The broad, long-term objective of this proposal is to understand which tissues and genes respond to caloric restriction, and to explain how such changes affect the overall physiology, health and longevity of animals, including humans. The hypotheses to be tested are: (1) An H1 linker histone, HIS-41, is a direct target of DAF-16 and is one key transcriptional output of scenarios that increase longevity. (2) HIS-41 is necessary, but not sufficient, for the metabolic shift and increased longevity conferred by reduced insulin-like signaling or caloric restriction. (3) Distinct longevity mutants induce different HIS-41 accumulation patterns appropriate for the affected target tissue. (4) Caloric restriction extends life span by activating two synergistic processes: HIS-41 dependent silencing that reduces metabolic rate and reactive oxygen species levels; and increased production of factors that are co-regulated with HIS-41, such as superoxide dismutase.
The specific aims are: (1) Identify the sequence elements required for DAF-l6- dependent induction of his-41 in vivo (hypothesis 1). (2) Assay fat accumulation and life span in calorie restricted his-41 mutants or his-41- gerontogene double mutants; and determine whether forced HIS-41 expression is sufficient to phenocopy longevity mutants (hypothesis 2). (3) Identify genes that regulate HIS-41 levels and genes that are coordinately regulated with his-41 (hypotheses 1,2). (4) Determine the cell type specificity of HIS-41 accumulation in calorie restricted vs. single and double mutant combinations of distinct longevity pathways (hypothesis 3). (5) Measure the life span of transgenic animals that constitutively express HIS-41, SOD-3, and genes that are co-regulated with HIS-41 (hypothesis 4). A central view of this proposal is that widespread genomic silencing, mediated by an H1 linker histone, is a common feature of many genetic pathways that extend life span and increase stress resistance. Environmental factors, including caloric restriction, increase longevity by turning on the H1- mediated repression of genes for rapid growth and glucose-based metabolism, thereby reducing the overall rate of metabolism and the production of reactive oxygen species. The activation of the H1 repression system is done by the same transcription factor (DAF-l6/forkhead protein) known to up regulate enzymes for fat storage and utilization, as well as enhanced life maintenance (e.g. superoxide dismutase).
| MacQueen, A J; Baggett, J J; Perumov, N et al. (2005) ACT-5 is an essential Caenorhabditis elegans actin required for intestinal microvilli formation. Mol Biol Cell 16:3247-59 |
