Project Summary/Abstract In addition to the circadian rhythms (~24h oscillation), ultradian rhythms (with period smaller than 24h) also exist, among which 12h rhythms were prevalently found in multiple species ranging from circatidal marine animals, to nematode C. elegans and mammals like mouse, baboon and even humans. Our group recently discovered a mammalian 12h-clock that is evolutionarily conserved, cell-autonomous and established independently from the circadian clock but dependent on the unfolded protein response transcription factor XBP1s. Liver-specific deletion of XBP1s globally impairs the murine 12h transcriptome, but not circadian rhythms in vivo. XBP1s- dependent hepatic 12h transcriptome preferentially peaks at dawn and dusk, and is remarkably enriched in pathways regulating innate immune functions and endoplasmic reticulum (ER) and the Golgi apparatus homeostasis, including translation regulation, protein processing and sorting in ER and Golgi, protein quality control and sphingolipid and glycerolipid metabolism. These pathways are often dysregulated during aging and aging-related diseases. While it has been recently established that the 24h circadian rhythms undergo prevalent reprogramming during aging, whether the 12h-clock dysregulation is also causally linked to aging and/or aging- related diseases remains ill defined. Very intriguingly, preliminary data revealed a very robust global reprogramming of 12h-cycling transcriptome to 24h circadian rhythms during aging in mouse liver, which is further associated with a conversion of 12h hepatic XBP1s oscillation to 24h circadian oscillation. Based upon these findings, we hypothesize that 12h-to-24h (circadian) reprogramming can accelerate liver aging. We will generate mouse models of hepatic 12h-to-24h reprogramming. Extensive phenotyping experiments will be performed to determine if genetically-induced 12h-to-24h reprogramming is sufficient to drive hepatic aging in mice. We will further perform temporal RNA-Seq and hepatic secretome profiling to identify the molecular mechanism underlying this reprogramming. This work will therefore establish 12h-clock dysregulation as a novel hallmark of aging and suggest that new therapeutics aimed at preventing this 12h-to-24h reprogramming could be effective at improving health span in humans.