Killing off Senescent Cells Extends the Life and Improves the Health of Laboratory Mice

Our bodies contain a mixture of cells that grow and others whose growing days are long since over. Such cells are called “senescent cells” and there is some indication that accumulations of worn out cells that have given up the ghost can contribute to the onset of age-related diseases.

A new study from the Mayo Clinic in Rochester, Minnesota has shown that eliminating senescent cells can extend the healthy lives of lab mice. These results constitute one of the first direct demonstrations that treatments that specifically target these deadbeat cells, either by killing them off of blocking their deleterious effects, might provide a new strategy to combat age-related diseases in human patients.

Aging is a fact of life for animals. Aging bodies contain cells that have lost the ability to divide. These senescent cells build up throughout our bodies and release molecules that can potentially harm nearby tissues. Diseases of advanced age, like type 2 diabetes, kidney failure, and heart disease, have been linked to the presence of large numbers of senescent cells.

Two Mayo Clinic molecular biologists, Darren Baker and Jan van Deursen, devised an ingenious way to test the relationship of accumulations of quiescent cells with age-related diseases. They engineered laboratory mice with a construct they called “ATTAC.” This construct expresses the FK506-binding-protein–caspase 8 (FKBP–Casp8) fusion protein and green fluorescent protein (GFP) under the control of a promoter that is only active when cells are senescent. The ATTAC construct is not harmful to cells, but if ATTAC-containing cells that have become senescent are hit with a drug called AP20187, they die. Baker and van Deursen injected one-year-old mice with AP20187 twice a week starting at one year of age. They injected a control group of mice with buffer only.

The AP20187 treatments extended the median lifespan in both male and female mice. To make sure that nothing strange was going on with the genetic backgrounds of these mice, they conducted these experiments in mice strains with two distinct genetic backgrounds, but the results were the same. The engineered mice that were injected with AP20187 showed consistent clearance of quiescent cells and extended, healthier life spans.

The AP20187-injected mice showed clearance of fat cells, their kidneys functioned at a higher level, and their hearts were more resilient to stress. These same mice also showed more energetic behaviors, since they explores their cages more and they developed cancers at later ages. There was also evidence of less inflammation in the AP20187-injected mice.  These mice had their lifespans extended by 20–30%. These results were published in the journal Nature on February 3rd of 2016.

Despite the rather fancy genetics involved with this experiment, the design is somewhat easy to follow and the results have a ring of credibility to them. “We think these [quiescent] cells are bad when they accumulate. We remove them and see the consequences,” says Baker. “That’s how I try to explain it to my kids.”

In 2011, Baker and van Deusen and others investigated mice that harbor a mutation that greatly accelerates aging. This mutation mimics the human genetic disease “progeria,” which is a rare, fatal genetic condition characterized by accelerated aging in children. The name of the condition, progeria, comes from Greek and means “prematurely old.” Classic progeria is also called “Hutchinson-Gilford Progeria Syndrome,” which was named after Dr. Jonathan Hutchinson and Dr. Hastings Gilford, who first described it.

In their 2011 Nature paper, Baker and others showed that removing senescent cells in mice with an engineered type of progeria benefited those mice. Therefore, this 2016 paper is a follow-up to that 2011 study.

On the coattails of these experiments, Baker, van Deusen and others in their laboratories are beating the bushes for drugs that can directly eliminate senescent cells, or, at least, stop them from secreting the damaging factors that do so much damage to nearby tissues. In fact, van Deursen has co-founded a company that has licensed patents to develop such drugs.

According to Dominic Withers, a clinician-scientist who studies ageing at Imperial College London, the experiments and Baker, van Deusen and their colleagues, “gives you confidence that senescent cells are an important target.” Withers also said: “I think that there is every chance this will be a viable therapeutic option.”

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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