Interventions to mimic the effects of calorie restriction

Abstract

Long term calorie restriction has the benefit of increasing life span. Methods to screen interventions that mimic the effects of calorie restriction are disclosed. Extensive analysis of genes for which expression is statistically different between control and calorie restricted animals has demonstrated that specific genes are preferentially expressed during calorie restriction. Screening for interventions which produce the same expression profile will provide interventions that increase life span. In a further aspect, it has been discovered that test animals on a calorie restricted diet for a relatively short time have a similar gene expression profile to test animals which have been on a long term calorie restricted diet.

1. A method of identifiing an intervention that mimics the effects of caloric restriction in cells, comprising:
 obtaining a biological sample;    exposing said biological sample to an intervention;    waiting a specified period of time;    assessing changes in gene expression levels, levels of RNA, protein, or protein activity levels related to one or more biomarkers of aging; and    identifying said intervention as one that mimics the effects of caloric restriction if one or more changes in said levels also occurs in caloric restriction.    
     
     
       2. The method of  claim 1  , wherein said biological sample comprises cells. 
     
     
       3. The method of  claim 2 , wherein said cells are obtained from a mammal. 
     
     
       4. The method of  claim 3 , wherein said mammal is a mouse. 
     
     
       5. The method of  claim 1 , wherein said change in gene expression levels, levels of RNA, protein, or protein activity levels corresponds to a change in gene expression for a gene encoding a chaperone protein. 
     
     
       6. The method of  claim 5 , wherein said gene encoding a chaperone protein is GRP78. 
     
     
       7. The method of  claim 1 , wherein said biomarker is apoptosis. 
     
     
       8. The method of  claim 1 , wherein said biomarker is aging. 
     
     
       9. The method of  claim 8 , wherein said biomarker of aging is a production of cancer cells. 
     
     
       10. The method of  claim 1 , wherein said changes in said gene expression level, levels of RNA, protein, or protein activity levels related to one or more biomarkers of aging occur in 6 weeks or less. 
     
     
       11. The method of  claim 10 , wherein said changes in said gene expression levels, levels of RNA, protein, or protein activity levels related to one or more biomarkers of aging occur is four weeks or less. 
     
     
       12. The method of  claim 11 , wherein said changes in said gene expression levels, levels of RNA, protein, or protein activity levels related to one or more biomarkers of aging occur in two weeks or less. 
     
     
       13. The method of  claim 12 , wherein said changes in said gene expression levels, levels of RNA, protein, or protein activity levels related to one or more biomarkers of aging occur in about two days or less. 
     
     
       14. A method according to  claim 1  wherein changes in gene expression are evaluated using a gene chip. 
     
     
       15. The method of  claim 14 , wherein the gene chip contains genes for immune system activation. 
     
     
       16. The method of  claim 14 , wherein the gene chip contains genes for DNA repair. 
     
     
       17. The method of  claim 14 , wherein the gene chip contains genes associated with apoptosis. 
     
     
       18. The method of  claim 14 , wherein the gene chip contains genes for the enteric nervous system. 
     
     
       19. The method of  claim 1 , wherein said biological sample is a test animal. 
     
     
       20. The method of  claim 19  additionally comprising determining changes in said levels in a reference animal having identifying characteristics of a long-term calorie-restricted animal wherein the reference animal has been on a calorie restricted diet for less than about 6 weeks and wherein said changes are used in said identifying said intervention as one that mimics the effects of calorie restriction. 
     
     
       21. The method of  claim 20 , wherein the reference animal has been on a calorie restricted diet for less than about 4 weeks. 
     
     
       22. The method of  claim 20 , wherein the reference animal has been on a calorie restricted diet for less than about 2 weeks. 
     
     
       23. The method of  claim 19 , wherein said test animal is a mouse. 
     
     
       24. The method of  claim 19 , wherein changes in gene expression are assessed in said test animal. 
     
     
       25. The method of  claim 19  which further comprises:
 obtaining a gene expression profile from a calorie-restricted reference animal;    comparing changes in gene expression for the test animal to the gene expression profile of the calorie-restricted reference animal; and    identifying said intervention as one that mimics the effects of calorie restriction if the gene expression profile of the test animal is statistically similar to the gene expression profile of the calorie restricted animal.    
     
     
       26. The method of  claim 25 , wherein the gene expression profile of the test animal is determined to be statistically similar to the gene expression of the calorie restricted animal by one-way ANOVA followed by Fisher's test (P<0.05). 
     
     
       27. A method of identifying an intervention that mimics the effects of caloric restriction in cells, comprising:
   obtaining a biological sample;        exposing the biological sample to an intervention;        waiting a specified period of time;        assessing changes in gene expression levels, levels of RNA, protein, or protein activity levels related to one or more biomarkers of aging; and        identifying the intervention as one that mimics the effects of caloric restriction if one or more changes in the levels also occurs in a reference animal subjected to short term caloric restriction.     
     
     
       28. The method of  claim 27 , wherein the short term caloric restriction is about two to about six weeks. 
     
     
       29. The method of  claim 27 , wherein the short term caloric restriction is about four weeks. 
     
     
       30. The method of  claim 27 , wherein the changes are determined in a test animal. 
     
     
       31. The method of  claim 30 , wherein the test animal is a mouse. 
     
     
       32. The method of  claim 27 , wherein the specified period of time is six weeks or less. 
     
     
       33. The method of  claim 27 , wherein the specified period of time is four weeks or less. 
     
     
       34. The method of  claim 27 , wherein the specified period of time is two weeks or less. 
     
     
       35. The method of  claim 27 , wherein the specified period of time is two days or less. 
     
     
       36. The method of  claim 27 , wherein the biomarker of aging is a gene encoding a chaperone protein. 
     
     
       37. The method of  claim 36 , wherein the chaperone protein is GRP78. 
     
     
       38. The method of  claim 27 , wherein the changes in gene expression are evaluated using an oligonucleotide- based high density array.   
     
     
       39. The method of  claim 38 , wherein the biomarker of aging is a gene encoding a protein involved in immune system activation. 
     
     
       40. The method of  claim 38 , wherein the biomarker of aging is a gene encoding a protein involved in DNA repair. 
     
     
       41. The method of  claim 38 , wherein the biomarker of aging is a gene encoding a protein involved in apoptosis. 
     
     
       42. The method of  claim 38 , wherein the biomarker of aging is a gene encoding a protein involved in the enteric nervous system.