Shedding old cells rejuvenates the brittle bones of ageing mice
New osteoporosis drugs that kill off senescent cells and rebuild bone may be a few years away. Ella Finkel reports.
The last few years have seen a novel idea emerge in anti-ageing science. Several studies have shown that pruning away old, inactive senescent cells can do wonders for aged mice, restoring their bald patches, strengthening their aged muscles, improving their cardiovascular function and repairing their damaged kidneys. “Oh, to be a mouse,” as Christopher Reeve once wistfully mused.
Unlike current treatments for osteoporosis, which muzzle bone-destroying cells, this approach doesn’t just halt the destruction of bone, it actually rebuilds it, according to the researchers. Treatments of this kind would also have the appealing side-effect of rejuvenating other tissues. “We targeted a fundamental aging process that has the potential to improve not only bone mass, but also alleviate other age-related conditions as a group,” says Sundeep Khosla, director of the Aging Bone and Muscle program at the Mayo Clinic.
For years Khosla, whose specialty is bone biology, had been watching the work of his colleague across the hall with great interest. Jim Kirkland focuses on the mechanism of ageing. The director of the Kogod Center on Aging, his research had identified factors that killed aged cells in the test tube, and when given to rapidly ageing mice, slowed the onset of their decline. For instance, ageing mice start losing muscle strength and the ability to clear glucose from their bloodstream, a harbinger of diabetes. Treatment with compounds that culled senescent cells, so-called senolytics, delayed these effects.
Encouraged by Kirkland’s results, Khosla checked to see if naturally aging mice also accumulate senescent cells in their bone. Last year he found that was the case. Some of the worn-out hangers-on were identified as osteocytes. These were of particular interest. Bone may appear inert but it is constantly being remodelled – chipped away here, filled out there – to cope with the changing physical stresses on our bodies. It is the osteocytes that orchestrate the sculpting process. Once they senesce, they may lose their touch and start pumping out an excess of inflammatory factors, as other senescent cells have been shown to do. The age-related tipping of the balance toward bone destruction may be the result.
Khosla, Kirkland and colleagues tested their hunch by treating 20-month-old mice (the equivalent of 70-year-old humans) with two senolytic compounds previously identified by Kirkland’s screens: quercetin and dasatinib. Quercetin is a plant-based natural product. Dasatinib is a drug used to treat leukaemia, though the doses used here were much smaller.
Mice received their senolytic cocktail once a month for four months. Those treated showed a 30% increase in their bone volume. Scans showed that not only had their bone mass increased – a finding that could be due to increased mineralization – but the structure of their bone revealed new deposition of bone tissue, increasing its strength. This ability to stimulate new bone growth is not seen with current osteoporosis drugs, says Khosla.
The bone-building effects seen with elderly mice were not evident in younger mice, supporting the interpretation that the compounds were acting on aged cells. “This is another piece of the mounting evidence that senolytic drugs are targeting basic aging processes and could have widespread application in treating multiple chronic diseases,” says Kirkland.
“With the aging of the population in the U.S. and around the world, age-related bone loss is going to continue to be an enormous public health problem, and patients with osteoporosis have a higher risk for other age-related comorbidities,” says Khosla. He says preliminary clinical trials with the bone-strengthening agents have already begun in people.