Advancing Ageing and Cancer Research

Friday, August 21st — Reading, UK — The Biogerontology Research Foundation in collaboration with the Institute for Biology of Aging funds research in hematopoietic stem cell transplantation in telomerase-knockout mice.

Mammals must finely balance stimulation and suppression of cell division: over-permissive cellular proliferation promotes cancer, whereas over-restrictive cell division promotes degeneration. This is especially true in tissues with a high cell turnover, such as the blood. Genetic manipulation of the machinery that maintains the ends of our chromosomes, combined with cell therapy, is potentially a very powerful way to alleviate this problem. However, such an approach is highly complex; as a result, researchers have been reluctant to investigate its components. In this new project, the blood will be used as an example to demonstrate the feasibility of such a manipulation.

Recent data suggest that impaired function of adult stem cells could contribute to the ageing process and decline of organ maintenance and function and there is mounting evidence that accumulation of DNA damage can limit stem cell function by triggering stem cell intrinsic checkpoints. Telomere shortening represents a cell intrinsic mechanism that leads to an accumulation of DNA damage in ageing cells. First noted as a mitotic clock for cellular ageing, telomere shortening has now been documented in most organs and tissues of ageing humans.

“This project will be the first ever test of whether intrinsically mortal stem cells can maintain a proliferating tissue indefinitely if periodically replenished. If the answer is yes, this will motivate exploring such treatments as part of an exceptionally robust cancer-prevention therapy”, said Aubrey de Grey, Chief Scientific Officer of the SENS Foundation, an American charity that works to develop new therapies to treat diseases of the elderly.

Previous experimental evidence in late generation telomerase knockout mice indicates that telomere dysfunction limits the hematopoietic stem cell (HSC) function and maintenance during ageing. To test the hypothesis that transplanting HSC with long telomeres can improve survival and organ homeostasis, the BGRF and the IBA will support the work of the international research team led by Zhenyu Ju, MD, PhD*together with Leonard Rudolph, MD**. Over the three year period the group will conduct series of experiments transplanting the HSCs from the wild-type mice into telomere dysfunctional mice.

In addition, the research team will also investigate whether telomerase has a role in HSC function independent of its role in regulating telomere length. The group will test whether HSCs from the early- generation telomerase knockout mice can repopulate and rescue the ageing of hematopoietic system in late-generation telomerase knockout mice.

* Zhenyu Ju, M.D. and Ph.D., Principal Investigator, Max-Planck-Partner-Group-Program on Stem Cell and Aging Research Associate Investigator, Sino-German Laboratory for Aging and Regenerative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China

** K. Lenhard Rudolph, M.D., Chairman, Department of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, Ulm, Germany