (d) measuring a second signal from a second protein produced by the second reporter gene; (e) comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell. 228/240 12591029. H0824.70430WO00 79. The method of claim 78, wherein the first reporter gene encodes a first fluorescent protein. 80. The method of claim 79, wherein the first fluorescent protein is mCherry. 81. The method of any one of claims 78-80, wherein the second reporter gene encodes a second fluorescent protein. 82. The method of claim 81, wherein the second fluorescent protein is eGFP. 83. The method of any one of claims 78-82, wherein the cell is a fibroblast. 84. The method of any one of claims 78-83, wherein the cell is a human cell. 85. A cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal. 86. The cell of claim 85, wherein the first reporter gene encodes a first fluorescent protein. 87. The cell of claim 86, wherein the first fluorescent protein is mCherry. 88. The cell of any one of claims 85-87, wherein the second reporter gene encodes a second fluorescent protein. 89. The cell of claim 88, wherein the second fluorescent protein is eGFP. 90. The cell of any one of claims 85-89, wherein the cell is a fibroblast. 91. The cell of any one of claims 85-90, wherein the cell is a human cell. 92. A pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 229/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 93. A pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 230/240 12591029. H0824.70430WO00 valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 94. The pharmaceutical composition of claim 92 or claim 93, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 95. The pharmaceutical composition of any one of claims 92-94, comprising three or more compounds selected from the group. 96. The pharmaceutical composition of any one of claims 92-95, comprising four or more compounds selected from the group. 97. The pharmaceutical composition of any one of claims 92-96, comprising five or more compounds selected from the group. 98. The pharmaceutical composition of any one of claims 92-97, comprising six or more compounds selected from the group. 231/240 12591029. H0824.70430WO00 99. The pharmaceutical composition of any one of claims 92-98, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 100. The pharmaceutical composition of any one of claims 92-99, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 101. The pharmaceutical composition of any one of claims 92-100, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 102. The pharmaceutical composition of any one of claims 92-101, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 232/240 12591029. H0824.70430WO00 RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 103. The pharmaceutical composition of any one of claims 92-102, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 104. The pharmaceutical composition of any one of claims 92-103, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; 233/240 12591029. H0824.70430WO00 linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 105. The pharmaceutical composition of any one of claims 92-104, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 106. The pharmaceutical composition of any one of claims 92-105, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. 107. The pharmaceutical composition of any one of claims 92-106, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate. 108. The pharmaceutical composition of any one of claims 92-107, comprising ascorbic acid and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). 234/240 12591029. H0824.70430WO00 109. The pharmaceutical composition of any one of claims 92-108, wherein the lithium salt is selected from lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, and lithium citrate. 110. The pharmaceutical composition of any one of claims 92-109, wherein the lithium salt is lithium chloride. 111. The pharmaceutical composition of any one of claims 92-110, wherein the laduviglusib (CHIR99021), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 112. The pharmaceutical composition of any one of claims 92-111, wherein the RepSox (E- 616452), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM. 113. The pharmaceutical composition of any one of claims 92-112, wherein the ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 10 µg/mL to about 100 µg/mL. 114. The pharmaceutical composition of any one of claims 92-113, wherein the valproic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 400 µM. 115. The pharmaceutical composition of any one of claims 92-114, wherein the tranylcypromine, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 2.5 µM to about 7.5 µM. 116. The pharmaceutical composition of any one of claims 92-115, wherein the forskolin, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 25 µM to about 75 µM. 235/240 12591029. H0824.70430WO00 117. The pharmaceutical composition of any one of claims 92-116, wherein the butyric acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 300 µM. 118. The pharmaceutical composition of any one of claims 92-117, wherein the basic fibroblast growth factor (bFGF), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 50 µg/mL to about 150 µg/mL. 119. The pharmaceutical composition of any one of claims 92-118, wherein the arotinoid acid (TTNPB), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 120. The pharmaceutical composition of any one of claims 92-119, wherein the Y-27632, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM. 121. The pharmaceutical composition of any one of claims 92-120, wherein the smoothened agonist (SAG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.25 µM to about 0.75 µM. 122. The pharmaceutical composition of any one of claims 92-121, wherein the linifanib (ABT- 869), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.5 µM to about 1.5 µM. 123. The pharmaceutical composition of any one of claims 92-122, wherein the alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 250 µM to about 750 µM. 236/240 12591029. H0824.70430WO00 124. The pharmaceutical composition of any one of claims 92-123, wherein the ascorbic acid is used at a concentration of about 25 µg/mL to about 75 µg/mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM. 125. A pharmaceutical composition comprising lithium ascorbate. 126. The pharmaceutical composition of claim 125, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 127. The pharmaceutical composition of claim 125 or claim 126, wherein the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM. 128. The pharmaceutical composition of any one of claims 92-127 for use in rejuvenating a cell, tissue, or organ. 129. The pharmaceutical composition of any one of claims 92-127 for use in restoring cellular function in a cell, tissue, or organ. 130. The pharmaceutical composition of any one of claims 92-127 for use in decreasing a biological age of a cell, tissue, or organ. 131. The pharmaceutical composition of any one of claims 92-127 for use in decreasing an apparent chronological age of a cell, tissue, or organ. 132. The pharmaceutical composition of any one of claims 92-127 for use in reprogramming a cell, tissue, or organ, wherein reprogramming comprises altering the expression of at least one gene associated with aging. 133. A kit comprising: (a) a container housing the pharmaceutical composition of any one of claims 92-94; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. 134. A kit comprising: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: 237/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate); and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. 135. A kit comprising: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of: 238/240 12591029. H0824.70430WO00 laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof. 239/240 12591029. H0824.70430WO00

Description

CHEMICALLY INDUCED REPROGRAMMING TO REVERSE AGING RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63/511,601, filed June 30, 2023, which is incorporated herein by reference. GOVERNMENT SUPPORT [0002] This invention was made with government support under AG019719 and AG058605 and AG028730 and HG011850 awarded by National Institutes of Health (NIH). The government has certain rights in this invention. BACKGROUND OF THE INVENTION [0003] In many animals, including vertebrates, vital organs have a limited intrinsic capacity for regeneration and repair. Acute injury and chronic disorders can damage vital organs and tissues, including the brain. Mature somatic cells, however, often cannot survive these insults, and even if they do, they are unable to self-renew and transdifferentiate to replace damaged cells. Furthermore, cells that are capable of self-renewal can be limited in quantity, have limited capacity and are susceptible to damage, especially with age. In contrast to somatic cells from adults, cells from individuals that are chronologically closer to fertilization, such as those from embryos and infants, display cellular youthfulness and have a greater capacity to resist injury and stress, heal, renew, and regenerate organs and tissues. Thus, compositions and methods directed at rejuvenating cells, thereby restoring them from an aged, mature state to a younger, more vital state, have long been sought to treat certain injuries and diseases, as well as generally reverse and prevent aging in entire organisms. [0004] There are two types of information in the body: digital and analog. DNA is digital information and the epigenome is analog information. Analog information typically does not last as long as digital, nor can analog information generally be copied with high fidelity compared to digital information. This has consequences for how long organisms live and thrive. [0005] Several “hallmarks of aging” are cited as key contributors to the systemic deterioration of tissue function over time [1,2]. Of the aging hallmarks, there is strong evidence that a loss of epigenetic information and a smoothening of the epigenetic landscape, leading to changes in gene expression and a loss of cell identity, are among the main causes of aging [3–7]. The Information Theory of Aging states that a loss of information, particularly epigenetic information, causes a cascade of events that instigate the emergence of additional aging hallmarks, including mitochondrial dysfunction, inflammation, and cellular senescence [5,7,8]. The breakdown of these processes leads to a progressive decline in cell and tissue function, which manifests as aging and age-related diseases. It has previously been shown that DNA double-strand breaks and cellular injury are a major cause of 1/240 12591029. H0824.70430WO00 epigenetic information loss, leading to a decline in health of the organism, with increased frailty and vulnerability to disease [5]. [0006] Cellular senescence is a state of permanent cell cycle arrest that facilitates wound repair, tissue remodeling, and avoidance of cancer by halting proliferation in aged and damaged cells [9]. Senescence is associated with alterations in cell morphology, chromatin architecture, and the release of inflammatory factors in a process referred to as the senescence associated secretory phenotype (SASP). The transition to cellular senescence can be initiated by telomere shortening, DNA damage, cytoplasmic DNA, or a loss of epigenetic information [7,10]. The accumulation of senescent cells with age increases inflammation and reactive oxygen species both locally and across the organism, contributing to a broad range of age-related diseases, from macular degeneration to increased blood pressure [11]. [0007] Starting in 1962, Gurdon and others demonstrated that the nuclei of adult cells, such as those from intestinal cells, contain the necessary information to generate new individuals with normal lifespans [12]. Then in 2006, Takahashi and Yamanaka showed that by expressing four transcription factors – OCT3/4, SOX2, KLF4 and c-MYC(OSKM) – it is possible to epigenetically reset adult cells in vitro to erase cellular identity then coax them into myriad cell types [12–15]. These findings began the field of stem cell reprogramming, with a string of publications in the 2000s showing that, through transient expression or varying the cocktail of Yamanaka factors in vitro, the identities of adult cells could be erased back to a pluripotent stem cell stage [8,16–18]. [0008] The remarkable potency of the Yamanaka factors raised a significant question: is it possible to reverse cellular aging safely without compromising cellular identity, as the latter is known to lead to uncontrolled cell growth and tumorigenesis, which can swiftly endanger the life of the individual [16]. It has been confirmed that it is possible to improve the function of