10 August 2016
The human body becomes more susceptible to infection with age because blood-forming stem cells lose the ability to build the immune cells needed to mount a proper defence. Researchers in Germany have now found the cause of this stem cell breakdown: a gene that is otherwise involved in controlling daily circadian rhythms.
Wiping out this gene’s function allowed mice to live longer, with better clearance of bacteria in response to tissue infection. If the process can be replicated in people, it could offer a new way to treat diseases of human aging.
In both mice and people, the capacity of hematopoietic stem cells (HSCs) to form pathogen-fighting white blood cells declines with age as the cells’ DNA accumulates damage. A team led by K. Lenhard Rudolph, scientific director of the Leibniz Institute on Aging – Fritz Lipmann Institute, set out to find the genes that would halt this process.
The researchers bred mice that were engineered to suffer from the kind of DNA damage that harms stem cell function, and then extracted HSCs for study in the lab. Using a pool of specialized RNA molecules that silence the activity of target genes, they then tested the role of 459 candidate genes. From this list, they discovered that a gene known as Per2 (short for period circadian clock 2) helped the capacity of HSCs to survive DNA damage caused by aging.
Eliminating Per2 function in mice helped boost the number of HSCs; in particular those stem cells that make immune cells known as lymphocytes. As a result, these mice were more resistant to infections and they lived on average 15% longer than mice with functional Per2 activity, with no elevated signs of cancer or other diseases.
“To my knowledge, our study provides the first evidence for a single gene deletion that leads to improved generation of lymphocytes and immune function in aging mice,” Rudolph says.
The researchers are now investigating whether Per2 acts the same way in human HSCs. If it does, Rudolph says, “we will start a program to develop chemical Per2 inhibitors to correct the defect and to improve immune functions in aging.”
But, thy will have to consider the risk of side effects. Per2 normally acts in the brain to control circadian patterns, and mutations in the gene have been linked to sleep disturbances. Rudolph hopes to avoid problems by only targeting Per2 in the blood, while leaving the brain alone.
- Wang, J., Morita, Y., Han, B., Niemann, S., Löffler, B., & Rudolph, K. L. Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nature Cell Biology (2016) | article