Researchers at the Mayo Clinic have identified a new class of drugs that appeared to reduce the effects of aging in mice by killing zombie-like cells that damage healthy neighbors and contribute to chronic aging-related diseases.
The study found two drugs that were especially good at getting rid of senescent cells. These are cells that have ceased to reproduce through division but also are resistant to dying. As they hang on in their suspended state, senescent damage cells and tissues around them and elsewhere in the body. They accumulate over time in the body and especially at the sites of many age-related diseases.
The researchers said a new class of drugs they investigated – known as senolytics – targeted and killed those senescent cells without harming nearby cells or tissue. In some cases, those benefits were seen after one dose.
The finding, though only a first step, could open the way to finding treatments that postpone the onset of age-related diseases and chronic ailments, the researchers said. It also represents progress in the field of science that is addressing the biological processes of aging with the hope that by arresting or slowing the process, people might be someday be able to avoid developing a host of other chronic conditions related to chronological age, such as osteoporosis, or Alzheimer’s and cardiovascular disease.
“One of the theories in the aging field is that if you target fundamental aging mechanisms, you may be able to hit multiple age-related diseases and disabilities as a group instead of hitting them one at a time,” James Kirkland, who heads the Mayo Clinic Kogod Center on Aging, said in a telephone interview.
The two drugs – dasatanib, which is used to treat cancer, and quercetin, which is a chemical found in plants with anti-inflammatory and heart-protecting qualities – were the most successful of 46 drugs investigated by the team. They also had a synergistic effect in reversing the signs of aging.
Kirkland, who was senior author on the study, said that if the results could be reproduced with humans, a drug or mix of drugs could be used to postpone the effects of aging and keep people healthy as they age. He said there was also a good chance that the results could translate to humans because the researchers used human cells in many of the tests.
But Kirkland strongly warned people about jumping to conclusions and using the drugs for such a purpose without further research. For one thing, senescent cells also have some benefits in the body, and it’s not clear what would happen in a person if a lot were killed off at once.
“There’s a whole bunch off things we have to do before people should even begin to consider using these things,” Kirkland said. He said the findings still need verification by other laboratories, including research – just now beginning – on the efficacy of the drugs in primates. Further research, to determine whether there are side effects or even the proper dosages, is also necessary.
The findings appeared Monday in the journal Aging Cell.
Kirkland said researchers focused on genetic pathways in senescent cells that allow them to cheat death.
Senescent cells – which can account for 5 to 15 percent of the cells with nuclei in the body — accumulate with old age and at sites of age-related diseases, but can also occur throughout life even in the embryo, Kirkland said. A number of causes, including cancer-causing mutations, metabolic disorders and inflammation, can alter the DNA or produce changes in the cell that cause them to stop dividing and become senescent. Despite their damage, they resist ordinary, programmatic death that occurs in other cells, he said.
Senescent cells can secrete cytokines and other things that trigger inflammation and other materials thought to contribute to chronic age-related diseases such as cardiovascular, osteoporosis, muscle weakness and neurological problems.
Researchers first studied ways to turn off gene expression in the pathways that keep senescent cells alive, despite its damaged state. They then tested drugs that target those genes in laboratory cultures and mice, including genetically altered animals that mimic progeria, which is a genetic condition that produces accelerated aging in children.
Using 24-month-old mice – which are the rough of equivalent of 80-year-old humans – the researchers detected improvement in heart functioning in the animals that received the drugs. In mice modeled to have accelerated aging, the researchers found that the drugs slowed the onset of age-related conditions that affected the mices’ gait or osteoporosis and collapsed spines.
In one experiment, the researchers exposed a single leg of a mouse to radiation, which creates senescent cells by damaging them, and then checked to see whether the drugs would neutralize the damage by clearing senescent cells. After receiving radiation exposure, the mice exhibited trouble walking on treadmills. Five days after receiving a single dose of the combined drugs, however, the mice performed much better. Seven months later, their exercise capacity was better than those that had been irradiated but left untreated with medicine; the researchers said the mices’ exercise capacity was “essentially identical” to control animals that had not been irradiated.
Felipe Sierra, director of the National Institute on Aging’s Division of Aging Biology, said in a statement that the work demonstrated a “novel and exciting way” to address chronic, age-related diseases.