Massachusetts Institute of Technology

Whitehead Institute for Biomedical Research

Leonard P Guarente

Brian Kennedy

Nicanor Austriaco, Jr

Shin-Ichiro Imai

Christopher Armstrong

Homayoun Vaziri

Shin-ichiro Imai

Marcia C Haigis

David A Sinclair

Methods of NAD-dependent of at least one lysine residue in an acetylated protein are disclosed. The methods include combining the acetylated protein with an isolated Sir2 protein or fragment that includes a core domain of the Sir2 protein. The Sir2 protein or fragment of the Sir2 protein can include a human Sir2 protein or a fragment of a human Sir2 protein.

Methods of NAD-dependent deacetylation of a lysine residue in a protein

Methods of identifying agents which alter the NAD-dependent deacetylation activity of a Sir2 protein or a fragment of a Sir2 protein are disclosed. The acetylated protein can be a nuclear protein, such as a histone protein, or a cytoplasmic protein. The Sir2 protein employed in the methods can include at least a core domain of a Sir2 protein, such as a human Sir2 protein.

Methods for identifying agents that alter NAD-dependent deacetylation activity of a SIR2 protein

Methods of modulating insulin secretion and treating metabolic disorders by modulating the expression or activity of Sirt4 are provided.

SIRT4 activities

Methods for screening a compound, by providing a test mixture comprising a transcription factor, Sir2, and a Sir2 cofactor with the compound, and evaluating an activity of a component of the test mixture in the presence of the compound are described.

Sir2 activity

This invention relates to methods of screening compounds that modulate cellular and organismal processes by modification of the activity of SIR2 and/or transcription factors, e.g., p53, particularly methods of screening for compounds that modify lifespan and/or metabolism of a cell or an organism by modulation of the activity of SIR2 and/or transcription factors, e.g., p53, and more particularly to methods of screening for compounds that modulate the activity of Sir2 and/or transcription factors, e.g., p53. In particular, the present invention relates to a method for screening a compound, by providing a test mixture comprising a transcription factor, Sir2, and a Sir2 cofactor with the compound, and evaluating an activity of a component of the test mixture in the presence of the compound. The invention further relates to therapeutic uses of said compounds. The invention further relates to a method of modifying the acetylation status of a transcription factor binding site on histone or DNA by raising local concentrations of Sir2.

SIR2 activity

Methods of identifying agents which alter the NAD-dependent acetylation status and mono-ADP-ribosylation of nuclear proteins are disclosed. The methods further include identifying agents which alter the life span or aging of a cell or an organism by determining the level of NAD-dependent acetylation and/or ADP ribosylation of a nuclear protein. The invention also relates to a mammalian Sir2 protein which acetylates or deacetylates nuclear proteins in a NAD-dependent manner and has mono-ADP-ribosyltransferase activity. Host cells producing the Sir2 protein and antibodies to the Sir2 protein are also provided.

Methods for identifying agents which alter histone protein acetylation

Methods of isolating mutant yeast cells with increased life span, as well as mutant yeast cells isolated by the methods, are disclosed. Also described are methods of identifying agents which increase life span of yeast cells, and methods of isolating genes which affect senescence in organisms.

Identifying lifespan-altering agents

Methods of identifying agents or compounds which are capable of inhibiting the replication and/or accumulation of DNA circles in cells are described. Also described are methods of assessing the ability of a compound to extend life span, as well as methods of extending life span, comprising administering to a cell a compound identified by the assays described herein which extends life span. The invention also pertains to isolated mWRN, or an active derivative or fragment thereof and to an isolated nucleic acid molecule which encodes mWRN, or an active derivative or fragment thereof.

Growing community of inventors

Newton, MA, United States of America

Leonard P Guarente