CASIN – fountain of youth for ageing mice
Researchers turn back the epigenetic clock

Ulm University

Anti-ageing researchers from Ulm and Barcelona have 'rejuvenated' elderly mice. As the mice's 'fountain of youth' served a substance called CASIN, which reduces the age-associated protein Cdc42. After only four days of CASIN therapy, the mice lived about 10 percent longer than their untreated conspecifics. The researchers had literally succeeded in turning back the rodents' epigenetic clocks. Their study was published in the journal “Aging Cell”.

How can we slow down or even reverse the ageing process? This question is the focus of the work of researchers led by Professor Hartmut Geiger, Director of the Institute of Molecular Medicine at Ulm University, and Yi Zheng from Cincinnati Children's Hospital Medical Center (CCHMC). At least for mice the researchers have found an answer: The substance CASIN seems to prolong their lifespan significantly. Prof. Geiger and Dr. Maria Carolina Florian, group leader at the Institut d'Investigació Biomédica de Bellvitge (IDIBELL) in Barcelona, describe the underlying mechanisms in their recently published study. In previous investigations the researchers found an increased activity of Cdc42 in various organs and in the bone marrow of older mice. This protein is associated with premature aging and a reduced lifespan. Significantly elevated Cdc42 levels were also detected in the blood of elderly people. With CASIN (Cdc42 activity-specific inhibitor), the scientists have found an inhibitor that reduces this age-associated protein. 'In a preceding study we were already able to show that CASIN can "rejuvenate" old haematopoietic stem cells by reducing Cdc42 activity. After treatment, they functioned just as well as young stem cells,' explains Hartmut Geiger.

This latest study tested whether short-term treatment with CASIN could extend the lifespan of geriatric mice. In the experiment, 75-week-old female mice – this age is the equivalent of about 60 to 70 human years – were given CASIN every 24 hours for four days. And indeed, the researchers found a significantly reduced activity of the age-associated protein Cdc42 in the bone marrow of the animals already one day after the treatment had ended. The animals' Cdc42 levels equalled those of significantly younger conspecifics. In the further course of the study it became apparent that the 'pharmacologically rejuvenated' mice lived up to 10 percent longer than their untreated conspecifics (average and maximum lifespan). 'CASIN is thus a substance that can extend the lifespan of mice even when their age is already very advanced and when the substance is only administered for a short time,' Geiger and Florian elaborate.

Nine weeks after this first experiment, the researchers, in collaboration with Professor Wolfgang Wagner from RWTH Aachen University, evaluated the so-called epigenetic clocks in the animals' blood cells. Indeed, significant changes were observed 8 to 10 weeks after the administration of CASIN: With the help of the substance the researchers managed to turn back the epigenetic clock of the treated rodents by about 9 weeks. Epigenetic changes thus appear to be the main cause for the mice's longevity.
Epigenetics refers to the interaction between environmental influences and genes. Genes can be switched on and off by attaching methyl groups to the DNA strand or via other modifications.
Furthermore, the serum levels of age-associated cytokines in the mice treated with CASIN were comparable to those of young animals.

Overall, the researchers were able to substantiate the hypothesis that a reduction of the age-associated protein Cdc42 prolongs the lifespan of older mice. The study also confirms epigenetic clocks as biomarkers of the aging process. Such markers are useful both for basic research on ageing as well as for testing new therapies for age-associated diseases.

Media contact: Annika Bingmann

M. Carolina Florian, Hanna Leins, Michael Gobs, Yang Han, Gina Marka, Karin Soller, Angelika Vollmer, Vadim Sakk, Kalpana J. Nattamai, Ahmad Rayes, Xueheng Zhao, Kenneth Setchell, Medhanie Mulaw, Wolfgang Wagner, Yi Zheng, Hartmut Geiger: Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice; Aging Cell.



Gel electrophoresis to determine the genotype of an elderly mouse (photo: Heiko Grandel / Ulm University)
Gel electrophoresis to determine the genotype of an elderly mouse (photo: Heiko Grandel / Ulm University)
Prof. Hartmut Geiger
Prof. Hartmut Geiger is Director of the Institute of Molecular Medicine at Ulm University (photo: Heiko Grandel / University Medical Centre Ulm)
Dr. Maria Carolina Florian
First author Dr. Maria Carolina Florian is group leader at the Institut d'Investigació Biomédica de Bellvitge (IDIBELL) in Barcelona (photo: Elvira Eberhardt / Ulm University)