New research has revealed that as mice age, the biological clock in their stem cells remains just as active but shifts focus onto other cell processes. It becomes less concerned with maintaining tissue and more involved in dealing with stress, carrying out such functions as repairing damaged DNA.
The findings may explain why mice age at a slower pace when put on a low-calorie diet, say the researchers. They suggest that calorie restriction delays the changes in circadian functions that occur in cells during aging.
The research team, including members from the Institute for Research in Biomedicine (IRB) Barcelona in Spain and the University of California, Irvine, reports the findings in two papers published in the journal Cell.
The discovery appears to discount the widely held idea that, over time, stem cells lose their circadian rhythm – that is, the pattern of 24-hour activity held in a group of genes.
Instead, older stem cells “conserve circadian rhythm but now perform another set of functions to tackle the problems that arise with age,” says senior study author Prof. Salvador Aznar Benitah, who leads a group studying stem cells and cancer at IRB Barcelona.
The researchers examined changes in stem cells taken from the skin, muscle, and livers of young mice aged 3 months, as well as from older mice aged between 18 and 22 months. Stem cells are precursor cells that divide to generate tissues.
The team found that, over time, while the genes that controlled circadian rhythm were just as active in the older mice as in the younger mice, they were influencing different cell processes.
For instance, in the younger mice, the circadian rhythm machinery was regulating normal cell processes concerned with tissue protection and maintenance. The processes include DNA replication, wound healing, and “autophagy,” which is a complex mechanism that, as well as eliminating waste, balances energy sources at critical times, such as in response to stress.
However, in the older mice, the circadian rhythm machinery was doing other things, such as controlling cell mechanisms for coping with stress, including repairing damaged DNA and responding to inflammation.
The researchers note that while they did not discover what triggers the “circadian reprogramming” that occurs as mice age, they did, to their surprise, discover that it is different and specific for each tissue type.
They suggest that this means that each tissue in the body ages differently with time, and that this needs to be taken into account in investigations of how to slow the aging process.
The team also carried out another experiment, wherein they compared mice that were on a low-calorie diet for 6 months with mice that were fed a normal diet.
They found that the circadian rhythm functions of the restricted-calorie mice stayed very similar throughout the period, whereas in the normal-diet mice, they changed over time to show signs of circadian reprogramming.
Prof. Aznar Benitah says that the “low-calorie diet greatly contributes to preventing the effects of physiological aging.”
“Eating less appears to prevent tissue aging and, therefore, prevent stem cells from reprogramming their circadian activities.”
Prof. Salvador Aznar Benitah
Earlier studies with fruit flies have shown that calorie restriction can extend lifespan. However, this new research is the first to show that it influences the effects of circadian rhythm on cellular aging.
Prof. Aznar Benitah explains that keeping the circadian 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.”
However, the researchers point out that these findings do not show whether or not calorie restriction would slow aging in humans.
“Such diets are [unlikely] 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,” explains Prof. Aznar Benitah.
The following IRB Barcelona video animation sums up the findings from the two studies.