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We are back with Dr. Tommy Wood for another edition of Ask the Doc. Three major areas covered in this episode:
Monitoring of the oxidation reduction potential or redox status of ultra runners post-race
Discussion on oxidative stress focusing on this new study: “Variations In Oxidative Stress Levels In Three Days Follow-Up In Ultra-Marathon Mountain Race Athletes“
ROS generation during strenuous exercise:
Activated neutrophils
Xanthine oxidase
Hypoxanthine (high ATP turnover and degradation) produced by exercising muscle. Converted to xanthine and urine acid by XO using oxygen w/superoxide as a byproduct
Allopurinol before TdF time trial resulted in lower levels of AST, CK, and lipid oxidation (malondialdehyde) compared to placebo
NADPH oxidase
Mitochondria – some
After (ultra)marathons, increases in:
CK, IL-6, CRP, 8-OH-2dG, cardiac troponin, ferritin, GSH
In this study: 12 males sampled at the Olympic Mythical Trail 103km ultra, in effort to find a better understanding of the adaptive mechanisms against oxidative stress induced by athletic events, overall to help improve recovery, health and performance.
24, 48, 72h post-race (8/12 males finished)
Lower glutathione (GSH) in red blood cells for 72hr afterwards
RedoxSYS Diagnostic System
Increased static oxidation reduction potential (sORP)
Decreased capacity oxidation reduction potential (cORP)
More oxidants (oxidized thiols, superoxide radical, hydroxyl radical, hydrogen peroxide, nitric oxide, peroxynitrite and transition metal ions
Fewer antioxidants (vitamin C, vitamin E, β-carotene and uric acid)
In the average person, antioxidant supplementation (vitamins C, E, ALA etc) decrease training response (less hormetic stress)
During repetitive or exhaustive exercise (sprints ie bleep test), NAC supplementation -> increased GSH and slower fatigue
Overall the data on anti-oxidants and performance is VERY conflicting
Depends on dose of drug, dose of exercise, and how trained the person is
Supplement or take NAC (or allopurinol?) during long or multi-day races
Minimize during training or high stress periods (travel etc)
If doing so much you need antioxidants over a long period of time, are you doing too much?
Fix other issues?
Increased intensity of exercise -> gut permeability and LPS translocation
Inflammation long-term -> cardiac damage and AF and arrhythmias?
Study of non-trainers vs moderate vs heavy trainers
Moderate groups had highest glutathione
What the heck are lipopolysaccharides (LPS) and why should we care?
Bulletproof Radio mention
LPS produced by Gram -ve bacteria
Absorbed either through a leaky gut
OR bound onto proteins in blood lipid fractions
Gets into chylomicrons after a fat-heavy meal
Causes increased cortisol levels, inflammation, increased cholesterol
Inflammation and mood or brain fog
Depression
U-shaped curve of LDL and mortality
LDL (chylomicrons, HDL as well) bind to LPS
Chronic increases and inflammation -> increased LDL (protective)
Indicates low-level endotoxinaemia
Acute or more severe inflammation:
Decreased liver synthetic capacity
Lipoprotein production drops
LDL drops
Lipids can’t leave liver -> fatty liver
Those with sepsis who get a drop in HDL and LDL are more likely to die (survivors increase cholesterol production)
Decreased LDL -> increased death rate from infections
Giving human blood lipids to mice exposed to toxic levels of endotoxin reduces mortality
Some people think that it ALL comes back to endotoxins
Increased LDL
Not causative necessarily
Chronic inflammation
Some bacteria (Strep mutans also inactivated by chylomicrons) incl. Klebsiella are associated with atherosclerotic plaques
Circulating endotoxins are higher in those with T2DM and CVD regardless of other factors (BMI, blood lipids, blood glucose etc)
T2DM people get increased endotoxin release after a “high fat meal”
Higher baseline values in obese and impaired glucose tolerant
Suggests increased gut permeability already (more LPS can get in)
Short-term insulin peaks can be anti-inflammatory to combat the effect of endotoxinaemia
So hyperinsulinaemia might be a protective response to endotoxins
Then causes issues with growth and intimal thickening/hypoxia -> greater lipid deposition
White adipose tissue inflammation means fat IR therefore fat is no longer a useful defence mechanism against extra calories?
Corn oil/PUFA lowers LDL by dramatically increasing endotoxinaemia?
Introducing fat bombs on top of a bad gut
More LPS -> more IR -> greater need to restrict carbs in a feed-forward manner
What about a high-fat diet causing an increase in cholesterol? Is this ok, and what you need to know about cholesterol and fat in the diet.
Western diet
Acellular carbohydrates promote a more inflammatory gut microbiota
Gut inflammation not just LPS-associated
Mice infected with E. coli with less inflammatory LPS still get IR and leptin resistance
Gluten etc increase gut permeability
Large amounts of fat increase translocation of LPS across gut
Ricardo Carvalho aka O Primitivo
WHO death from various causes vs total cholesterol
Lowest all-cause mortality at 200-240
Lower cholesterol -> increased mortality from infectious diseases
Iron-Deficiency Anemia
Female athlete hoping for some insight regarding iron deficiency anemia
Mechanisms involved in the etiology of iron deficiency anemia beyond insufficient iron intake, such as iron absorption and transport.
Other solutions instead of “eat more red meat”? Something else going on downstream?
Adverse GI outcomes associated with iron supplementation.
Studies show reduced iron bioavailability in vegetarian diet despite similar iron intakes.
Get iron from haem-iron i.e. animal based foods for better absorption and consume with fruits and veggies to enhance absorption further (vitamin C).
Proferrin is a haem iron
What to avoid having when you’re eating iron rich foods (i.e. caffeine, etc)?
Grains, nuts, seeds (phytates)
If celiac, best to just remove all grains
Coffee/tea/red wine – polyphenols and tannins
BUT moderate alcohol can increase uptake (beer the most?)
Dairy products (calcium)
Other metals (from supplements)
Do non-weight-bearing cross-training?
Most iron “intake” comes from recycling of old RBCs and iron stored in macrophages in the liver and spleen
1-2mg/day vs 22mg/day
Need 20-25mg/day
Women need ~1mg/day more
70% of body iron is in Hb
High prevalence of iron deficiency +/- anaemia in athletes (>50% in some studies)
Higher sTfR (not an acute phase protein) – TIBC
Lower ferritin (<20)
An athlete’s iron stores are compromised via several well-established exercise-related mechanisms:
Haemolysis, haematuria, sweating, and GI bleeding
Check for FOB
Menstruation in females
“Regular weight-bearing exercise of moderate to high intensity can increase iron losses by 30% to 70%”
Iron lost in sweat decreases with heat acclimation
Under intensive training, 5-7ml (doubled) blood loss in the gut per day
Lose ~0.5mg/ml of iron
Exercise duration and intensity are negatively associated with Hb, Hct, and serum ferritin concentrations in highly-trained athletes
Replacing iron in iron deficient women leads to improved speed, reduced HR, and reduced lactate in a treadmill test
Exercise-induced hepcidin regulation
Serum iron and inflammation (esp. IL-6) increase after exercise (>70% VO2Max)
Direct impact (runners), inflammation (IL-6) and ROS can induce haemolysis to increase serum iron during/after exercise
Seen in swimming, cycling, rowing, weight training
More IL-6 when glycogen is depleted and in hot environments
Results in increased hepcidin production in the liver
Variable response – responders vs non-responders?
Marathon runners 24-72h after race.
Non-responders had higher baseline levels
May have sampled too late
Can rapidly reduce serum iron and Hb production
Decreased ferroportin on brush border of duodenal gut cells (enterocytes) -> decreased iron absorption
Sequestration of iron into macrophages
Reduced iron recycling
Smaller hepcidin response in the iron deficient
In matched intensity/volume cycling vs running, running seems to cause a greater increase in hepcidin
Most studies include single periods of exercise or races, rather than an accumulated effect over time.
9 weeks of military combat training in females leads to decreases in iron status, with decreases associated with worse performance
Ferritin decreased
RDW increased
sTfR increased
Of 94 women, 7->17 became iron deficient
1-1.5h of high-intensity exercise 4-6d/week (16,000 steps)
Combated with a high-iron supplement bar?
8 Weeks of interval and fartlek training in women
Increased sTfR
Decrease in Hb and RBCs
Decrease in hepcidin (smaller responses due to deficiencies?)
More long-term studies done in females
Experimentally, injecting LPS -> IL-6 (and CRP) -> hepcidin peak 3h later
Almost identical to that seen after high-intensity exercise
People at risk of lower iron stores:
Infections esp. H. pylori – blood loss
Other gut infections
Part of the job of hepcidin is to drive the sequestration of iron to prevent iron being available to pathogens
Also used to generate ROS to kill pathogens
When iron is scarce, certain bugs upregulate iron sequesters (siderophores)
E. coli, Klebsiella, proteus, citrobacter, enterobacter (Gram -ves)
Enterochelin – highest affinity of any siderophore
Candida – transferrin
NSAIDs
Vegetarian or vegan diets? Especially females
Heavy menstrual bleeding or IUD
Genetics
80% of French Olympic champions have some kind of HFE mutation
12 tested
More likely in aerobic or fight sports
Not necessarily associated with increased Hb
May reduce exercise-induced hepcidin increases
Maintain a higher serum iron
Improved recovery and cardiac function
Hypothyroid (thyroid meds?)
In one person, changes in thyroid status result in changes in ferritin
Iron and bugs
All bacteria (except, most commonly, Lactobacilli) need iron
Old blood in transfusions increases risk of bacteraemia
Free iron from haemolysed blood supports bacterial growth
Iron deficiency protects against malaria
In theory iron supplementation will promote bacterial growth BUT
If iron deficient, need to figure out the cause
Restricting iron isn’t going to fix an infection or improve iron status