Stem cells 'reprogram' circadian functions, exacerbating ageing

It is widely believed that stem cells cease to differentiate between day and night cycles over time — in other words, they lose their circadian rhythm — and that this loss promotes ageing. However, Spanish and US researchers claim this is not the case.

According to scientists at the Institute for Research in Biomedicine (IRB Barcelona), Pompeu Fabra University (UPF) and the University of California, Irvine, stem cells continue to show rhythmic activity during ageing but reprogram their circadian functions. As explained by IRB Barcelona’s Salvador Aznar Benitah, leader of the two studies, “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.”

Associate researcher Guiomar Solanas and PhD student Francisca Oliveira Peixoto, both at IRB Barcelona, 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 — skin, muscle and liver — every four hours over one day. They found that gene reprogramming — for example, in response to accumulated DNA damage, inflamed tissues or an inefficient cell self-cleaning process (autophagy) — occurs differently for each tissue.

“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,” said Pura Muñoz-Cánoves, a co-author on the study from UPF. “This observation implies that although the entire organism is ageing, each tissue goes through this process in a different way.”

This is DNA damage accumulation (in green) in old mice skin. Image credit: Guiomar Solanas and Francisca Peixoto, IRB Barcelona.

The researchers also proved that a low-calorie diet delays the signs of ageing, feeding mice a low-calorie diet for six months and compared them with counterparts on a normal diet. The animals on the low-calorie diet were found to conserve most of the rhythmic functions of their youth.

“The low-calorie diet greatly contributes to preventing the effects of physiological ageing,” said Aznar Benitah. “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. Eating less appears to prevent tissue ageing and therefore prevents stem cells from reprogramming their circadian activities.”

The researchers said their studies explain why a calorie restriction diet slows down ageing, though they are not certain as to whether low-calorie diets would keep ageing at bay in humans. Aznar Benitah noted, “Such diets are unlike to become widely followed because they entail constant hunger and so require a lot of willpower; also, such eating regimes provide the body with the minimum energy to perform its basic functions, which in the long term may have negative effects on people’s everyday lives.”

Aznar Benitah said 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.

The two studies were published in the journal Cell.

Top image credit: Iris Joval Granollers.