Researchers at the Mayo Clinic have revealed a causal link between senescent cells and bone loss in mice. Senescent cells are one of the hallmarks of aging, and removing them has been proposed as a way to prevent or delay age-related diseases.
As your body ages, increasing amounts of your cells become senescent. Senescent cells do not divide or support the tissue they are a part of; instead, they emit a range of potentially harmful chemical signals, known collectively as the SASP, which encourage other nearby cells to also enter the same senescent state.
Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer.
A new study shows that targeting these cells for destruction leads to an increase in bone mass and strength in mice.
What is osteoporosis?
Osteoporosis is the failure of tissue maintenance in bone, which causes bones to become weak and fragile, increasing the risk of falls and driving age-related frailty. According to the National Osteoporosis Foundation, low bone mass and osteoporosis are estimated to be a major threat to public health for nearly 44 million men and women aged 50 and older in the U.S.
In osteoporosis, the balance between the destruction of old bone tissue and the creation of new bone tissue gets disrupted. Bone structure is maintained by osteoclasts, the cells that break down bone tissue, and osteoblasts, which build new bone tissue. Bones are in a constant state of balance between removal and renewal, but as we age, the balance shifts in favour of osteoclasts and the removal of bone tissue.
So, why does this process become unbalanced? Senescent cells are well-known for driving inflammation via the toxic signals of the SASP, so they were hypothesized to be one of the causes of osteoporosis.
In this study, the researchers used an unusual approach: they tested multiple ways to remove senescent cells from aged mice with established bone loss. The mice ranged between 20 to 22 months of age, making them the equivalent of 70-year-old humans.
Three different approaches were used:
A genetic mouse model in which senescent cells can be destroyed using a genetic switch similar to the original work that sparked interest in the field
A small molecule approach, using senolytic drugs previously developed at Mayo Clinic
A Janus kinase inhibitor which blocks the activity of Janus kinase enzymes – to eliminate the toxic SASP created by senescent cells
All three approaches produced very similar results in the mice, and they all enhanced bone mass and strength by reducing bone resorption and maintaining or increasing bone formation.
Another noteworthy observation was that the benefits observed in aged mice were not observed in younger mice. Taken with the results from previous studies showing that senolytic drugs are effective when taken periodically, this supports the link between senescent cells and age-related bone loss.
The researchers noted that even though the combination of senolytic drugs they used were only present in the system for a short period, it destroyed senescent cells and produced a long-lasting effect. The researchers suggest that this is due to the senolytic drugs targeting a fundamental aging process, which could have wide applications for treating many age-related diseases.
This is yet another study that supports clearing senescent cells from the body to improve tissue maintenance in order to prevent age-related diseases. With Unity Biotechnology moving to human clinical trials this year using compounds related to the ones in this study, it will likely not be long now before the first human data arrives.
If the results observed in the preclinical tests of the last few years translate to humans, and there is plenty of reason to believe they might, then we can finally say that the first repair-based therapies against aging have finally arrived.
Senescent cells are implicated in a myriad of age-related diseases, so having a working therapy demonstrated in humans could well be the catalyst that brings more funding and interest to the field. It has taken over a decade to reach this point, but for senescent cell clearance that targets one of the reasons we age, we are getting closer to the finish line.
 Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir, Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland & Sundeep Khosla (2017). Targeting cellular senescence prevents age-related bone loss in mice. Nature Medicine (2017) doi:10.1038/nm.4385.
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