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

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-sp an-extending caloric restriction (CR) on gene expression among young and ol d mice and between long-term CIR (LT-CR) and short-term CR (ST-CR) were exa mined. This experimental design allowed us to accurately distinguish the ef fects of aging from those of CR on gene expression. Aging was accompanied b y changes in gene expression associated with increased inflammation, cellul ar stress, and fibrosis, and reduced capacity for apoptosis, xenobiotic met abolism, normal cell-cycling, and DNA replication. LT-CR and just 4 weeks o f ST-CR reversed the majority of these changes. LT-CR produced in young mic e 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, whic h extend into old age, are key to the life- and health-span-extending effec ts of CR. Further, ST-CR substantially shifted the "normo-aging" genomic pr ofile of old control mice toward the "slow-aging" profile associated with L T-CR. Therefore, many of the genomic effects of CR are established rapidly. Thus, expression profiling should prove useful in quickly identifying CR-m imetic drugs and treatments.