January 16, 2009
COX-2 Enzyme Decline Impairs Bone Repair With Age

As we age the levels of cyclooxygenase 2 (COX-2) declines in stem cells. Researchers at U Rochester found that the decline in COX-2 causes a reduction of conversion of stem cells into cartilage and this slows or prevents bone repair with age.

"The skeleton loses the ability to repair itself as we age," said Regis J. O'Keefe, M.D., Ph.D., chairman of the Department of Orthopaedics at the University of Rochester Medical Center and corresponding author of the article. "Our results position the COX-2 pathway as one of several under exploration with the common goal of accelerating healing in aging humans, and with the potential to come together in future combination therapies."

Turning Back the Clock

In the current study, healing rates were compared between a group of young mice (7-9 weeks old) and a group of old mice (52-56 weeks of age), with healing evaluated by imaging and gene expression studies. Specifically, the current study found that the older mice experienced delayed fracture healing, decreased bone formation and decreased resupply of blood vessels to the healing site in aging mice. Expression of the gene that codes for production of the COX-2 was reduced by 75 percent in fractures between aged mice and young mice during the early healing phase five days after a fracture. COX-2 expression in young mice peaked at the exact time that stem cells were changing into cartilage within the fracture callus of young mice, and was reduced during that period in older mice.

In addition, experiments confirmed that COX-2 is expressed primarily in early stem cell precursors of cartilage that also express collagen, type II, alpha 1 (col2a1), the gene that codes for production of a key part of type II collagen in mice and humans, the fibrous, structural protein that lends strength to bone. Researchers observed in aged mice a dramatic decrease as well in the expression of other genes known to contribute to bone formation as well (e.g. osteocalcin and type X collagen). Altogether the results suggest that in aging animals gene expression is altered early in fracture repair with consequences for the entire healing cascade.

The researchers demonstrated that a drug which boosts prostaglandin E2 (PGE2) production improves bone healing ability.

Researchers found further proof that COX-2 is responsible for loss of bone healing ability with age when they were able to reverse the process with a drug known to encourage the COX-2 signaling effect. COX-2 catalyzes the conversion of a fatty acid to prostaglandin E2 (PGE2), a hormone with many functions in the animal body depending on the type of cell they interact with, from blood vessel dilation to embryo implantation in the womb to bone healing. PGE2 is known to have it effect on cells by reacting with one of four receptor proteins (EP1–EP4) on the surface of cells, including the surfaces of bone marrow stem cells, cartilage cells and bone-producing cells (osteoblasts). Human cells send and receive signals that switch on life processes through workhorse proteins called receptors that enable messages to penetrate cells.

You might think that a drug which acts like COX-2 to cause more prostaglandin E2 (PGE2) production and therefore more bone healing is the ticket. But every time we hear about a drug that can reverse some metabolic change that comes with aging we have to ask why the body changed with age in the first place. The decline of COX-2 with age down-regulates stem cells to inhibit stem cell activity. Why? Just an accident of decay? Or was this selected for because older stem cells are at risk of becoming cancerous when they divide?

I hope that drugs which up-regulate stem cells for repair do not boost our risk of cancer. Alternatively, once cancer becomes easily curable we'll be able to take more risks by stimulating cell growth because any resulting cancer will eventually become easy to snuff out. We need cures for cancer that have only mild side effects both because we want to avoid our existing risk of death from cancer and also so we can turn up cell activity in aged cells without running a greater risk of death from cancer.

What I would be curious to know: Would stem cells from young mice stuck into old mice express youthful levels of COX-2 or lower older levels of COX-2? To put it another way: does the environment which the stem cell finds itself in send signals to the stem cell that suppress COX-2? Or does the cell internally change with age in ways that reduce COX-2 expression? The latter possibility is in some ways a better answer. If we can just replace stem cells to get better repair then future stem cell therapies will be easier to develop. If the whole body is suppressing repair then rejuvenation becomes a much taller order.

Share |      Randall Parker, 2009 January 16 12:41 AM  Aging Mechanisms

John Cuccia said at January 16, 2009 8:24 AM:

Ironically enough, the most popular remedies for arthritis pain are COX-2 inhibitors.

So, as we age, our body loses the ability to repair cartilage because of a decline in COX-2 production, resulting in arthritis pain for which we take drugs that further inhibit COX-2 production.

David Govett said at January 16, 2009 2:24 PM:

Clone new bodies. Move on in.

Lou Pagnucco said at January 16, 2009 3:46 PM:

This may explain why intentionally inducing inflammation (prolotherapy - still controversial) in damaged joints can sometimes accelerate healing - and, maybe also why high omega-3 fish oil can slow healing.

I've read a few paper on stem cells, their niches, the system factors they rely on, etc.

The organization of the tissue looks bewilderingly fractal - at least to me.

It appears that continually retransplanting tissue from aging to younger hosts keeps the tissue healthy well beyond the lifespan of the original host, even with the trauma that transplantion must cause. See -

"Effects of Aging and Niche Microenvironment on Spermatogonial Stem Cell Self-Renewal"

'However, when stem cells were consecutively passaged at 3-month intervals to testes of young males, these stem cells continued to produce spermatogenesis for more than 3 years. Thus, SSC self-renewal continues long past the normal life span of the animal when the stem cell is continually maintained in ayoung niche/microenvironment. Moreover, these data suggest that infertility in old males results from deterioration of the SSC niche and failure to support an appropriate balance between stem cell self-renewal and differentiation.'

Perhaps, if the "scrawny" gene, which seems to preserve "stemness" was upregulated, tissue aging could be slowed. See -
'Scrawny' gene keeps stem cells healthy

But, then there are systemic factors originating elsewhere that play a role too. Refer to -
"Stem Cell Review Series: Aging of the skeletal muscle stem cell niche"

Randall Parker said at January 16, 2009 8:20 PM:


The work of Thomas Rando at Stanford and others on how younger and older cells act more like the their environment strikes me as problematic for rejuvenation. We can bring in young organs and that'll help some. But those parts of the body that are old will probably secrete compounds that'll suppress the cells in the younger pieces.

I see a few questions:

1) Can we suppress the compounds that inhibit cells?

2) Are there key organs we can replace to remove major sources of inhibiting factors?

3) If we reduce the inhibiting factors will this cause cancer or perhaps types of cell growth that cause misshapened or otherwise metabolically imbalanced parts of our body?

Tom said at January 17, 2009 7:25 AM:

Natural selection does not act once the organism is past reproductive age, except indirectly if you take into account the role of post-reproductive adults in caring for younger individuals. And most mice in the wild live nowhere near 52 weeks. The idea that natural selection has acted to curb Cox-2 expression in 52-week old mice only makes sense if the elderly mice who benefit from these genetic variations can pass those variations to their offspring. that seems likely to be an extremely rare event, compared to, say, passing on improved instincts to avoid cats and owls. It is more likely that the downregulation of Cox-2 in aging had some reproductive benefit for some common mammalian ancestor millions of years ago, but no longer affects reproductive success one way or the other.

Randall Parker said at January 17, 2009 8:34 AM:


Yes, natural selection does work beyond reproductive age. Long-Lived Grandmothers Increase Childbearing Of Their Children.

David said at January 17, 2009 9:12 AM:

I doubt that mouse grandmothers are as helpful as human grandmothers, eh?

Randall Parker said at January 17, 2009 10:19 AM:


The failure of these mouse grandmothers to lend a helping paw is probably why they all get cancer and die. The mothers should start telling them that if they help out then future mice will live longer.

Lou Pagnucco said at January 17, 2009 4:26 PM:


Regarding your question: Can we suppress the compounds that inhibit cells?

My guess is yes (to some degree) - For example, see -

Transcriptional Networks and Cellular Senescence in Human Mammary Fibroblasts

Motif module map reveals enforcement of aging by continual NF-kappaB activity

Both papers indicate that a continuing expression of Nuclear Factor-kappaB seems to keep cell in their senescent state. Very speculative, but maybe NF-kB suppressors (e.g., aspirin, caffeine, theophylline, curcumin, ginger, betaine, cocoa polyphenols, ....) might restore some youthful functions to old cells.

Certainly organs influence one another. I know that kidney malfunction can have many collateral effects. Transplanting an old kidney into a younger body can accelerate some signs of aging. I recall also that blood from an older animal shunted into a younger one by parabiosis accelerates collagen aging and slows healing in the young lab animal.

On your last question, I can only guess, but it is pretty remarkable that tissue seems to age in such a well synchronized way - seems like there must be some central control. I have a paper on the subject somewhere. If I can find it, I'll forward it.

Randall Parker said at January 17, 2009 4:36 PM:


My guess is we are not going to want to get cells to switch back out of the senescent state. At least for some tissue types we are going to want to induce senescent cells to undergo cell death (apotosis). Cells messed up enough to be in the senescent state should probably stay that way until we can figure out how to kill them. Cells less messed up can divide to replace them.

Neurons are probably an exception. Try to rejuvenate as many senescent neurons as possible so that we do not cause assorted brain functions to partially decay.

Let me reword my question more precisely: Can we suppress the ability of messed up cells to suppress healthy cells? Currently the suppression is just too wide spectrum. My guess is the secret is to find ways to kill off (or repair) the messed up cells so that whatever damage that causes them to release suppressing compounds is no longer present.

If I'm right then this means we can't derive the most of the benefit of cell therapies without developing the ability to kill off or repair damaged cells. Supply replacement cells might be less important than killing the most messed up cells.

Mind you, all this is speculation on my part.

Lou Pagnucco said at January 18, 2009 9:39 AM:


Note that in the paper -
"Motif module map reveals enforcement of aging by continual NF-kappaB activity"
- the authors reach following tentative conclusion:

'Our data suggest that many molecular and cellular
features associated with mammalian aging, at least
in epidermis and possibly other tissues, may be actively
enforced until late in life, and age-associated phenotypes
can be substantially reversed by a single gene intervention.
Furthermore, NF-kappaB action in skin aging appears to
be cell-autonomous since we were able to reverse multiple
characteristics of aging in patches of epidermis by
NF-kappaB blockade in otherwise old animals. These results
bode well for the possibility of targeted therapies to reverse
features of aging to alleviate age-related pathologies
in the elderly. An important caveat of our study is
the transience of NF-kappaB blockade; optimal strategies of
NF-kappaB blockade to induce healthful effects in aged tissues
in the long term need to be addressed in future

This in encouraging, since at least some manifestations (i.e., phenotypes) of aging in skin are due to strictly local factors - not circulating ones. If this is true in some others, e.g., muscles, vascular system, blood-brain barrier, etc., and we can target them, this kind of intervention might let us add a few more years to our depressingly short lifespans. (Note that the Bush administration's pseudo-science advisors think that our lifespans are long enough, and opposed extending them - Leon Kass, for instance.) Perhaps too, some detrimental circulating factors would be reduced if the tissues where they originate are targeted.

The paper does not really explore too deeply into whether such therapies might release the brakes on pre-neoplasms and, possibly, promote cancer. I have read that there are research programs (hopefully) developing ways to coax some senescent cells to self destruct.

Regarding the brain, there are some papers conjecturing that neurons might be victims of the aging dividing support cells, e.g. vascular.

Randall Parker said at January 18, 2009 10:04 AM:


What do they mean by "cell-autonomous" here:

Furthermore, NF-kappaB action in skin aging appears to be cell-autonomous since we were able to reverse multiple characteristics of aging in patches of epidermis by NF-kappaB blockade in otherwise old animals.

Does each cell make its own NF-kappaB? Even if it makes its own NF-kappaB is that due to changes external the cell? I would expect more oxidative stress in the cell's environment with age.

One of the sources of that greater oxidative stress might be mutated mtDNA in some cells causing their mitochondria to spew free radicals. I know that Aubrey de Grey believed this was happening back when he wrote his Ph.D. thesis. But I haven't kept up with the research in this area. Have you?

Lou Pagnucco said at January 18, 2009 5:29 PM:


As I understand it, "cell-autonomous" here means that old cells are overexpressing NF-kappaB, probably due to epigenetic changes rather than some cirulating factor. Don't forget that the reversal of skin aging was achieved in a living animal by locally suppressing NF-kB rather than by systemic treatment. The paper indicates that there are indeed other changes in gene expression/repression in old vs. young cells, so sure there might be additional measures to further rejuvenate older tissues, but it's impressive that even this first try was seemingly successful.

No, I haven't kept up with the mito-theory. I need a refresh. Perhaps a subject for one of your future posts?

Apparently, even if mitochondrial damage is one of the initiating events, it might be partially remediable.

Doesn't some old saying go something like - "The worst enemy of good is the notion of 'the best'"?

Randall Parker said at January 18, 2009 5:47 PM:


The NF-kB could be getting made due to external factors, either from nearby cells or from the bloodstream. I'm wondering whether the problem is due to genetic clock changes or aging in each cell, changes in the local cellular environment due to a small fraction of all cells, or coming from stuff in the bloodstream.

Mito-theory: Yes, I need to start watching for recent research reports on this. Maybe I'll ask Aubrey.

Lou Pagnucco said at January 19, 2009 2:22 PM:


I find these signaling cascades bewilderingly complicated. I am not sure how surface receptor activation differs between old vs. young cells. Maybe receptor blockers, or decoy receptors would also work and target more tissues? If my memory is correct, cells in old tissue are fairly heterogeneous, so I'd guess (but am not sure) that most of the problem is due to a fraction of them.

Lou Pagnucco said at January 20, 2009 8:54 AM:


Here is a postscript -

A similar rejuvenation is apparent in aged human skin transplanted to immune-deficient mice. Refer to:

"Aging of human epidermis: reversal of aging changes correlates with reversal of keratinocyte fas expression and apoptosis"


So I am assuming that the circulating Fas activating factor (the FasL ligand) is absent in the strain of immune deficient mice. Fas is one of the initiators of the NF-kappaB signaling cascade. See:

"NF-κB determines localization and features of cell death in epidermis"

Since NF-kappaB and the apoptosis-inducing caspases appear to be involved with the more benign aspects of differentiation also, I wonder whether this is a case of "antagonistic pleiotropy" -i.e., a process required early in life that becomes destructive later.

alan russell said at June 8, 2010 1:54 PM:

what is the bset cure for a broken cox bone please

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