In a breakthrough paper published in 2011 by a team of scientists at the Mayo Clinic it was demonstrated that the artificial removal of senescent cells extended the lifespan of progeroid mice. But would removing senescent cells also extend the lifespan of normal mice? To answer this question the team redid their experiments on normal mice and found that removing senescent cells indeed extends medium lifespan and improves health.
An ingenious approach
The method engineered by this team to remove senescent cells is quite ingenious and involves the creation of an artificial genetic construct that instructs senescent cells to commit suicide. This construct is made of two main components, a caspase-8 and a senescence-specific promoter. How this system works is explained in the figure below.
Senescent cells produce high amounts of a protein known as p16 andyThe genetic construct contains a DNA sequence that is recognized by p16. Upon binding of p16 to this so called promoter sequence it causes the production of the protein encoded behind this sequence. In this case the scientists have put a suicide protein behind the promoter. Normal cells do not produce p16 and hence have an activation of the promoter and produce no suicide protein.
As a second safety mechanism the scientists tweaked the suicide protein in such a manner that it would only be turned on in the presence of a specific drug. As the number of senescent cells increases with age, it makes little sense to start a senescent cell clearance protocol early in life. Furthermore, recent evidence suggests that, strangely enough, senescent cells play a role in embryonic development and in wound healing. Indeed, wound healing was actually impaired in mice with the suicide construct when the activating drug was administered during the wound healing process. Healing returned to normal when the activating drug was withheld during the period of wound healing. To minimize side effects from the senescent cell removal, scientists chose to start administering the drug that activates the suicide protein from the age of 12 months onwards.
How effective is the strategy?
The authors verified that their construct was indeed eliminating senescent cells in multiple tissues (fat tissue, skeletal muscle, eye, kidney, lung, heart, liver, colon and spleen). The construct successfully removed senescent cells in all but two tissues (colon and liver). With age there is a loss of fat mass in mice as well as a decrease in the size of fat cells, both of which were prevented in the mice with the activated suicide construct. Deleting senescent cells also offered protection against the development of cataracts, delayed the appearance of tumors, prevented age-related decline in kidney function, and improvement in some markers of cardiac function. Furthermore, the authors also discovered a decreased expression of inflammatory markers in the mice with an activated suicide construct. No effect of senescent cell clearance on memory, motor coordination and balance, exercise ability, muscle strength, fasting glucose levels, glucose tolerance and insulin sensitivity were found. The clearance of senescent cells also did not prevent age-related changes in the profile of circulating blood cells.
Removing senescent cells can increase lifespan by up to 35%
The effect of removing senescent cells on lifespan was investigated in two mice strains (one of mixed genetic origin and a pure C57BL/6 line). Mean lifespan extensions ranged between 17% and 35% (see table 1). Maximum lifespan was only significantly extended in the mice of mixed genetic origin when the data from male and female mice were combined. The researchers observed that the lifespan of animals without the genetic construct but injected with a placebo drug was lower than would be expected. This suggests that the stress from the repeated injections may decrease lifespan. Hence the true effect of clearing senescent cells on lifespan may be greater than what was observed in this study. The lifespan extension by removal of senescent cells is not solely due to increased survival in animals with cancer as survival of cancer-free animals was also increased (with 30% in males and 42% in females of the mixed genetic background).
More background information on the role of senescent cells will be provided in our upcoming series on the Hallmarks of Aging.
A movie explaining the work published in 2011 can be found here
Read more in Nature