At different times, I have written about 8 different anti-inflammatory supplements, including aspirin, ibuprofen, omega 3 oils, curcumin, berberine, resveratrol, ashwaghanda, and boswellia, in addition to eating foods such as ginger, rosemary, tea and several mushroom species with anti-inflammatory effects. There is good evidence for benefits from each of these individually, but I have no idea how they interact with one another. Just last week, I learned that they all act (in part) through inhibition of NF-kB.
It’s certain that the separate benefits of each of these don’t just add up in combination. It could be that all of them together are no better than just one of them individually. It might even be that they interfere destructively with one another, competing for a common receptor, so that piling on more supplements is counter-productive. There is no research on interactions among longevity supplements.
In this (2007) study, a multidisciplinary team performed a systematic search for blood factors that change most consistently with age over a sample of mammalian models, and organized these into modules that tend to vary in a coordinated way. They then searched for transcription factors that can turn each module on or off. Their most prominent finding was that NF-κB turns on the suite of factors characteristic of old age. Out on a teleological limb, they were bold enough to call it “Enforcement of aging by continual NF-κB activity” in the title of the article. (In this perspective, senescence is an active process, coordinated by the genome. I agree there is good evidence for this.)
After a long path leading to NF-κB as their prime subject, the authors go on to test whether inhibiting NF-κB can have anti-aging effects. The first obstacle that they encounter: NF-κB has important developmental functions (in young animals) and also is essential for regulating apoptosis (in older animals as well). Mice with genes for NF-κB knocked out don’t survive gestation. So they arranged to selectively “blockade” the binding of NF-κB to DNA in old mice, in skin cells only. The result was a dramatic rejuvenation of the skin.
Research with rodents and humans suggest that there are factors in the blood that keep us young and, more important, factors that make us old. Prime suspects in the latter category are the signals that dial up inflammation. It’s my hunch that the most effective anti-aging strategy over the next 10 years will be to re-adjust signal molecules in the blood, adding what we lose with age but, more important, neutralizing or inhibiting pro-aging factors.
For various reasons, NF-κB is a good place to start.
“NF-kB has been termed the central mediator of the immune response. Gene knockout and other studies establish roles for NF-kB in the ontogeny of the immune system but also demonstrate that NF-kB participates at multiple steps during oncogenesis [ref] and the regulation of programmed cell death [ref].” [John Hiscott]
It is a complex of different molecules that acts as a master transcription factor. It is always resident in the periphery of the cell, waiting so that it can be activated quickly when needed. Latent, NF-κB is bound to an inhibitor molecule called IκB. When a stimulus comes along that phosphorylates the IκB, the NF-κB is freed to enter the cell nucleus and switch on a variety of different genes, which varies from one cell type to another. The best-known activity of NF-κB is in white blood cells (T and B cells) where it activates an inflammatory response involving TNFa and IL-6. Overactivity of NF-κB with age is a mediator of the systemic inflammation that contributes so much to cancer, heart disease and dementia.
NF-κB itself is not circulated in the blood, but signals in the blood can cause it to be turned on. The Conboys early recognized NF-κB as one of the pathways that promote aging in parabiosis and transfusion experiments, where blood from older mice is introduced into younger mice. It is a very good bet that inhibiting NF-κB would slow inflammaging, perhaps relieving arthritic and other auto-immune symptoms immediately, while reducing long-term risk of mortality and disease.
Inflammaging and Auto-immunity
Exponential amplification is a basic principle of the body’s immune response. When the signal is received announcing an invader or an infection, there are just a few cells involved. These send signals that trigger an immune response in other cells, triggering a chain reaction.
The beauty of such a system is that it ramps up quickly, and can mobilize a response throughout the body in short order. This is also the danger of the system. It requires an accurate and reliable switch to turn it off; otherwise, it can become like the Sorceror’s Apprentice, each magic broomstick producing two more to carry water until the workshop is flooded.
Note: Dr. Katcher, in a note below, makes an important point about this positive feedback loop.
- Senescent cells spit out inflammatory cytokines
- This activates NF-κB, which blocks apoptosis that could get rid of the senescent cells.
- Inflammation from NF-κB turns more cells senescent, beginning the cycle over again.
NF-κB is a master switch that sets in motion a chain of events that is specific to a cell type and its environment. Some auto-immune diseases (e.g., arthritis, type 1 diabetes, asthma, Crohn’s disease and irritable bowel) are associated with an excess of NF-κB [ref]. Its activation generally rises with age [in mice, in humans], but it is necessary at all ages, particularly for its contribution to the regulation of apoptosis (the selective elimination of cells that are potentially damaging). Animals lacking NF-κB are not viable; so it will probably be necessary to strongly but selectively inhibit NF-κB, beginning in middle age.
Inflammatory responses are complex and focused on the immediate threat at hand. NF-κB is a master switch that sets in motion a chain of events that is specific to a cell type and its environment It’s true that without NF-κB this response doesn’t happen, but the response to NF-κB varies from cel to cell. In this sense, inhibiting NF-κB is a kind of blunt instrument. It works to damp the body’s inflammatory response globally, but even better would be if we could selectively shut off the body’s attack on itself. It’s true that NF-κB activation rises with age [in mice, in humans]. But the real problem is not too much NF-κB expression, but the fact that NF-κB becomes defocused, so that the inflammatory response is not focused on a particular threat, but generalized throughout the body [ref].
Here’s an angle I learned about recently from Steve Cole: While inflammation is an important defense against bacterial infection, it is actually counter-productive against viruses. Inflammation can create an environment that invites viral infection, perhaps because apoptosis is suppressed. (NF-κB suppresses apoptosis.) Viruses aren’t so dumb, and some of them have learned the advantage of promoting NF-κB. Some of the reason that NF-κB is upregulated with age may be a residue of chronic viral infections. [Hiscott, again] (Just to confuse us, NF-κB can also promote apoptosis in other contexts.)
All the anti-inflammatory agents that I have been able to catalog work by one or both of these two pathways: NF-κB and COX2. By most accounts, NF-κB is upstream of COX2, but the two are interrelated. NF-κB regulates COX2, and also COX2 feeds back to regulate NF-κB.
NSAID drugs (aspirin, ibuprofen, naproxen, celecoxib, etc.) target cyclooxygenase-2=COX2. Common herbal anti-inflammatories, including curcumin, resveratrol, vitamin D and omega 3 oils (the last two not exactly herbs) are active both against COX2 and NF-κB. Inhibiting COX2 is a classic strategy for combatting arthritis. The more potent COX2 inhibitors have a tendency to decrease cancer risk, while increasing cardiovascular risk. This doesn’t necessarily mean, “it’s a wash”–rather the stronger NSAID’s are right for people with some genetic risk profiles and should be avoided by others. Aspirin is the cheapest and oldest of the NSAIDs, for which there is copious data available on tens of millions of individuals. There is reasonably good evidence that aspirin leads to lower heart risk as well, probably because of anti-clotting rather than anti-inflammatory action [read more]. Daily aspirin also lowers risk of several cancers.
Intermittent fasting or caloric restriction tends to prevent NFκB binding to chromosomes.. There’s also a long list of natural products that inhibit NFκB.
There are a few pharmaceutical products that inhibit NFκB, though none has been developed explicitly for this purpose. These include emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib. Emetine (as the name suggests) is used to induce vomiting and also to treat amoebic diseases. It is the most potent inhibitor of NFκB among the listed drugs. Sunitinib and Lestaurtinib are cancer drugs. Bithionol is used in de-worming animals. Narasin is an uncommon antibiotic. Tribromsalan is used externally as an antiseptic. None of these is marketed to inhibit NF-κB, and none have (to my knowledge) been tested for anti-aging properties. The larger pool of prescription drugs that affect NF-κB are all steroids. For example, dexamethasoneis a glucocorticoid (steroid) drug that was one of the earliest inhibitors of NF-κB to be discovered.
Many items in the list of natural products have multiple benefits. Silymarin has been reported to promote telomerase. Rosemary and cloves protect against infection. Berberine helps maintain insulin sensitivity, and was found to be as good as metformin in one test. Tea polyphenols and resveratrol have been promoted as generally anti-aging. Too much has already been written about curcumin.
New to me in this list is celastrol, an ingredient in thunder god vine (Tripterygium wilfordii). This is a Chinese herb (leigong teng = 雷公藤), that has been prescribed for centuries in formulas to relieve arthritis, along with lupus, MS and other autoimmune disorders. It is reported to be a powerful appetite suppressant and weight loss aid. The trouble is that it is toxic, and the thunder god root must be prepared carefully in order to exclude triptolide, which is yet more toxic. Experienced practitioners of traditional Chinese medicine know how to mix with other herbs and control dosage to minimize side-effects. In the absence of this kind of expertise, I can only counsel experimenting gingerly with tiny quantities of thunder god vine in order to guage your personal response.
How important is inflammation?
It would be interesting (from a theoretical and a practical vantage) to know what is the maximum benefit available from manipulating the inflammatory pathway. Inflammaging is linked to all the diseases of old age. Suppose we dialed the systemic inflammation in a 80-year old back to where it was when he was 20, but we made no other change in the body. What would be the effect on mortality and morbidity? On vitality, resistance to infection, and stamina? In other words, how much of the aging process is directly attributable to inflammation?
We might try to get a handle on this question via an epidemiological calculation: What is the correlation between inflammation and all-cause mortality? If we extrapolate back to the inflammation level of a 20-year-old, how far does that go toward restoring the mortality rates of a 20-year-old?
We might think to look at genetically modified mice without NF-κB; however, they die in utero. (There are no pure aging genes; aging is caused by re-balancing hormones and proteins, all of which have life-supporting as well as life-denying functions.) There is a genetic variant of NF-κB that tends to be more common in centennarians than the rest of us [ref].
How much does inflammation rise with age?
Erythrocyte Sedimentation Rate and C-Reactive Protein
120 years old, the ESR test is still the most basic (and cheapest) measure of systemic inflammation. The quantity measured is the number of red blood cells that clump together and fall out of solution in one hour. Inflammation makes red blood cells sticky, and I’ve seen two explanations for the reason. One is that fibrinogen, the clotting protein, rises with inflammation; the other is that the negative charge (zeta potential) naturally associated with oxygen-carrying red blood cells decreases with inflammation, so there is less mutual electrostatic repulsion. The increase in blood’s tendency to clot that is associated with inflammation is part of the reason that inflammation is a risk for heart attacks and stroke.
C-Reactive Protein is a protein created in the liver as part of the response to inflammation. It is easily measured with an antibody, so it has become the second most common blood test for inflammation.
ESR rises with age, but not dramatically compared to interpersonal variation:
In fact, the difference between women and men is more than the difference between an 80-year-old and a 20-year-old of either sex. Increase in CRP with age is even more subtle. (This article claims it doesn’t rise at all, in a small sample of <400 patients.)
This article claims that CRP does rise with age (using a sample of 21,000):
A Glasgow study of 160,000 patients found strong correlation between CRP and near term mortality (within a year, HR=20) but not much for longer term. This is not what I was expecting.
In 26,000 patients, inflammatory markers were associated with a 1.5-fold increase in all-cause mortality (ACM) over 8 years.
A Norwegian study of 7,000 men and women found that high levels of CRP raised ACM only by a factor 1.25 (equivalent to just 2 years of aging). For comparison, the ACM risk for an 80-year-old male is 60 times higher than a 20-year-old male. The corresponding number for females is nearly 120.
The implication is that either inflammation is a minor (though significant) cause of mortality, or else the markers that we have for inflammation (including ESR, CRP and leucocytes) are not capturing the rise in systemic inflammation.
Hint: “Centennarians, on the other hand, manage to stave off these deleterious sequelae.Despite signs of inflammation, such as high levels of interleukin-6 (IL-6), fibrinogen, and coagulation factors, they are remarkably free of most age-related diseases that have an inflammatory component.” [ref]
NF-κB in the Brain
It is my favorite hypothesis that aging is mediated through hormonal signaling, under control of a clock in the neuroendocrine regions of the brain. So I am interested in changing NF-κB activity in the aging brain. This paper describes roles for NF-κB in brain development, regeneration after injury, and also evidence that NF-κB can be activated in response to nerve signals. In the other causal direction, neural signaling (and presumably behavior) can change in response to NF-κB. Directly on target (in my book) is this paper from Nature (2013). “By systematically controlling NF-kB activity in the hypothalamus alone, the authors are able to increase the healthspan as well as the lifespan of mice.”
The Big Picture
In the Prelude above, we found evidence that NF-κB is a master regulator that turns on a suite of genes that “enforces aging”. But in the section, How important is inflammation?, we found evidence that, while inflammation certainly increases with age, the increase is not large compared to the scatter among individuals. Centennarians commonly have high levels of inflammation, along with robust health. Large increases in inflammation are common just in the last year of life, but they are not well correlated with the gradual increase in mortality with age.
The combination of these two findings suggests that NF-κB has other powerful roles in promoting senescence, in addition to its well-known role as effector of inflammation. Maybe it is a master regulator of development and aging, akin to mTOR and FOXO. It is a hypothesis worth testing that carefully tailored inhibition of NF-κB is a life extension strategy, so long as we can preserve apoptosis at an appropriate level.