Resumen de Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress
Abstract The correct timing of adult stem cell function is essential for tissue homeostasis. Our group was among the first to show that circadian rhythms segregate important stem cell functions along the day. For instance, in mouse epidermal stem cells this mechanism ensures that their proliferation occurs at night and not during day, when maximal oxidation takes place. Likewise, circadian rhythms separate DNA replication from the time when human epidermal stem cells are exposed to UV radiation. Importantly, circadian control of stem cells is a general mechanism operating in hematopoietic, mesenchymal, muscle, neural, and intestinal stem cells, as shown by others. A current dogma in the field is that circadian rhythms dampen during ageing, and that this dampening is in fact a major cause of many traits associated to ageing. With this in mind we decided to ask: is the timing of stem cell function altered during ageing? If so, how is it perturbed? Are the changes common, or stem cell-specific? To study these questions, we have performed a large-scale analysis of the circadian transcriptome of FACS-sorted stem cells from adult and aged mice, which has provided us with an unprecedented understanding of how their physiology changes during ageing. We chose two types of stem cells for our study, those from the epidermis and the skeletal muscle, since they represent two populations with very different behaviours (the former being highly proliferative, while the latter remaining predominantly quiescent throughout the lifetime of the mouse).
Unexpectedly, we find that aged mice remain behaviourally circadian, and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components (Bmal1, or Period-1 and Period-2) did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological ageing. Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during ageing.
Age-associated rewiring of the oscillatory diurnal transcriptome is significantly prevented by longterm caloric restriction in aged mice. This striking effect further highlights the anti-ageing benefits of this type of diet. Conversely, although a high-fat diet strongly reprograms the circadian output of both stem cells, there is little overlap with the age-related rewired oscillating transcriptome. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific agerelated traits.
