gene regulation; photoperiod; aging; circadian oscillator
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2.1 SUMMARY: Age-related changes of the liver circadian oscillator2.1.1 BACKGROUNDAging alters a variety of cellular and physiological processes, which increases the probability of disease and finally death. Although our knowledge regarding recently defined ‘hallmark processes of aging’, which adversely affect cellular and physiological processes (e.g., genome stability or mitochondrial function), the overall picture is less clear. In particular, the transition from primary aging, i.e. age-related changes that are not harmful to the organism, to secondary aging or senescence may either be programed or stochastic. To address this issue, it would be useful to have easy-to-follow primary aging programs at our disposal from which deviations can be monitored over time. Previously, we investigated the behavior of the circadian oscillator in mouse liver with age and found it to behave as a robust primary aging program. An auto-regulatory feedback loop comprised of the circadian output factors of the PAR-bZip family appears to govern age-related increases in amplitude and magnitude of circadian oscillations. However, it is not yet clear how this feedback loop is regulated and how many target genes are affected. Hence, the analysis of the circadian oscillator may provide new insights into aging.2.1.2 WORKING HYPOTHESISPAR-bZip factors govern age-related changes of the liver transcriptome.2.1.3 SPECIFIC AIMSI. Analysis of the flexibility of the circadian oscillatorIt was found that electro-physical properties of neurons in aged mice mimic those of mice kept in long photoperiods. We are interested in the flexibility of the circadian oscillator in the liver in response to the photoperiod and want to compare the circadian oscillator network in both conditions (i.e. photoperiod and age). We will measure mRNA and protein accumulation at two hours resolution to determine phase and amplitude of the circadian oscillator. Using affected mouse mutant strains in their circadian oscillator, it will be possible to compare the underlying process permitting flexibility in either situation.II. Analysis of the impact of circadian PAR-bZip factorsPreliminary data suggests that an auto-regulatory feedback loop generated by PAR-bZip factors causes age-related transcriptional changes in the liver. ChIP experiments with antibodies for PAR-bZip factors revealed an unexpected high number of genomic binding sites. Hence, PAR-bZip factors may act as universal amplifiers of transcription similar to c-Myc, and thus may affect the entire liver transcriptome. This new concept will be verified by additional ChIP-sequencing experiments using chromatin derived from mice of different age and functional characterization of PAR-bZip factor mouse mutant strains.2.1.4 SIGNIFICANCEThe increase of elder persons and the emergence of age-related diseases are upcoming issues for our society. Here we analyze age-related changes of the liver circadian oscillator as a starting point to understand the transition from healthy primary aging to damaging secondary aging.