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The increase in chronic inflammation – and not that of time – is the main reason why injured bones do not heal as well with age. This is the discovery of a study in mice and humans published March 18 in the Proceedings of the National Academy of Sciences (PNAS).
The results are based on the known deterioration, due to wear, of protein machines and large molecules necessary for the life of human cells, whose remains trigger the immune system. First studied for its role in the destruction of invading microbes, this system can also react to the body's proteins to cause inflammation, a response that fights the infection at the site of the injury and the transition into the healing process.
The present study explains how this increase in age-related immune signals decreases the ability of stem cells to multiply, essential ingredients of bone repair. The authors of the study claim that the number of stem cells in the aged skeleton decreases, compromising their ability to contribute to the formation of a new bone after a fracture. The research team also restored the number and function of skeletal stem cells by treating aging mice with an anti-inflammatory component of aspirin.
"Our results argue that age-related inflammation – called" inflammatory aging "- is responsible for the decline in the number and function of skeletal stem cells that allow bones to heal," says Philipp Leucht. MD, badistant of the study. Professor in the Departments of Orthopedic Surgery and Cell Biology, NYU School of Medicine.
Skeletal debilitating diseases are among the most common deficiencies in the United States, with one report stating that more than three out of five injuries were in the musculoskeletal system. Although rarely fatal, bone fractures significantly reduce the quality of life, researchers say – and even more so with advanced age, when some fractures never heal.
These are not the years
The current study is based on the observation in human patients that the number of stem cells in the bone marrow decreases significantly with age, and that fractures take longer to heal when the number of stem cells decreases. The research team then turned to mouse models to explore the badociated mechanisms.
The researchers found that exposing the stem cells of young mice to the blood serum of older mice made their stem cells four times less likely to divide and multiply, an irreversible state called senescence. Previous studies have also shown that senescent stem cells send signals that promote inflammation in a vicious cycle.
Specifically, the team found that the exposure of young mouse stem cells to the blood serum of older mice indirectly activated the immune-related key protein, NFKB. As the centerpiece of the immune response, NFκB interacts with DNA to activate several pro-inflammatory genes. Experiments revealed that the signals of this protein led to the stop of the multiplication of the skeletal stem cells.
In addition, treatment over time with sodium salicylate, an ingredient of aspirin, suppressed NFκB signals and caused age-induced chronic inflammation, increasing the number and contribution of cells. skeletal stumps to bone healing. Other experiments have revealed that anti-inflammatory therapy alters the action of thousands of genes in stem cells, restoring them to a genetic profile seen in young skeletal stem cells.
"These findings suggest that it is the inflammation, and not the chronological age, that prevents bone healing in the elderly," says Anne Marie Josephson, first author of the study , graduate student at the NYU School of Medicine. According to her, a hindrance to translating results into future treatments is that rejuvenating bone stem cells with anti-inflammatory drugs right after a fracture, would also block the acute inflammation necessary for successful bone healing .
This suggests, she says, that a more immediate application might be to use anti-inflammatory drugs to build up stem cell pools, not after bone fracture, but in the weeks leading up to optional orthopedic surgery such as as hip or knee replacements. In these cases, anti-inflammatory drugs would be used prior to surgery, but would then be discontinued just before giving way to the acute inflammation necessary for normal healing.
In addition, the genetic results suggest signaling pathways that could be targeted by future drug treatments to reduce age-related chronic inflammation on stem cells without compromising the type of inflammation that quickly follows a bone lesion.
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Alongside Leucht and Josephson, the authors of the study at the NYU School of Medicine were Vivian Bradaschia-Correa, Lee Sooyeon, Kevin Leclerc, Karan Patel, Emma Muinos Lopez, Hannah Litwa, Neibart Shane, Manasa Kadiyala, Madeleine Wong, Matthew Mizrahi and Nury. Yim, Austin Ramme and Kenneth Egol.
This work was funded by grant 1R01AG056169 from the National Institute of Aging and by grant K08AR069099 of the National Institute of Arthritis and Musculoskeletal and Skin Disorders. The Foundation for Research and Education in Orthopedics (OREF) and the Orthopedic Trauma Association also funded the study.
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