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Monday, 27 January 2014

Does reductive stress drive an adaptive inflammatory response, in depression linked to diet and lifestyle?

Everyone knows (I hope, because if they do it will save me a lot of time explaining) that inflammation can cause depression by activating the enzymes that degrade tryptophan, thus depleting the brain of serotonin.
Basically, macrophages hoover up tryptophan and pass it through Indoleamine 2,3,-Dioxygenase (IDO), where it is broken down. This is the pathway for the synthesis of niacin and nicotinamide, which is used to make NAD+.

(Note the other product, picolinic acid, thought to assist in absorption of minerals chromium and zinc)

There is the "sickness behaviour" explanation, whereby this response to infection, by making us less active, assists recovery, and the "sequestering" explanation whereby the macrophages act to deny tryptophan to pathogens, so that they don't have the advantage of extra NAD+. However, inflammation has many forms, and neither of these explain the response to chronic inflammation, when more activity and nicotinamide supplements are usually beneficial (nicotinamide seems to help in fighting infections too).

Supposing you are in the state known as reductive stress (not enough NAD+, too much NADH). This is associated with metabolic inflexibility, metabolic syndrome, and so on.
Reductive stress is mentioned by Peter D in this post. It is associated with fatty liver (steatosis) of chronic Hep C infection here, in these words:

the impairment of NADH oxidation to NAD, with consequent NADH accumulation, is a characteristic figure of mitochondrial dysfunction occurring in fatty liver due to high fat diet (HFD) in rats*.
So, how can NADH be converted back to NAD+ in these states? If lactate is available, metabolising this will restore NAD+, if ketone bodies are available, ditto for their interconversion (so exercise or carbohydrate restriction/fasting are protective against reductive stress). Electrophilic methyl groups in the diet - choline, carnitine, SAMe - may accept the H+ from NADH to form methane, which is dissipated.
But electrophilic methyl groups are hard to come by in the type of diets that cause reductive stress. No choline in flour, sugar, or vegetable oil. (Brilliant analysis of why this matters by Paul Jaminet here, also explaining that "high fat diet (HFD) in rats" line above*).

Also, fresh NAD+ can be supplied from outside the cell. From B3 if you're supplementing or eating good food (in which case your cells shouldn't have easily got into a reductive stress state, but requirements for B3 are unusually high for a co-enzyme vitamin). Or, if you're in the fasting state or your dietary B3 is inadequate, from tryptophan via IDO (Tryptophan 2,3-Dioxygenase is the hepatic equivalent). Which inflammation will upregulate.

So the hypothesis is, that reductive stress is an emergency (perhaps mimicking pellagra) that warrants an inflammatory response if this is what it takes to supply extra NAD+. But this process can not only deplete tryptophan and serotonin, but also produce a number of intermediate compounds that can are potentially neurotoxic.

The concentration of potentially neurotoxic compounds, such as 3OH-kynurenine, 3-OH-anthranilic acid, and quinolinic acid (QUIN) that are formed along the metabolic pathway leading from tryptophan to NAD (the kynurenine pathway) significantly increases in blood and cerebrospinal fluid of patients affected by a number of inflammatory neurological disorders and in animal models of immune activation.
So what is the messenger that reductive stress state cells produce, which triggers IDO in macrophages?
Why not the extra superoxide that is produced? This potentiates NF-kappaB,

Under normoxic conditions, NFκB is bound to one of several inhibitory proteins (e.g., IκB) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, freeing NFκB and allowing it to bind to target gene promoters.

These target genes include INF-gamma and TNF-alpha. INF-gamma drives IDO in macrophages.
Nicotinamide is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that, through enhancement of nuclear kappa B-mediated transcription, plays a pivotal role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Through interaction with CD38 and inhibition of IL-1, IL-12, and TNF-α production, nicotinamide produces a mild TH2 bias. 

(in other words, the product of the inflammatory cascade that begins with reductive stress will inhibit it.)
So this may be part of a homeostatic 
mechanism in B3 deficiency (pellagra), which reductive stress imitates. In which case inflammation and depression is secondary to metabolic disregulation in diet-and-lifestyle related diseases. It is, so to speak, a perfectly natural, adaptive consequence of eating the wrong things and forgetting to exercise.

Edit: Aubrey de Grey's mitochondrial theory of ageing describes a mechanism by which surplus electrons from cytosolic NADH can be exported from the cell, recycling NAD+, via the plasma membrane redox system (pdf). Jettisoned into intercellular space, the electrons combine with O2 to form the superoxide reducing radical; reduction of transition metals (ferretin, ceruloplasmin) by superoxide also creates conditions for generation of oxidising radicals such as hydroxyl and peroxide. (note that RBCs lack the ability that other cells have to transfer electrons to O2 and form superoxide; RBC PMRS is an antioxidant system, other cell-types' PMRS are more likely to produce pro-oxidant effects)
In both that paper and this one, by two different sets of authors, there is a role 
in the PMRS for ascorbic acid (AA) and its oxidised
dehydroascorbic acid (DHA is the product of 2-electron oxidation, the 1-electron product of AA is a free radical that becomes more common in the senescent leaves of plants pdf.) 

The authors hypothesize that the increased PMRS in erythrocytes during aging may be a protective mechanism of the system for efficient extracellular DHA reduction and ascorbate recycling under condition of increased oxidative stress.

And, perhaps, increased cycling of ascorbate is also a response to reductive stress. Oxidative stress, when not adaptive, as in the immune response, or toxic in nature, is the product of reductive stress, and both are increased by hypercaloric intakes of micronutrient deficient diets.



raphi said...

Hi George,

2 things:

1. I'm trying to understand whether diseases like pellagra are on the same spectrum as other conditions strongly linked to inflammatory states...or if such diseases eventually appear when specific, yes or no, binary type conditions are met at some point. Threshold? Spectrum? Both? What beast are we dealing with as regards the subject of your post?

2. I'm trying to wrap my head around the ubiquity of inflammatory processes found at the scene of the crime of so many diseases. How can we start understanding when inflammation is a 'cause' and when it's a 'protective response'? Do we have specific models where this has been settled for certain conditions?

I have ideas floating around my head which are hard for me to pin down as clear questions - please excuse my vagueness/lack of clarity!

George Henderson said...

1. Inflammation, of this sort, if I'm right, is how we round up extra NAD when we're deficient, this being adaptive and protective. But if we have low NAD+/NADH ratio when overfed, this isn't likely in evolution, and getting extra NAD+ from tryptophan may be less protective.
Inflammatory responses are meant to serve a short-term purpose, this is protective, or at least "patches us up" to survive.

2. Chronic inflammatory processes, what happens to the liver in chronic Hep B or C might be a guide to what goes wrong. Unfinished business becomes dangerous, like repeated DIY repairs that eventually compromise structure and function.

Good inflammation/bad inflammation, understanding the difference, seems to be very complicated. I'll need a kaleidoscope, not a microscope, for this.

George G said...

I tend to think inflammation is seen as the bad guy too often.
Like firemen being blamed for the fire.
Even with chronic inflammation like hep B and C.
They are good examples actually because the root cause is obviously still there as replicating virus.
If there was no inflammation the disease would probably progress faster.
People who are immunosuppressed have faster progression of hep C and B.

raphi said...

"If there was no inflammation the disease would probably progress faster" - that is what drives me crazy! We need to reconcile these empirical observations with other types of evidence suggesting an overall decrease in inflammation might actually be helpful for the pathology in question.

Thanks for addressing the contradictory points and not shying away from them - this is a practice that is all too rare in most of the paleo/health/blogosphere (especially with i.e., RS, Kitavans, Inuits, apoB, cholesterol etc....)

Jack Kruse said...

The free radical theory of aging that Harman proposed long ago that oxidized macromolecules accumulate with age to decrease cell function and shorten life-span has little support these days (Harman, 1968). Unfortunately today this is biologic dogma because no one else has any better ideas how mitochondria are really designed to work in nature. Recent experimental work has shown it is dead wrong. When your experiments do not match your theory, your theory is wrong. Moreover, recent nutritional and genetic interventions to boost antioxidants have generally failed to increase life-span. The overall result of 19 clinical trials finds supplementation with the lipid-soluble antioxidant vitamin E failed to reduce mortality (Miller et al., 2005). The water soluble antioxidant vitamin C is also generally ineffective in reducing all-cause mortality (Bjelakovic et al., 2007). An even more important test of the free radical theory of aging involves genetic overexpression of antioxidant enzymes. To date, increases in SOD, or catalase or a combination, while lowering oxidized macromolecules, fail to increase lifespan in mice (Perez et al., 2009). Only overexpression of the peroxide and redox active thioredoxin 1 (Mitsui et al., 2002) and mitochondrial targeted catalase (Schriner et al., 2005) have been shown to increase mouse lifespan. In addition, the free radical theory fails to explain why higher levels of oxy-radical damage occurs constantly with exercise (Powers et al., 2008), which generally promotes healthy human aging (Nakamura et al., 1996) and extends lifespan in some rodents (Navarro et al., 2004) (Holloszy et al., 1985). The answer is not increasing the ORAC levels of food. It is found in metabolic epigenetic redox switches that happen upstream to mitochondria to alter where and how subatomic particles are fed into the ETC when nutrients are delivered to this organelle for processing. . The metabolically initiated redox shift happens "upstream" of the commonly observed increase in reactive oxidative damage to lipid membranes, receptors, and macromolecules in tissues. This shift has been constantly observed experimentally in normal aging; It occurs in the oxidized direction of the relative levels of important reductants and oxidants in cells. It manifests itself as an extracellular decrease in the ratio of cysteine/cystine in tissues with a simultaneous intracellular decrease in the ratio of GSH/GSSG and NAD(P)H/NAD(P). The oxidized redox shift is initiated by low demand for bursts of energy produced by mitochondria. The loss of energy efficiency is the key signal This low demand for energy also is manifest by observed low levels of physical and mental activity in people with this issue. This initiates a vicious cycle of oxidized membrane receptors, signaling molecules, transcription factors and epigenetic transcriptional regulators on a chronic basis. This increase ubiquination and the process steepens with respect to time. Organ failure and aging increase with respect to chronologic age. Epigenetic factors modulated by aging include the histone deacetylase family which includes the sirtuins as well as histone acetylases and DNA methyltransferases. Together and collectively, the epigenetic mediators impose the metabolic shift away from use of mitochondrial energy toward reliance on glycolysis. All of these complex epigenetic coupled factors are tied to inflammation generation via the NRF2 and KEAP1 transcription factors. This is why inflammation appears to be tied to all these things we talk about in the blogosphere. The key is understanding what happens proximal to the mitochondria and then how the mitochondria respond.

Jack Kruse said...

Confusion occurs when you only focus on input, thru put or output. What happens inside them and upstream of them is far more important. Understanding aging is the best way to prevent illness. This metabolic shift is further mediated by insulin resistance since a sedentary life does not require the metabolic demands that need to be regulated by insulin. Collectively, this epigenetic oxidative redox shift in aging results in a downward spiral of inability to respond to energy demands or environmental stressors which leads to stress-induced catastrophic initiation of cellular death pathways and organ failure. Complex.......but understandable when you get what mitochondria are really designed to do with charges subatomic particles from our environment.

George Henderson said...

Great stuff Jack.
In this paper, evidence that oxidised LDL can be anti-atherogenic

Earlier I posted a paper about endotoxin being an important endogenous hormone

This makes sense if you realise we are not designed to live forever, necessary repairs will never be as perfect as the original material, everything has a cost, and everything thrown up by evolution can be re-used by evolution to create a survival advantage.
Thus damage generates damaged molecules that are adapted into signals that trigger repair. These signals look bad, because they're associated with damage, and you can produce them in test-tubes by doing bad things to the orginal cells or macromolecules but by God we need them to get damaged.
We just need enough nutrition so our tool chest is stocked for the repairs we'll be doing, and so that we have the energy to carry them out.
Supplementary antioxidants are VERY helpful when you're acutely ill with hepatitis because their local protective effect outweighs any damping of the overall signalling, but are probably not how we should live our whole lives.
Nietzsche was a physiologist; what doesn't kill us does make us stronger in many ways.

Probably better to retain the immunosuppressive response to chronic infection unless you're sure of being able to clear it, or unless it's causing obvious problems. A chronic virus isn't TRYING to kill you, its natural selection would prefer you to live on a bit longer.

George Henderson said...

Coronary calcium scoring: the thinner the calcium is, the more dangerous it appears to be:

This is consistent with Linus Pauling's idea that atherosclerosis was a protective response.
When the job's half-done, or was carried out by incompetent or improperly informed tradesmen, using the wrong tools, it's more dangerous.

- link from Richard Lehman's very excellent blog

George Henderson said...

The cost of IDO activation, and how viruses exploit it:

MDSC produce high levels
of indoleamine-2,3-dioxygenase (IDO), which catalyzes the
degradation of tryptophan into kynurenine and results in cell starvation
and apoptosis [75]. When T cells are exposed to IDO, they
undergo apoptosis and significant dysfunction [76]. Interestingly,
when SIV-infected rhesus macaques receiving antiretroviral
therapy were treated with the IDO inhibitor 1-methyl-D-tryptophan
(d-1mT) for 13 days, they showed increased plasma level of
tryptophan and lower virus load [77]. Treatment with this IDO
inhibitor in cancer setting also reduced the suppressive effects of
MDSC and enhanced the anti-tumor effects [78,79].