Chronic Inflammation as the Primary Cause of Declining Bone Regeneration with Age
Researchers here show that it is the chronic inflammation of aging that is the dominant contributing cause of loss of capacity in bone regeneration in later life. We should all feel a degree of relief whenever it turns out that chronic inflammation is the primary proximate cause of an age-related condition. Age-related inflammation is driven by senescent cells and immune system failure. Therapies to remove senescence cells are well advanced in clinical development, and there are many potential lines of work that will lead to ways to reverse the dysfunction of the aged immune system in years to come. The inflammatory profile of an old individual twenty years from now will look very different from the inflammatory profile of an old individual today.
A new study finds that increases in chronic inflammation - not the passage of time - is the main reason why injured bones do not heal as well with age. The results revolve around the known breakdown, due to wear and tear, of the protein machines and large molecules necessary for the life of human cells, the remnants of which trigger the immune system. First studied in its role in destroying invading microbes, this system also can react to the body's own proteins to cause inflammation, a response that fights infection at the site of injury and transitions into the healing process. The current study explains how this age-driven increase in immune signals diminishes the ability of stem cells - essential ingredients in bone repair - to multiply
The current study is based on the observation in human patients that stem cell number in the bone marrow significantly declines with increasing age, and that fractures take longer to heal as the stem cell number drops. The research team then moved to mouse models to explore the related mechanisms. The researchers found that exposing stem cells from young mice to the blood serum of the older mice made their stem cells four times less likely to divide and multiply, an irreversible state called senescence. Past studies had also shown that senescent stem cells send signals that encourage inflammation in a vicious circle.
Furthermore, treatment over time with sodium salicylate, an ingredient in aspirin, repressed NFκB signals and related aged-induced chronic inflammation, increasing the number and bone-healing contribution of skeletal stem cells. Further experiments revealed that anti-inflammatory treatment changed the action of thousands of genes in the stem cells, restoring them to a genetic profile seen in young skeletal stem cells. These results suggest that it is inflammation, not chronological age, that hinders bone healing in the elderly.
An obstacle to the translation of the findings into future treatments is that rejuvenating bone stem cells with anti-inflammatory drugs just after a bone fracture would also block the acute inflammation that is necessary for successful bone healing. This suggests that a more immediate application may be to use anti-inflammatory drugs to build up stem cell pools, not after bone breaks, but during the weeks before elective orthopedic surgeries like hip or knee replacements. In these cases, anti-inflammatory drugs would be used leading up to a surgery, but then be cut off just before to make way for the acute inflammation necessary to normal healing.
Link: https://www.eurekalert.org/pub_releases/2019-03/nlh-cl031319.php