Elusive mitochondrial connection to inflammation uncovered | Hacker News Reader

Elusive mitochondrial connection to inflammation uncovered

nature.com

242 pointsdtawfik153 comments

Interesting post and comments, as usual. I wanted to give some pragmatic information related to this.

I have a genetic condition that makes my mitochondria to malfunction. I was diagnosed about 10 years ago. At first, I started taking supplements to increase the production of ATP, but my "vitality" did not improve much. I could workout normally, but my recovery ability was poor, and from time to time I would just crash and burn for 2-3 days.

After much reading, I came to the conclusion that the problem was not a shortage of ATP. Rather, it was the mess created by all the workarounds my body was doing to maintain a level of ATP that could keep me alive. So, I started taking the following pre-bed stack. It is meant to be a clean-up the mess, anti-inflammatory:

- 2g Vitamin C

- 500 mg reduced glutathione

- 500 mg curcumin (I prefer BCM-95)

- 1-5 mg melatonin (depending on activity level)

- 100 mg CoQ10

(I am also considering adding Ashwagandha to the stack)

As of today, I workout 4-5 times per week, with 2 sessions of boxing (like punching in the face, not the aerobic variation), 1 heavy lifting session (usually squats) and 1-2 metabolic circuit sessions.

Sure I feel tired at times, but it is not liked the deep, extreme fatigue I felt before starting this stack.

Hope this helps.

I'm curious. if you occasionally have fatigue in a cycle, consistent with some kind of infection growth life cycle, you should try removing vitamin C and gluthatione for 10 days and see if you feel even better. if you do, you need to go see a doctor to get screened for parasitic infections that cannot be found with just looking at a regular blood test. 99% chance you don't have one, but I am curious.

Interesting comment. I have thought about this in the past as mitochondria, roughly speaking, is a bacteria. As such, it is in a constant flux of fission and fusion cycles and targeting this cycle is a potential target to treat my disease.

For a fascinating experiment, check out Longecity's "Manipulating mitochondrial dynamics" post [1]. Worth reading. Based on this, I am still trying to set up a protocol for my disease, but have not tried that yet.

[1] https://www.longecity.org/forum/topic/94224-manipulating-mit...

Interesting! Do you take pure ascorbic acid, or a buffered form such as magnesium ascorbate, or a liposomal version?

Also, how big do you estimate the impact CoQ10 has? Have you considered ubiquinol?

From my own toolbox, I can highly recommend near infrared therapy (easy to setup your own little sauna for about 50 bucks, just buy some lamps and drill the sockets onto a wooden board); also CBD is a great recovery aid, in case you haven’t tried it (up the dose slowly, there IS a Goldilocks dose for everyone).

>>> Do you take pure ascorbic acid, or a buffered form such as magnesium ascorbate, or a liposomal version?

Pure ascorbic acid.

>>> how big do you estimate the impact CoQ10 has?

I am taking CoQ10 since I was diagnosed and it has been really helpful to improve my vitality. I have changed the dosage over the time (100mg-600mg daily). Right now, 100mg at bedtime is working great for me.

>>> Have you considered ubiquinol?

Yes, I have tried ubiquinol, but haven't noticed any improvement over plain CoQ10. Note that I take CoQ10 with improved bio-availability (Q-absorb).

>>> I can highly recommend near infrared therapy

Thanks! I recently bought one [1], but have not used it much.

[1] https://redlightman.com/product/infrared-830-device/

>>> From my own toolbox

Do you also have a mitochondrial dysfunction ?

Thank you! I will check out Q-absorb.

I have a very similar device from RLM, but the one that produces 4 different wavelengths. I use ordinary heat lamps more often though as I want to provoke sweating.

Re mito dysfunction - I don’t know for sure, I have a few MTHFR related „mutations“ (which can affect mitos), but have no diagnosis regarding mito dysfunction yet. I strongly suspect that I do, though.

Diagnosis has improved a lot lately. Tell your doctor to order a kit at mitoswab dot com. I have not tried them, but they claim that "MITOSWAB has an 84% correlation to the muscle biopsy" and it is simple, non-invasive test.

Take care.

I'd recommend turmeric instead of curicumin and to not take melatonin but I'm happy you are feeling better, so whatever works for you.

Thanks for the recommendation.

Could you elaborate a bit, specially about melatonin ?

On the melatonin I would add that studies have shown negligible increase in effectiveness over 0.3mg. Yes, most pharma stores offer only 3mg and above, but that seems to be wrong.

Personally I've only taken melatonin when I most needed it, and then gave up on it. You should try giving it up, too, unless you really can't do without it.

You should check the vitamin D level, too, whenever you do your next blood test.

As for curcumin, the Longvida formula seems to be most effective. I can't say I've noticed any effects from it myself, but I haven't taken it daily, and I've also read that you need to take curcumin for 2+ weeks to see the effects.

https://www.turmericforhealth.com/curcumin-benefits-and-dosa...

On the melatonin, note that I do not take it to fall asleep, but for its protective effects in the mitochondria. This [1] is a good review.

[1] https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-079X...

Here is an interesting video re melatonin:

https://www.youtube.com/watch?v=2q1ln6vaSE0

Here is a video re Melatonin: https://www.youtube.com/watch?v=2q1ln6vaSE0

Why tumeric over curriculum?

From this guy:

https://nutritionfacts.org/video/turmeric-curcumin-plants-vs...

I find him convincing in general in terms of diet etc and he has a lot of other good content.

My opinion on melatonin comes from him too, but I can't find the relevant material.

What were the symtoms? How did you get diagnosed?

>>> What were the symptoms?

It varies greatly, both in number and severity, between patients, but in my case main symptoms are ptosis (droopy eyelids), diplopia (double vision), muscle weakness and general fatigue

Other symptoms include exercise intolerance, gut motility problems, cognitive problems, heart problems, etc

>> How did you get diagnosed?

Diagnose took 2 years. At the end, a muscle biopsy revealed my disease (mitochondrial myopathy [1] due to a large-scale single mtDNA deletion). My phenotype is known a CPEO [2]

[1] https://www.mda.org/disease/mitochondrial-myopathies

[2] https://en.wikipedia.org/wiki/Chronic_progressive_external_o...

is there a way to get a hold of you privately? I want to ask you some questions. post a throw away email?

You can see my email in my profile page

Thanks, this is a really interesting post.

Have you ever tried N-Acetylcysteine?

>>> this is a really interesting post.

Glad you liked it !

>>> Have you ever tried N-Acetylcysteine?

Yes, before reduced glutathione was available I took NAC from time to time, but I feel that in my case reduced glutathione works way better than NAC. Maybe I have a problem converting NAC to glutathione.

What brand of reduced glutathione do you use?

Could some of your problems come from being punched in the face regularly?

I wish it would ! Would be an easy fix.

I fight with headhear and 16oz gloves, and we do not seek to knock out our partner. It’s boxing, that is, a sport for gentlemen, not for brainless savages.

If you are interested in more information about Autophagic processes, this video interview is great: https://www.reddit.com/r/fasting/comments/6qobj7/rhonda_patr...

Rhonda Patrick interviews Dr Guido Kroemer, an expert in Autophagy. Its one of the most accessible, well-referenced and thorough discussions on Autophagy (including Mitophagy), that I've come across.

Transcript and other resources available here. https://www.foundmyfitness.com/episodes/guido-kroemer

Thanks for sharing!

Dr Rhonda Patrick's podcast, Found My Fitness, is excellent.

Oxidative stress and inflammation go hand in hand. Aging has rising levels of both.

Mitochondrially targeted antioxidants such as SkQ1 were first approved for use against inflammatory eye conditions. They act to dampen the consequences / amount of inflammation, and do this by cutting down on oxidizing molecules produced within mitochondria. They were first developed out of an interest to slow aging through this sort of modulation of mitochondrial oxidative stress and damage. They do slow aging to some degree, but don't do anywhere near as well as calorie restriction - say 10% in flies, something less than that in mice, which isn't impressive.

The first earnest human trials for mitochondrially targeted antioxidants such as MitoQ (which from the studies is actually less effective than SkQ1) suggest it can reduce the impact of oxidative stress or inflammation on the smooth muscle cells in blood vessel walls. Their dysfunction produces some fraction of the stiffening of blood vessels with age. That stiffening causes raised blood pressure, which in turn causes too many bad things to list here.

So these are not massive effects. You can probably do as well as MitoQ by bumping up your exercise level to the next tier. But then you can always both exercise and take a mitochondrially targeted antioxidant. The costs are not high, so it may be worth it based on the preliminary data.

Not a cure for aging, and thus not worth spilling immense amounts of ink and effort over it. Just something to think about doing and then get on with better development projects with better expected outcomes.

Then melatonin supplementation might be the way to go.... https://scholar.google.com/scholar?as_ylo=2018&q=melatonin+m...

Wow, I did not expect to find you here reason !!

mitomutant from Longecity speaking.

One mental model which may help in visualizing "oxidative stress" in mitochondrial networks is to liken it to a "first-order phase transition" in solid-state physics. Gene expression regulates structure. And structure determines function.

But whereas a typical sample of inorganic material may possess a handful of stable states under room temperature conditions. Nuclear genomics in mammals express 1000s of proteins.

MIT's Broad Institute has begun compiling a reference atlas:

MitoCarta 2.0: An Inventory Of Mammalian Mitochodrial Genes

https://www.broadinstitute.org/scientific-community/science/...

If you could acurately simulate biological systems with a computer model, you could do drug development in the cloud without the need for clinical trials. Unfortunately, protein folding and even predicting whether a molecule will be an agonist at a particular receptor site are very slow algorithms.

Accurately simulating biological systems in the cloud to run a virtual clinical trial is like trying to predict the exact weather for Washington DC at a specific date and time hundreds of years from now using weather forecast models. It’s pretty much impossible with current biomedical knowledge.

To simulate humans well enough to eliminate a clinical trial, you would have to simulate every single cell, organ, and organ system as well as the substantial population of bacterial and fungal microorganisms that live on and inside humans (as well as all their unique biology too). Building such a simulation would require a level of knowledge of biology that the human race currently does not possess.

Also, computronium.

That is and will stay impossible no matter how many resources for simulation you have, actually.

> This technique, when applied to the real world, is sometimes useful, but can sometimes also lead to self-deception. This technique is called modelling. When constructing a model, the following idealization is made: certain facts which are only known with a certain degree of probability or with a certain degree of accuracy, are considered to be “absolutely” correct and are accepted as “axioms”. The sense of this “absoluteness” lies precisely in the fact that we allow ourselves to operate with these “facts” according to the rules of formal logic, in the process declaring as “theorems” all that we can derive from them.

> It is obvious that in any real-life activity it is impossible to place total reliance on such deductions, if only because the parameters of the phenomena studied are never known absolutely exactly and a small change in parameters (for example, in the initial conditions of a process) can totally change the result. It is for this reason that a reliable long-term weather forecast is impossible and will remain impossible, no matter how much we develop computers and devices which record initial conditions.

https://dsweb.siam.org/The-Magazine/All-Issues/vi-arnold-on-...

This is actually very interesting.

Low-grade inflammation is often linked to aging and cancer developments, it is however often unclear whether its cause/effect or correlation - https://academic.oup.com/biomedgerontology/article/69/Suppl_...

But mechanisms of inflammation are many and still pretty illusive, this is a great step towards understanding aging mechanisms in general.

This is highly interesting. After taking ciprofloxan 10 months ago I'm still trying to get my damaged mitochondria back in order.

If it affected your tendons Magnesium is recommended. I'd also speculatively suggest iodine (a few mg per day) and glycine (1-20 grams per day). I am not a doctor, but then that's who prescribed you that crap ;-)

I have chronic fatigue likely brought on by mitochondrial dysfunction. Iodine ended a 12 month long mono infection and is the difference between having enough energy to spend the day reading.

I'm curious what you mean by that. It sounds like an odd way to frame it.

I've personally never struggled so hard to recover from anything. I couldn't do it justice in a short post. Lost 75 pounds in a 45 days. Heartrate over a 100 for a month.

Here is a link to another nature article on it: https://www.nature.com/articles/d41586-018-03267-5

Yes, I've recovered from long term prescription drug use. It was awful.

I just thought mitochondrial damage was a strange framing.

Thanks.

Edit: The article does talk about mitochondrial damage, though it didn't appear at first glance to address this. It's towards the end of the article.

The negative effects of Ciprofloxacin and other fluoroquinolone antibiotics was touched on in this post:

https://news.ycombinator.com/item?id=13273770

Wow thanks for your post. I had to look up and I was surprised that antibiotics can damage your mitochondria. But it makes sense because I was told, back in biology, the mitochondria were actually a bacteria and "swallowed up" by mammal cells. (forgive me, that's a extremely trivial recall of my memories and I am not an expert in this field)

If you are interested (and very brave, there are risks here), apparently there is a SARM that can help your mitochondria grow back. It's called Stenabolic SR9009. I have never tried it (because I have no need), but I'd be interested in what you think about it. You can find information on it online, I don't want to post anything because I am not qualified to vet the information -- information is all over the web however.

For me the experience has made me less risky in general (this was a standard 10 day treatment for sinus infection). Fasting / exercise for now. My biggest issue is the gut and repopulating bacteria. Once that's in order I may try something like the Stenabolic.

2012: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536340/

Vitamin D3 (+ K; 10 IU D3 : 2 mcg+ MK-4) + chelated/TRAACS magnesium. Magnesium is released by the body to clear inflammation. Vitamin D induces autophagy, and counters inflammation and oxidation.

Riboflavin (selenium, vitamin E, etc) is involved in the recycling of glutathione. MSM + silicon (monomethylsilanetriol) + vitamin C. 4g:1g MSM:C.

So this could be what is causing all these nearly undiagnosable cases of autoimmune disease?

There are about half a dozen solid rock band names in this headline:

Hello [City], we are [Choose one below]! Duh nuh nuh nuh nuh, Duh nuh, Duh nuh nayayayayay

- Inflammation Uncovered - Mitochondrial Connection - Elusive Mitchondria - Elusive Inflammation - Mitochondria Uncovered ...

I wonder why we developed the STING protein in the first place. Was it perhaps an early form of immunity, or a precursor to an immune response?

The name stands for STimulator of INterferon Genes, where interferons are essentially message-carrying molecules involved with the immune system. STING protein, I believe, is essentially a detector which gets triggered when a cell is invaded by a virus or encounters a parasite. For that, it still serves an important purpose.

Ray Peat anyone? :)

Absolutely, nobody knows better how to take care of our mitochondria than Ray Peat.

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