Lamin A, An Activator of Longevity/Anti-Aging SIRT1 Protein

Abstract

In one embodiment, the present invention provides methods of modulating the deacetylase activity of SIRT1 in one or more cell by modifying the binding affinity of lamin A to SIRT1 via one or more interaction modifying compound. In another embodiment, the present invention provides methods of screening SIRT1-activating/inhibiting compounds based on the interaction between lamin A and SIRT1 proteins and SIRT1-activating property of lamin A. In another embodiment, the present invention provides uses of SIRT1-activating compounds to treat patient(s) suffering from metabolic and/or aging-related degenerative diseases, and uses of SIRT1-inhibiting compounds to treat human malignancies.

What is claimed is: 
     
         1 . A method of modulating the deacetylase activity of SIRT1 in a mammalian cell, the method comprising modifying the binding affinity of lamin A to SIRT1 via an interaction modifying compound. 
     
     
         2 . The method of  claim 1 , wherein the deacetylase activity of SIRT1 is increased by an increased binding affinity of lamin A to SIRT1. 
     
     
         3 . The method of  claim 1 , wherein the deacetylase activity of SIRT1 is decreased by a decreased binding affinity of lamin A to SIRT1. 
     
     
         4 . The method of  claim 1 , wherein the interaction modifying compound comprises resveratrol, wherein resveratrol increases the binding affinity of lamin A to SIRT 1. 
     
     
         5 . A method for increasing in a mammalian cell the deacetylase activity of SIRT1, the method comprising contacting the cell with a lamin A peptide in an amount effective to increase the deacetylase activity of SIRT1. 
     
     
         6 . The method of  claim 5 , wherein the lamin A peptide comprises the amino acid sequence of SEQ ID NO:2, or an analog thereof 
     
     
         7 . The method of  claim 5 , wherein the lamin A peptide comprises the carboxyl domain of lamin A, or an analog thereof. 
     
     
         8 . The method of  claim 5 , wherein the lamin A peptide comprises amino acids 567-646 of SEQ ID NO:2, or a fragment thereof. 
     
     
         9 . The method of  claim 8 , wherein the fragment is from about 3 amino acids to about 50 amino acids in length. 
     
     
         10 . The method of  claim 9 , wherein the fragment is an analog. 
     
     
         11 . A method for treating a disease or condition in which modulated SIRT1 deacetylase activity is beneficial, comprising administering to a subject in need of such treatment, an effective amount of an agent that modulates SIRT 1 deacetylase activity. 
     
     
         12 . The method of  claim 11 , wherein the agent increases SIRT1 deacetylase activity. 
     
     
         13 . The method of  claim 12 , wherein the agent is a carboxyl terminal peptide of lamin A, or analog thereof. 
     
     
         14 . The method of  claim 12 , wherein the increased SIRT1 deacetylase activity results in increased number of bone marrow stromal cells. 
     
     
         15 . The method of  claim 12 , wherein the increased SIRT1 deacetylase activity results in increased number of hematopoietic stem cells. 
     
     
         16 . The method of  claim 11 , wherein the agent decreases SIRT1 deacetylase activity. 
     
     
         17 . The method of  claim 16 , wherein the disease or condition being treated is neoplasia. 
     
     
         18 . A method of screening for agents that modulate SIRT 1 deacetylase activity, wherein the method comprises:
 contacting a candidate molecule with cells expressing SIRT1 in a test sample;   determining deacetylase activity in the test sample; and   selecting the candidate molecule as the agent that modulates SIRT1 deacetylase activity if said molecule changes the level of SIRT1 deacetylase activity in the test sample.   
     
     
         19 . The method according to  claim 18 , wherein the candidate molecule is a fragment of the lamin A carboxyl domain, or an analog thereof 
     
     
         20 . The method according to  claim 18 , wherein the candidate molecule is a compound that enhances the binding of lamin A to SIRT 1. 
     
     
         21 . The method according to  claim 18 , wherein the candidate molecule is a compound that modulates lamin A protein level.