Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice

Abstract

We present genome-wide microarray expression analysis of 11,000 genes in an aging potentially mitotic tissue, the liver. This organ has a major impact on health and homeostasis during aging. The effects of life-and health-span-extending caloric restriction (CR) on gene expression among young and old mice and between long-term CR (LT-CR) and short-term CR (ST-CR) were examined. This experimental design allowed us to accurately distinguish the effects of aging from those of CR on gene expression. Aging was accompanied by changes in gene expression associated with increased inflammation, cellular stress, and fibrosis, and reduced capacity for apoptosis, xenobiotic metabolism, normal cell-cycling, and DNA replication. LT-CR and just 4 weeks of ST-CR reversed the majority of these changes. LT-CR produced in young mice a pattern of gene expression that is a subset of the changes found in old LT-CR mice. It is possible that the early changes in gene expression, which extend into old age, are key to the life-and health-span-extending effects of CR. Further, ST-CR substantially shifted the ''normo-aging'' genomic profile of old control mice toward the ''slow-aging'' profile associated with LT-CR. Therefore, many of the genomic effects of CR are established rapidly. Thus, expression profiling should prove useful in quickly identifying CRmimetic drugs and treatments.P ublished microarray studies of mammalian aging have focused on the postmitotic tissues, muscle and brain (1-3). These studies found that aging was associated with changes in gene expression linked to the development of the characteristic age-related pathologies of these tissues. In contrast to muscle and brain, the liver is a potentially mitotic tissue that is thought to age well from a clinical perspective (4). The liver is the central organ for the regulation of glucose homeostasis, xenobiotic metabolism and detoxification, and steroid hormone biosynthesis and degradation. This organ also has a major impact on health and homeostasis through its control of serum protein composition. While differentiated hepatic functions are generally well maintained with age, changes do occur. Serum and biliary cholesterol rise, liver regeneration declines, hepatic drug clearance decreases, and liver volume and blood flow decrease (4). The resilience of the liver to aging, and its central role in the maintenance of whole body health and homeostasis make it an intriguing target for genome-wide expression analysis of aging.Caloric restriction (CR) is the only intervention shown to extend lifespan in mammals (5). It is also the most effective means known of reducing cancer incidence and increasing the mean age of onset of age-related diseases and tumors (6). Our studies made use of an experimental design that allowed us to clearly distinguish the effects of diet from those of age on genome-wide expression patterns. Another distinctive aspect of the study allowed us to resolve changes in gene expression induced directly by CR from those that arise over time as a consequence of ...

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