Mayo Clinic and UMCG researchers discover tactic to delay age-related disorders

Researchers at Mayo Clinic and the University Medical Center Groningen have shown that eliminating cells that accumulate with age could prevent or delay the onset of age-related disorders and disabilities. The study, performed in mouse models, provides the first evidence that these “deadbeat” cells could contribute to aging and suggests a way to help people grow older healthier.

The findings appear in the journal Nature, along with an independent commentary on the discovery.
Because this study shows a way to attack these cells and what they produce, the researchers expect one day to break the link between aging mechanisms and predisposition to diseases like heart disease, stroke, cancers and dementia. There is potential for a fundamental change in the way we provide treatment for chronic diseases in older people.

Six decades ago, scientists discovered that cells undergo a limited number of divisions before they stop dividing. At that point the cells reach a state of limbo – called cellular senescence -- where they neither die nor continue to multiply. They produce factors that damage adjacent cells and cause tissue inflammation. This alternative cell fate is believed to be a mechanism to prevent runaway cell growth and the spread of cancer. The immune system sweeps out these dysfunctional cells on a regular basis, but over time becomes less effective at keeping house.
As a result, senescent cells accumulate with age. Whether and how these cells cause age-related diseases and dysfunction has been a major open question in the field of ageing. One reason the question has been so difficult to answer is that the numbers of senescent cells are quite limited and comprise at most only 10-15% of cells in an elderly individual.

"Because this has been such a mysterious class of cells, we were taking a big risk in trying to show that they play a major role in the development of aging and age-related disorders," says Jan M. van Deursen, Ph.D., a molecular biologist both at Mayo Clinic and University Medical Center Groningen and senior author of the study. “All we had was an idea of how to kill them, and the hope that getting rid of a small number of cells could have a big impact in the way a tissue functions.”
Dr. van Deursen and colleagues genetically engineered mice so their senescent cells harbored a suicide bomb of sorts – a molecule called caspase 8 – that was only turned on in the presence of a drug that has no effect normal cells. When the transgenic mice were exposed to this drug, caspase 8 was activated in the senescent cells, drilling holes in the cell membrane to specifically kill them.
The researchers found that life-long elimination of senescent cells delayed the onset of age-related disorders such as cataracts and muscle loss and weakness. Perhaps even more importantly, they showed that removing these cells later in life could slow the progression of already established age-related disorders.

The findings support a role of senescent cells in the aging process and indicate that chemicals secreted by these cells contribute to age-related tissue dysfunction and disease.

“Our discovery demonstrates that in our body cells are accumulating that contribute to these age-related disorders and discomforts,” said Dr. van Deursen. “Therapeutic interventions to get rid of senescent cells or block their effects may represent an avenue to make us feel more vital, healthier, and allow us to stay independent for a much longer time.”

The Ellison Medical Foundation, the Dutch Noaber Foundation, the Robert and Arlene Kogod Center on Aging, and the National Institutes of Health funded the study.