Even though damaged cells may enter senescence, sacrificing their powers of division and growth to preserve us from cancer, they shy away from making the ultimate sacrifice. They linger, consuming resources and secreting factors that are, on the whole, harmful. These factors damage neighboring cells causing chronic inflammation, which is closely associated with frailty and age-related diseases.
The downside of cellular senescence has been confirmed by researchers at the Mayo Clinic. Previously, these researchers tried removing senescent cells from a mouse model of accelerated ageing. They showed that when senescent cells are removed, the onset of several disease-related processes can be delayed. More recently, the researchers have gone further. They have generated results suggesting that cellular senescence is directly related to aging. Moreover, they have shown that selectively eliminating senescent cells can extend lifespan by as much as 35%.
These results appeared February 3 in the journal Nature, in an article entitled “Naturally occurring p16Ink4a-positive cells shorten healthy lifespan.” This article describes how the Mayo Clinic researchers used a transgene that allowed for the drug-induced elimination of senescent cells from normal mice.
Essentially, mice were engineered to carry a transgene called INK-ATTAC, which produces a caspase enzyme in cells that become senescent and begin expressing another gene, p16Ink4a. Then, with the administration of a drug called AP20187, the caspase enzyme becomes activated, inducing cell death.
“We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds,” wrote the authors. “The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively.”
“Senescent cells that accumulate with aging are largely bad, do bad things to your organs and tissues, and therefore shorten your life but also the healthy phase of your life,” said Jan van Deursen, Ph.D., chair of biochemistry and molecular biology at the Mayo Clinic and the senior author of the Nature paper. “And since you can eliminate the cells without negative side effects, it seems like therapies that will mimic our findings—or our genetic model that we used to eliminate the cells—like drugs or other compounds that can eliminate senescent cells would be useful for therapies against age-related disabilities or diseases or conditions.”
Darren Baker, Ph.D., a molecular biologist at Mayo Clinic and first author on the study, is also optimistic about the potential implications of the study for humans. “The advantage of targeting senescent cells is that clearance of just 60–70% can have significant therapeutic effects,” he noted. “If translatable, because senescent cells do not proliferate rapidly, a drug could efficiently and quickly eliminate enough of them to have profound impacts on healthspan and lifespan.”