SENS6 Favorites: Senescent Cell Clearance

Posted by Iain Inkster on January 16, 2014 | SRF Outreach


Click here to read more about Shahar's work in 2013

Attending the SENS6 conference was an awesome experience for me. Fascinating presentations about the latest advances in a wide range of regenerative medicine fields enthralled me from dawn till dusk. Each day was also punctuated by discussions about science and life experience, which usually continued deep into the night, and I can wholeheartedly say were no less informative than the scientific presentations themselves. I met a bunch of fellow students and researchers, who are also passionate about SRF’s mission. Finally, meeting well-known professors, whom I had previously only known through their publications, was a bit surreal to say the least.

I presented findings from my SRF summer internship in Dr. Valery Krizhanovsky’s laboratory during the poster session. The opportunity to receiving feedback from respected figures in the field as well as offer my own insight to other presenters was an amazing experience. As you can read in my intern spotlight post, my research dealt with the role of cellular senescence in the pathogenesis of chronic obstructive pulmonary disease (COPD). So, imagine my excitement when Dr. Jan van Deursen from the Mayo Clinic College of Medicine explained how clearance of senescent cells was able to delay and mitigate many symptoms of aging in a mouse model of progeria, a rare genetic disorder in which an afflicted individual experiences premature characteristics of aging.

The van Deursen lab used a progeroid mouse model in which BubR1, a key mitotic checkpoint gene that ensures accurate chromosome segregation, has been partially inactivated. Mutant mice accumulate large amounts of p16INK4a-positive cells in the eyes, skeletal muscle, and fat at a young age, which results in a markedly shortened lifespan and a variety of age-related phenotypes. These mice underwent a treatment that “persuaded” senescent cells to “suicide” when a selective molecular “execution message” is given.

This system of senescence cell clearance was called INK-ATTAC (or INK-linked apoptosis through targeted activation of caspase). The INK-ATTAC transgene was designed to allow researchers to selectively remove senescent cells via drug-induced apoptosis (programmed cell death). Using this strain, the van Deursen lab explored two distinct treatment strategies: lifelong senescent cell clearance and late-life senescent cell clearance. In a lifelong clearance strategy, senescent cells are immediately removed after their genesis, preventing any irreversible tissue damage from occurring. On the other hand, the late-life treatment strategy tested whether removal of senescent cells could rejuvenate aged tissues in BubR1 progeroid mice that were already manifesting age-related tissue deterioration.


Removing senescent cells over the course of the life of the progeroid mouse delayed cataract formation and the onset of the loss of skeletal muscle mass and strength, prevented loss of muscles fiber size and function, and reduced the loss of adipose tissue. Although late-life clearance of senescent cells did attenuate the progression of already established age-related disorders in skeletal muscle, fat, and the eyes, the treatment failed to revert any existing conditions.

I think van Deursen’s work presents an important milestone in the field of regenerative medicine by beginning to address some big questions.  How does cellular senescence affect aging? How significant a role does cellular senescence play in aging? Can selective clearance of senescent cells be used to treat or even prevent age-related conditions? And, how effective will such treatments be in different stages of life? I know I will be following the progress of Dr. van Deursen’s lab eagerly in the coming years!
 

Click here to read Shahar's 2013 spotlight