Clarifying Circadian Rhythm in Stem Cell Aging

Circadian rhythms, repeated 24-hour cycles of change, run in many parts of our biochemistry. Like most aspects of metabolism and its regulation, circadian rhythms become disrupted in later life. Numerous research groups have put in time trying to map this disruption, attempting to find its place in the chains of cause and effect that take place in aging and age-related disease. The research noted here is an example of incremental progress in this part of the field, a clarification of the role of circadian rhythm in stem cell aging. The activity of stem cells declines with advancing age, and thus tissue maintenance and function declines with it. The research community is seeking points at which to interfere safely to slow or reverse this decline, though to my eyes much of this work takes place too far down the lengthy chain of cause and effect that leads from fundamental molecular damage to age-related disease. Addressing root causes should be far more effective than attempting to clear up consequences.

It is widely believed that, with the passage of time, stem cells cease to differentiate between day and night cycles, in other words they lose their circadian rhythm, and that this loss promotes ageing. However, this has been found not to be the case. Two recent studies reject this hypothesis. During ageing, stem cells continue to show rhythmic activity but reprogram their circadian functions. "Aged stem cells conserve circadian rhythm but now perform another set of functions to tackle the problems that arise with age. The problem is that as they age, stem cells lose the rhythmic functions necessary for tissue protection and maintenance, which become replaced by functions aimed at coping with stress. Loss of the previous circadian functions of stem cells during natural ageing contributes in some way to greater damage and greater ageing".

In both studies, researchers compared stem cells from young mice (three months old) with those of aged mice (between 18 and 22 months old) in three kinds of tissue, namely skin, muscle and liver, every four hours over one day. It is known that a low-calorie diet delays the signs of ageing in primates and mice. In another set of experiments, researchers gave mice a low-calorie diet for six months and compared them with counterparts on a normal diet. The animals on the low-calorie diet conserved most of the rhythmic functions of their youth. According to the researchers, this would explain why a calorie restriction diet slows down ageing. What is not clear is whether low-calorie diets would keep ageing at bay in humans. In this regard, it is important to further examine why metabolism has such a dominant effect on the stem cell ageing process and, once the link that promotes or delays ageing has been identified, to develop treatments that can regulate this link.

"Although ageing always involves circadian reprogramming, an interesting aspect of our results is that such reprogramming is specific and distinct for each type of tissue studied. This observation implies that although the entire organism is ageing, each tissue goes through this process in a different way. So to address the slowing down of ageing, it will be necessary to study each tissue separately. Keeping the rhythm of stem cells "young" is important because in the end these cells serve to renew and preserve very pronounced day-night cycles in tissues."



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