The first article in this series on the bone-building effects of the omega-3 essential fatty acids began to explain why balance between the omega-6 and omega-3 fatty acids is so important for healthy bones. We talked about the fact that the omega-6s tend to promote inflammation, while the omega-3s lessen it.
Specifically, we saw that if encouraged by omega-3s, our mesenchymal stem cells, the bone marrow cells that can develop into either bone-building osteoblasts or fat cells, choose to become osteoblasts, but if omega-6s take charge, our mesenchymal stem cells become adipocytes (fat cells) instead.
This article explains:
Why, increasingly as we age, not getting enough omega-3s causes us to produce more and more unnecessary fat and less needed muscle and bone.
As we age, not getting enough omega-3s causes us to produce fat instead of muscle and bone. You may remember from our first article in this series that mesenchymal stem cells (MSCs) are immature cells produced in our bone marrow that haven’t yet decided what they want to grow up to be. MSCs have two possible career paths: they can become osteoblasts, the specialized cells that build new bone for us, or they can become adipocytes (fat cells). When our MSCs interact with pro-inflammatory omega-6s, they tend to become fat cells, but if they interact with anti-inflammatory omega-3s, our MSCs are encouraged to become osteoblasts. Recently, researchers have learned that not only are MSCs are highly interactive cells that are very responsive to influences in their environment (such as who gets to give them career advice, an omega-6 or an omega-3), but MSCs in younger individuals are far less likely to become adipocytes (fat cells) even in response to pro-inflammatory omega-6 career counseling than are the MSCs in older folks. In MSCs taken from young to middle-aged subjects, inflammation actually decreases the production of fat cells, but doesn’t also lessen the production of osteoblasts. In other words, in younger folks, inflammation is seen as a signal to build less fat and more bone.In MSCs from older subjects, however, inflammation lowers the production of osteoblasts but doesn’t lower the production of fat cells. In other words, in older individuals, inflammation causes MSCs to become adipocytes, so we build fat instead of bone. In addition, as we age, our MSC’s capacity to grow up at all — whether into either an adipocyte or an osteoblast – decreases. Plus more of the MSCs that do manage to mature choose the easier life of the fat cell (the adipocyte). The end result is that, as we age, our tendency is to produce fewer bone-building osteoblasts, more fat and less bone. When we’re young, chronic low grade inflammation is interpreted by our MSCs as a signal to produce more osteoblasts and more bone, but as we age, chronic low grade inflammation suppresses bone repair and increases fat production. What an unappealing situation! Are we doomed to grow fat and lose our bones as we age?Absolutely not! We’re not stuck with this unhappy version of aging! Growing older does not have to mean developing sarcopenia (which is the medical term for when muscle and bone are increasingly replaced by fat)! We can lessen inflammation and boost osteoblast production as we age. How? By enlisting the help of the omega-3 fatty acids, EPA and DHA. When we consume enough of the omega-3s to balance our intake of the omega-6s (which are way too plentiful in the typical modern diet), we greatly lessen our risk of sarcopenia—seeing our bones and muscles turn to fat.
Why does providing a balanced intake of omega-3 and omega-6 prevent sarcopenia?
Because the parent compounds of both the omega-3s (alpha linolenic acid [ALA]) and the omega-6s (linolenic acid [LA]) partner with the very same enzymes to produce their offspring.
So, when omega-3 and omega-6 are both around in balanced amounts, they compete for these enzymes, which then get used to produce a balanced supply of the powerful anti-inflammatory offspring derived from omega-3, along with some of the potent pro-inflammatory offspring derived from omega-6.
The omega-3s protect us from developing sarcopenia in two ways.
First, the omega-3s, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) help prevent inflammation from starting by competing for the same enzymes that would otherwise be used to produce pro-inflammatory compounds from omega-6, like arachidonic acid (AA).
Secondly, EPA and DHA use these enzymes to produce their own anti-inflammatory children, the resolvins and protectins. The resolvins are so named because they resolve [shut down] the inflammatory process, and the protectins further protect us from chronic inflammations’ harmful effects.
Thus, balance between the omega-3s and omega-6s creates an anti-inflammatory environment in which MSCs are encouraged to become osteoblasts instead of fat cells (adipocytes). Since MSCs become more and more likely to choose to become fat cells as we grow older, a healthy balance between omega-6 and its pro-inflammatory offspring, AA, and omega-3 and its anti-inflammatory offspring, EPA and DHA, becomes increasingly more important for our bones with age. Ensuring that we are consuming enough omega-3 to balance our intake of omega-6 helps protect us against obesity, sarcopenia and osteoporosis.The following diagram shows the specifics of how this all works out. It outlines how the parent compound of all the omega-6s, linoleic acid (LA), and the parent compound of all the omega-3s, alpha-linolenic acid (ALA) are progressively modified by the very same enzymes to produce either the pro-inflammatory offspring of omega-6 or the anti-inflammatory offspring of omega-3. Yes, the diagram looks really complicated, but don’t worry.(1) I’m going to walk you through it step by step and (2) As soon as you get the main idea about what’s happening, you will completely understand why balancing your intake of omega-6 and omega-3 is absolutely essential to keep your bones and muscles healthy as you age.
So, what’s going on in the above diagram?
On the left hand side, you can see linolenic acid (LA), the parent compound of all the omega-6s. Three steps down from LA, you’ll find AA, the key pro-inflammatory child of omega-6. AA is then used to produce two really nasty pro-inflammatory children:
Prostaglandin E2 (PGE2) & Leukotriene B4 (LTB4)
These grandkids of LA (the parent omega-6) really get the inflammatory troops rolling.Both PGE2 and LTB4 are strongly associated with both postmenopausal bone loss and obesity.
PGE2 gets produced from AA by an enzyme called cyclooxygenase-2 (COX-2), and specifically, by a special form of the COX-2 enzyme called inducible COX-2 because its production is induced by inflammation. In other words, our bodies produce COX-2 in response to inflammation.
LTB4 is produced from AA via the action of another enzyme called 5-lipoxygenase (5-LOX).
Okay, now look at the right hand side of the diagram. At the top you’ll see ALA, the parent of all the omega-3s, and mid-way down, you’ll find EPA, the first anti-inflammatory child produced from ALA.EPA is then used to create two highly anti-inflammatory children:
Prostaglandin E3 (PGE3) and leukotriene B5 (LTB5)
What’s most important to see here is that the very same enzymes, COX-2 and 5-LOX, are used to produce both the pro-inflammatory offspring of AA and the anti-inflammatory offspring of EPA. So, we should get to know these enzymes. Knowing what turns on COX-2 and 5-LOX can help us know how to motivate them to decide to work with anti-inflammatory EPA rather than pro-inflammatory AA.
Let’s hang out with the COX-2 enzyme first.
COX-2 has a split personality, like Dr. Jekyll and Mr. Hyde, so COX-2 activity can be either protective or damaging to our bones.COX-2’s harmful Mr. Hyde personality is quickly brought to the fore by many pro-inflammatory triggers. As Mr. Hyde, COX-2 prefers to partner with AA and will use AA to produce AA’s pro-inflammatory PGE2 offspring.But, if plenty of EPA is around, COX-2’s Dr. Jekyll side will be show up, and COX-2 will partner with EPA to produce EPA’s anti-inflammatory PGE3-children.Plus, COX-2 in Dr. Jekyll mode is also essential for the production of the anti-inflammatory children of EPA – the PGE3s and LTB5. And, DHA, whose offspring – the resolvins, protectins and maresins are all anti-inflammatory and are required for the resolution of inflammation — can only be metabolized by COX-2. COX-2 can even play an anti-inflammatory Dr.Jekyll role with omega-6. If you look at the diagram, you’ll see that the first child of the parent omega-6 compound, linolenic acid (LA), is gamma linolenic acid or GLA.GLA gets converted into dihomo gamma linolenic acid or DGLA.At this point, the Dr. Jekyll side of COX-2 can convert DGLA into the anti-inflammatory PGE1 seriesOr COX-2 as Mr. Hyde can act upon DGLA to produce AA, which will then generate the pro-inflammatory PGE2 series.In other words, COX-2 produces both anti-inflammatory and pro-inflammatory compounds from omega-6 plus more anti-inflammatory compounds from omega-3. What brings out the Dr. Jekyll side of COX-2? You guessed it: the presence of sufficient omega-3 to maintain balance with omega-6. (In case you’re wondering what the best balance of omega-6 to omega-3 might be, we’ll be talking about this issue in depth in the next article in this series, but as a preview, many experts think the optimal omega-6:omega-3 ratio is 4:1.)
The key here is not completely shutting down COX-2 (as the non-steroidal anti-inflammatory drugs like ibuprofen [e.g., Advil] and acetaminophen [e.g. Tylenol]) do), but balancing its pro-inflammatory and anti-inflammatory actions!
When enough omega-3 is around to ensure a healthy balance, COX-2 will active as both Dr. Jekyll and Mr. Hyde. As Dr. Jekyll, COX-2 will produce EPA, DHA and their offspring, quickly resolving inflammation and encouraging MSCs to become bone-building osteoblasts. As Mr. Hyde, COX-2 will work with AA to produce enough pro-inflammatory offspring to ensure our immune troops are on duty and can defend us against infections and cancer, and our osteoclasts are called in to work, but only long enough to clear out old or damaged bone and promote healthy bone remodeling.
OK, now let’s check out what’s happening with the LOX-5 enzyme.
Take a quick look at the diagram, and you’ll see the very same story unfolding with LOX-5.
On the diagram’s left side, LOX-5 is in bad boy mode and is producing pro-inflammatory offspring called leukotriennes from AA. On the diagram’s right side, however, LOX-5 is a Peace Corps enzyme, working with EPA to produce the inflammation-ending E-series resolvins and LBT5, and also with DHA to produce the anti-inflammatory D-series resolvins and neuroprotectins.
What’s the take-away from all this?
When we give our COX-2 and LOX-5 enzymes an overdose of omega-6s to work on, the compounds produced will be inflammatory and will promote bone loss.When we give our COX-2 and LOX-5 enzymes enough omega-3s to balance the omega-6s, the compounds produced will be largely anti-inflammatory. We’ll lower inflammation, prevent sarcopenia (medical jargon for our bones and muscles turning to fat as we age), and encourage just the right amount of osteoclast (bone breakdown) and osteoblast (bone-building) activity to maintain healthy bones. Unfortunately, our modern Western diet (also called the standard American diet or SAD) promotes sarcopenia. A key reason why is that the SAD is loaded with omega-6s (both the parent omega-6, linolenic acid and pre-formed arachidonic acid), and is also sorely lacking in omega-3s (both the parent omega-3, alpha linolenic acid and pre-formed EPA and DHA). Our next article will explain why.
For the next article, click here.
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Laschober GT, Brunauer R, Jamnig A, et al. Age-specific changes of mesenchymal stem cells are paralleled by upregulation of CD106 expression as a response to an inflammatory environment. Rejuvenation Res. 2011 Apr;14(2):119-31. doi: 10.1089/rej.2010.1077. Epub 2011 Jan 8. PMID: 21214384
Kelly OJ, Gilman JC, Kim Y, et al. Long-chain polyunsaturated fatty acids may mutually benefit both obesity and osteoporosis. Nutr Res. 2013 Jul;33(7):521-33. doi: 10.1016/j.nutres.2013.04.012. Epub 2013 Jun 10. PMID: 23827126
Kruger MC, Coetzee M, Haag M, et al. Long-chain polyunsaturated fatty acids: selected mechanisms of action on bone. Prog Lipid Res. 2010 Oct;49(4):438-49. doi: 10.1016/j.plipres.2010.06.002. Epub 2010 Jun 17. PMID: 20600307
Diagram from Poulsen RC, Moughan PJ, Kruger MC. Long-chain polyunsaturated fatty acids and the regulation of bone metabolism. Exp Biol Med (Maywood). 2007 Nov;232(10):1275-88. PMID: 17959840