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

Comments

I wonder if the inflammation is suppressed with , say rapamycin, that colds hear too slower recovery but the recovery might be more robust.
Is it possible to do a meeting analysis for the transplant patients on immuno suppressive drugs or patients with allergies on anti inflammatory drugs. Probably done percentage of those had broken bikes or injuries...

Posted by: Cuberat at March 21st, 2019 8:35 AM

So, low dose asprin therapy? (A treatment I suspect most posters on this board already do)

Posted by: JohnD at March 21st, 2019 9:08 AM

We've seen dramatic improvements in bone density in aged mice treated with our combination p16+p53 senolytic therapy at Oisin, so we can confirm the benefits. And before anyone asks, yes, the aged mouse study remains on-going, though all controls are dead.

Posted by: Gary at March 21st, 2019 9:46 AM

@Gary

And how many mice are still alive? And more importantly, home many mice were alive when all controls have died? That cold suggest an estimate of improvement of life expectancy, even if the max lifespan is not improved

Posted by: Cuberat at March 21st, 2019 10:56 AM

Not aspirin. Naproxen.

Posted by: JLH at March 21st, 2019 4:39 PM

It is true. But Bones can be regenerated through exercises with dumbbells and nutritious food.

Posted by: Manikonda Prakash Rao at March 22nd, 2019 10:49 AM

Hi @Gary, I'm a fan of what you guys are doing at Oisin.
However, one thing that puzzled me was, for the p16/p53/p16+p53 mice trial, correct me if I'm wrong but why did you only run it with a total population N=40?

That means only about 10 mice in each group, given 1 control and 3 treatment groups. Since it was potentially a multi-year experiment, why not have at least 20 or 30 mice in each group for finer graduation and also better statistics?

The total would only have been about 100 mice or so give or take, surely within Oisin's budget & resources, given that it is on the verge of demonstrating a "Methuselah mouse"?

PS. Also thanks for running this website @Reason, and shout out to @Aubrey, thank you for your work & advocacy.

Also @Gary, if you don't mind could you share the current survival curves or perhaps a link to some latest updates on that experiment?

Posted by: WK from Singapore at March 24th, 2019 1:13 AM

@WK: 41 mice were all we had in the vivarium that were of the appropriate starting age for treatment (104 weeks, 2 years). We'd have liked to do more but this was meant to be a short one year pilot effort and we were surprised by the results. If resources permit we'll conduct a larger trial and also are willing to support competent labs that want to replicate the work with larger "n".

At the moment, all controls are dead. At last formal report about one month ago, 3/9 combo treated mice were alive, but I believe the vet protocol will require sacrifice of the survivors soon. A paper is being prepared.

Posted by: Gary at March 24th, 2019 11:36 AM

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