Mouse model for aging

Abstract

A mouse model for mammalian aging is disclosed. In one embodiment, the invention comprises a mouse having a genomic mutation in the exonuclease domain II (ExoII) of a mitochondrial DNA polymerase gamma (POlG) gene, wherein the mutation leads to high levels of mutations in polymerase mtDNA.

1 . A transgenic mouse model for mammalian aging comprising a mouse having a genomic mutation in the exonuclease domain of a mitochondrial DNA polymerase gamma (Polg) gene, wherein the mutation results in elevated mitochondrial mutation frequency in at least two tissues.  
     
     
         2 . The mouse model of  claim 2  wherein the mutation is selected from the group consisting of a single or double base pair nucleotide substitution.  
     
     
         3 . The mouse model of  claim 1  having a genomic mutation in the exonuclease domain II (ExoII) of a mitochondrial DNA polymerase gamma (Polg) gene, wherein the mutation is a nucleotide change within nucleotide residues 1026 through 1067 of the mouse Polg gene.  
     
     
         4 . The mouse model of  claim 1  wherein the impairing of the exonuclease domain activity results in the expression of a DNA proof-reading deficient version of the mitochondrial DNA polymerase gamma (Polg) gene and accumulation of mitochondrial DNA mutations in both mitotic and post-mitotic mouse tissues, which is correlated with the activation of caspase-3 and the induction of apoptosis in mouse tissues.  
     
     
         5 . The mouse model of  claim 3  wherein a double base substitution results in a change in the coding of amino acid residue 257 from an aspartic acid (D) to an alanine (A) in the exonuclease domain II (ExoII) of Polg.  
     
     
         6 . The mouse model of  claim 1  wherein the mouse is D257A.  
     
     
         7 . The mouse model of  claim 1  wherein the mouse Polg gene sequence has an Accession No: NM — 017462 as set forth in SEQ ID NO: 1.  
     
     
         8 . The mouse model of  claim 1  wherein the mutated mouse Polg gene sequence has the mutation as set forth in SEQ ID NO: 3.  
     
     
         9 . The mouse model of  claim 1  wherein the mouse exhibits symptoms of accelerated or premature aging compared to a mouse not having the mutation in the exonuclease domain of the Polg gene.  
     
     
         10 . The mouse model of  claim 1  wherein the aging symptoms are selected from the group consisting of abnormalities in tissues of high cellular turnover, heart dysfunction, graying hair and alopecia, auditory function loss, cochlear degeneration, immune cell loss, anemia, male germ cell loss leading to lack of sperm and infertility, skeletal muscle mass loss (sarcopenia), neurodegeneration, increased presence of apoptotic markers, and loss of bone mass.  
     
     
         11 . A method of screening for a potentially therapeutic agent useful for delaying the onset of aging-related symptoms, the method comprising the steps of: 
 (a) providing a mouse model of  claim 1 , wherein the mouse exhibits aging-related symptoms;    (b) administering the agent to the mouse model; and    (c) determining whether the agent is capable of delaying the onset of aging-related symptoms in the mouse model treated with the agent compared to an untreated mouse model.    
     
     
         12 . The method of  claim 11  wherein the aging-related symptoms are selected from the group consisting of abnormalities in tissues of high cellular turnover, heart dysfunction, graying hair and alopecia, auditory function loss, cochlear degeneration, immune cell loss, anemia, male germ cell loss leading to lack of sperm and infertility, skeletal muscle mass loss (sarcopenia), bone loss, neurodegeneration and increased presence of apoptotic stress markers.  
     
     
         13 . The method of  claim 11  wherein the age-related symptoms are selected from the group consisting of altered hearing function, altered heart function, loss of bone, loss of muscle mass and induction of apoptosis.  
     
     
         14 . The method of  claim 11  wherein the therapeutic agent is a genetically-, a pharmaceutical- or a dietary-based agent.  
     
     
         15 . A method of screening for a potentially therapeutic agent useful for treating medical conditions comprising progressive external ophthalmoplegia, sensorimotor polyneuropathy, ataxia, Parkinson's syndrome or early menopause defined by mitochondrial DNA mutations in a POLG gene, the method comprising the steps of: 
 (a) providing a mouse model of  claim 1 , wherein the mouse exhibits symptoms of progressive external ophthalmoplegia sensorimotor polyneuropathy, ataxia, Parkinson's syndrome or early menopause;    (b) administering the agent to the mouse model; and    (c) determining whether the agent is capable of improving symptoms for any of the medical conditions of step (a) in the mouse model treated with the agent compared to an untreated mouse model.    
     
     
         16 . A method for generating a mouse model for mammalian aging, comprising the steps: 
 (a) introducing into a mouse a germlne transmission of a mutation an exonuclease domain of a mitochondrial DNA polymerase gamma (POlG) gene, wherein the mutation results in a decrease in the POlG exonuclease activity, and wherein the mutation results in the production of a PolgA exo−/+  mouse;    (b) crossbreeding the PolgA exo−/+  mouse of step (a); and    (c) generating a homozygous PolgA exo−/+  mouse which exhibits at least one symptom of aging, wherein the symptoms of aging are selected from the group consisting of abnormalities in tissues of high cellular turnover, heart dysfunction, graying hair and alopecia, auditory function loss, cochlear degeneration, immune cell loss, anemia, male germ cell loss leading to lack of sperm and infertility, skeletal muscle mass loss (sarcopenia), loss of bone mass, neurodegeneration and increased presence of apoptotic stress markers.    
     
     
         17 . The method of  claim 16  wherein the mutation is a double base substitution (AC to CT) at nucleotide residues 1054 to 1055 of the mouse Polg gene.