title: Temporal linkage between the phenotypic and genomic responses to caloric restriction.
abstract: Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, decelerates the rate of aging and the development of age-related diseases. CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 (P = 0.000017) and 6.0 months (P = 0.000056), respectively. The rate of age-associated mortality was decreased 3.1-fold. Between the first and second breakpoints in the CR survival curve (between 21 and 31 months of age), tumors as a cause of death decreased from 80% to 67% (P = 0.012). Genome-wide microarray analysis of hepatic RNA from old control mice switched to CR for 2, 4, and 8 weeks showed a rapid and progressive shift toward the gene expression profile produced by long-term CR. This shift took place in the time frame required to induce the health and longevity effects of CR. Shifting from long-term CR to a control diet, which returns animals to the control rate of aging, reversed 90% of the gene expression effects of long-term CR within 8 weeks. These results suggest a cause-and-effect relationship between the rate of aging and the CR-associated gene expression biomarkers. Therefore, therapeutics mimicking the gene-expression biomarkers of CR may reproduce its physiological effects.
authors.affiliation: BioMarker Pharmaceuticals, Incorporated, 900 East Hamilton Avenue, Campbell, CA 95008, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Dhahbi
authors.forename: Hyon-Jeen
authors.initials: HJ
authors.lastname: Kim
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Mote
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Beaver
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spindler
mesh_terms: D000367:Age Factors; D000818:Animals; D031204:Caloric Restriction; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016019:Survival Analysis; D013997:Time Factors