期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：15
页码：5524-5529
DOI：10.1073/pnas.0305300101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
