Per2 Deletion Improves Immune Function, Extends Life in Mice

To what degree does the age-related decline of the immune system contribute to mortality and loss of longevity? How important is it in comparison to other aspects of aging? This study offers one useful data point, as the authors describe a genetic alteration that can boost the supply of new immune cells in old mice. The decline in that supply with age is one of the factors leading to poor immune function - and that means more than just vulnerability to infections, as the immune system is also responsible for destroying potentially cancerous and senescent cells, as well as clearing out forms of damaged proteins and unwanted metabolic waste. Various possibilities for increasing the number of new immune cells already exist in principle, such as regenerating the thymus, or cell therapies in which a patient's immune cells are grown outside the body and regularly infused, but this genetic approach is a new discovery.

There's no other age group suffering more from infectious diseases than seniors. With growing age, the risk of chronic and cute infections increases. This is due to the diminishing potential of hematopoietic stem cells (HSC) to build blood and immune cells in an appropriate number. In particular, HSC's capability to build lymphocytes is strongly declining, which leads to imbalances in blood cell composition and, thus, to immune defects limiting overall fitness and organismal survival during aging. There is experimental evidence that the accumulation of DNA damage contributes to these aging-induced immune impairments. Researchers identified gene Per2 as a genetic switch for a better immune system in mice: Per2 gene deletion ameliorates DNA damage responses in HSC leading to stabilization of hematopoietic stem and progenitor cells in aging mice. Hence, mice were less prone to infections and exhibited an elongated lifespan by 15% without increases in cancer.

For their study, in vivo RNA-mediated interference (RNAi) screenings were conducted in mice. 459 putative tumor suppressor genes were targeted to identify genes that limit the self-renewal capacity of HSC in response to DNA damage and aging. This screen identified "period circadian clock 2 (Per2)"-gene - usually one out of various genes regulating sleep-wake cycle - to represent a major factor limiting the maintenance and repopulation capacity of HSC in the context of various types of DNA damage and aging. Interestingly, Per2 deletion was sufficient to maintain a balanced production of lymphocytes, and hence, to improved immune function in aging mice. A similar effect was also found for DNA damages caused by the shortening of telomeres - the protective caps at our chromosomes' ends - a mechanism thought to be relevant for human aging.

"All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly". It will be of future interest to study if the results are transferable to humans. Although humans and mice are genetically quite similar, genes usually regulate myriad of processes in an organism, and possible side-effects of Per2 deletion will have to be elucidated very carefully. Interestingly, Per2 gene mutations in humans have been associated with advanced sleep disorders leading to advanced tiredness of the patients in the early evening hours. "It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging - it is of great interest for us to further investigate this question."