Compositions for manipulating the lifespan and stress response of cells and organisms

• US 7,544,497 B2
• Filed: 07/01/2004
• Issued: 06/09/2009
• Est. Priority Date: 07/01/2003
• Status: Active Grant

• Current Assignee: Biopool International, Inc. (Bio-Techne Corporation), President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Biopool International, Inc. (Bio-Techne Corporation), President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Lamming, Dudley W., Sinclair, David A., Bitterman, Kevin J., Howitz, Konrad T., Zipkin, Robert E.
• Primary Examiner(s): Davis; Ruth A
• Application Number:
  US10/884,879
• Publication Number:
  US 20050136537A1
• Time in Patent Office: 1,804 Days
• Field of Search: 514/2, 514/9, 514/80, 514/733, 435/366, 435/183
• US Class Current: 435/183
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/175 having the group , >N—C(O)—N=N— or , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C12N 9/16 : acting on ester bonds (3.1)
• CPC Class Codes: C12Q 1/34 : involving hydrolase
• CPC Class Codes: G01N 2333/916 : acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)
• CPC Class Codes: G01N 2500/02 : Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)

Abstract

Provided herein are methods and compositions for modulating the activity of sirtuin deacetylase protein family members; p53 activity; apoptosis; lifespan and sensitivity to stress of cells and organisms. Exemplary methods comprise contacting a cell with an activating compound, such as a flavone, stilbene, flavanone, isoflavone, catechin, chalcone, tannin or anthocyanidin; or an inhibitory compound, such as a sphingolipid, e.g., sphingosine.

Claims

1. A method for increasing the deacetylase activity of SIRT1in a eukaryotic cell, comprising contacting a eukaryotic cell with a non-naturally occurring agent that binds SIRT1, reduces the K_m of SIRT1 for substrate and thereby increases the deacetylase activity of SIRT1.

2. The method of claim 1, wherein the agent is an organic molecule.

3. The method of claim 1, wherein the agent is an isolated agent.

4. The method of claim 1, wherein the agent does not have significant anti-oxidant activities.

5. The method of claim 1, wherein the agent reduces the K_m of SIRT1 for substrate by a factor of at least about 30.

6. The method of claim 1, wherein the agent reduces the K_m of SIRT1 for NAD⁺by a factor of at least about 3.

7. The method of claim 1, wherein the agent activates the deacetylase activity of SIRT1 by a factor of at least about 10.

8. The method of claim 1, wherein the agent causes at least a 10% greater induction of the deacetylase activity of SIRT1 relative to that caused by the same concentration of resveratrol.

9. The method of claim 1, wherein the eukaryotic cell is a mammalian cell.

10. The method of claim 9, wherein the mammalian cell is a human cell.

11. The method of claim 1 further comprising contacting the eukaryotic cell with a second agent that binds SIRT1, reduces the K_m of SIRT1 for substrate and thereby increases the deacetylase activity of SIRT1.

12. The method of claim 1, further comprising contacting the eukaryotic cell with another agent that binds another sirtuin, reduces the K_m of the other sirtuin for substrate and thereby increases the deacetylase activity of the other sirtuin.