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.C aloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, is a robust method of decelerating aging and the development of age-related diseases (1). The effects of CR are conserved in nearly every species tested, perhaps including humans (2). CR delays the onset and reduces the incidence and severity of age-related diseases, including cancer (2, 3).Quantitative changes in the activity of genes can control the rate of aging and the development of age-related diseases in invertebrates and mammals (4, 5). Numerous cross-sectional studies of the relationship between CR and gene expression have been published (6). Almost without exception, they have been interpreted as though they were performed longitudinally. This has led to the widespread view that the major effect of CR is to prevent agerelated changes in gene expression. Funding and publication bias has reinforced this notion (6).We previously found that in old mice, a 4-week shift from long-term control (LT-CON) to short-term CR (ST-CR) reproduced 55% of the gene-expression changes induced by long-term CR (LT-CR; ref. 7). ST-CR reversed Ϸ70% of the age-related changes in gene expression seemingly prevented by LT-CR (7). These results suggested for the first time that many of the gene expression changes produced by LT-CR respond rapidly to diet.The studies described above left several important questions unanswered. First, which of the changes in gene expression are related to the health and longevity effects of CR? Further, what are the kinetics of the changes in gene exp...

Skew-normal, skew-Cauchy, skew-Laplace, skew multivariate distributions, 62F03, 62A05,

monitored variable, profile likelihood, screening, skew-normal distribution,

No abstract

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