Wednesday, April 15, 2009

Gene-Environment Interaction: Get Into My Genes, Part 2

The latest book I've been slogging through is Nick Lane's Power, Sex, Suicide: Mitochondria and the Meaning of Life (Oxford University Press, 2005).

I *heart* mitochondria.

Our silent ancestral roots can be traced through mitochondrial DNA (as can coyotes -- see previous post). Mitochondrial DNA are vastly different from our nuclear DNA which carried down from our parents. We hyper-produce mitochondria in response to anoxia, exercise and high intensity/heavy resistance strength training. Multiply your mitochondria...(and keep them happy)... and you will multiply your lifespan. SUPER power and SUPER endurance... SUPER antioxidant capacities... and SUPER longevity. It's all in the mitochondria baby.

And... We're only as strong as our weakest mitochondrial link.

With that said, is it possible to improve the DNA from our parents via our mitochondria? We are already aware the gene expression can be altered very simply from good Paleo eating, appropriate movement, consumption of antioxidants (EPA DHA omega-3s, GLA, flavonoids/carotenoids, vitamins, enzymatic cofactors, vitamin D, saturated fatty acids MCTs, etc) and avoidance of toxic macro- and micronutrients (high carbs/wheat, refined veggie omega-6 oils, toxins, pesticides, heavy metal poisons, etc).

Prior Posts on Mitochondria:
G-Flux: E ≠ MC2 (power up your mitochondria with power exercises)
Dr.Mao...the brain and mitochondrial disorders
CoQ10 and the Ubiquinone System (last energy step in mitochondria for ATP (energy-packet) generation)
PPAR-Delta Dagger in the Heart of CAD -- mitochondrial biogenesis and PPAR-Delta




Gene Transfer: Our Genes Are Not Permanently Programmed as Previously Believed

Our genetic programming are not immutable. Our genes can and do change. It's not a revolutionary idea. In Drosphilia over ten years ago, gene transfer from mitochondria to the nucleus was discovered. Also daily we have genetic mutations occurring on the single base-pair level. Dr. Bruce Ames PhD has shown that a deficiency in almost any essential micronutrient can lead to DNA damage equivalent to that induced by radiation damage.


Nick Lane writes "For those not familiar with the 'stickiness' and resilience of DNA, it may seem akin to a conjuring trick for genes for the mitochondria to suddently appear in the nucleus, like a rabbit produced from a top hat. How on earth did they do that? In fact such gene hopping is commonplace among bacteria (hence high rates of multidrug resistance in TB, and now we're seeing record community-acquired skin strep infections that are resistant to EVERY known antibiotic). We have already noted that lateral gene transfer is widespread, and that bacteria routinely take up genes from their environment. Although we normally think of the 'environment' as outside the cell, acquiring spare genes from inside the cell is even easier.' (p. 131)

'Gene transfer continues today, occasionally making itself noticed. For example, in 2003, Clesson Turner, then at the Walter Reed Army Medical Center in Washington, and collaborators, showed that a spontaneous transfer of mitochondrial DNA to the nucleus was responsible for causing the rare genetic disease Pallister-Hall syndrome in one unfortunate patient. How common such genetic transers are in the pantheon of inherited disease is unknown.' (p. 133)

' Gene transers occur predominantly in one direction. Think back again to the first chimeric eukaryote. If the host cell were to die, it would release its symbionts, the proto-mitochondria, back into the environment, where they may or may not perish-- but regardless of their fate, the environment in chimeric co-existence would certainly have perished. On the other hand, if a single mitochondrion were to die, but a second viable mitochondrion survived in the host cell, then the chimera as a whole would still be viable. To get back to square one, the surviving mitochondrion would just have to divide. Each time a mitochondrion died, the genes released into the host cell could potentially be integrated into its chromosome by normal genetic recombination. This means there is a GENE RATCHET, favouring the transfer of genes from the mitochondria to the host cell, but not the other way around.' (p. 133)


Just as nations, 3rd world countries, businesses, conglomerates, Microsoft, big Pharma merge/coalesce to dominate, our DNA is looking out for itself whether you pro-actively are or not. It appears that mitochondrial DNA can insert itself into the bigger nuclear DNA picture, so to speak, and in fact can stay there silently or not so silently.

Nuclear gene control are primarily affected by nuclear receptors... This is the boss of us. these are nearly ALL cholesterol-derived sex steroid receptors. Why do I talk about S-E-X all the time. Now you are starting to GET IT. *SMILE*
--Liver, Pancreas, Gallbladder, GI Lining: PPAR, FXR, LXR, VDR (vitamin D), RXR/RAR (carotenoids, vitamin A), TR (thyroid), PTH
--Thyroid, A.Pituitary: TR (thyroid), VDR, PPAR, RXR, RAR, ROR/RZR, PTH, ER (estrogen), AR (testosterone)
--Muscles, Heart, Bone, Vasculature, Kidneys: PPAR, VDR, RXR/RAR, TR (thyroid), PTH, Testosterone (AR androgen receptor), ER (estrogen)
--Sex Glands: AR (testosterone), ER (estrogen), PR (pregnane), Progesterone, TR (thyroid), VDR, PPAR, RXR/RAR
--Brain, Nervous System, Skin/Hair/Nails/Teeth, Breasts: VDR, PPAR, RXR/RAR, Testosterone (AR), ER (estrogen), Progesterone, TR (thyroid)
--Adrenals, P.Pituitary: GR (glucocorticoid receptor Cortisol), SF-1, PTH, VDR, TR (thyroid)



Is a pattern emerging?

(At TYP we love Vitamin D. VDRs (vitamin D receptors) are found everywhere.)

NRs control everything. Some NRs can be activated even in the absence of hormone. Synergism as well as surrogate control appears to exist.

The fact that medicine is subdivided by organ specialities (eg, Endocrinology, Gastro/Hepatic, Neurology, Derm, Card, etc) belies that fact that organ systems are all intimately related, not independent entities. NRs may have tissue-specific roles but they also share regulatory functions.

Though the major players are listed above, there are still many 'orphan' NRs (nuclear receptors) that are uncharacterized and their respective binding agonists are unknown.




Dr. Davis deserves a Nobel!

At Track Your Plaque, Dr. Davis advises control, management and optimization of every nuclear receptor.
--Thyroid
--Vitamin D, potent pro-hormone
--Estrogen, Testosterone
--Insulin (low carb, gluten-free, PALEO diet)
--Cortisol (stress reduction, rest, recovery, relaxation, sleep)
--Melatonin (binds ROR/RZR in the pituitary; J of Pineal Research
18(4), Pages 171 - 178.)
--PPAR (fiber, SCFAs, omega-3, ALA, grassfed/wild protein)
--RXR, RAR (carotenoids, vit A, Paleo diet)
--LXR, FXR (fiber, oat bran, Taurine)




Evolutionary Meaning of our Embryonic Tissue Origins

Genes are elaborate on/off by switches controlled by environment, lighting, food, and the subsequent expression of hormones and their respective feedback loops. As elegant as the most brilliant piece of genius software programming or symphonic composition, things can go awry when... let's say a loop goes out of whack (a non-sense line of code or an entire orchestral string group disappearing for a bathroom break).

Not only does optimizing mitochondria in every cell in our body produce excellent health, targeting the evolutionary source tissue improves all tissues which are derived from that particular germ layer and embryonic tissue. For instance, for the vascular and circulatory system 'rejuvenation' and healing, all things 'work' that work for the other Mesoderm-originated tissue. Help your skeletal bones...and ur b*ne-r... You'll help your 'bone' (eg, inappropriate calcifications) in the plaque of your blood vessels (excuse my inappropriate French terminology).

Mesoderm:
Muscle, bone, cartilage, collagen, bone marrow
Vasculature, lymphatic system, blood
Kidneys, gonads (ovaries, uterus, testes, prostate) and reproductive ducts
Dermis (middle layer of the skin)




PPAR Nuclear Receptors, Ultimate Anti-Aging Switches

PPAR receptors are the NRs ubiquitous and abundant in the mammalian body, not excluding the entire circulatory system and the major coronary arteries (LAD, LCx, RCA) .

The best activators in nature for PPAR are:
--ketones, intermittent fasting, carb-restriction, insulin-control, muscle-building activities, all things anti-inflammatory
--omega-3 fatty acids
--CLA
--dietary protein (Leucine, etc) via the mTOR pathway
--short-chain saturated fatty acids (butyrate produced by our micro flora/fauna (eg, gut bacteria fermenting dietary fiber/Paleo plant material) or grassfed dairy, etc)
--medium-chain saturated fatty acids (coconut oil, sat fats in nuts like almonds, fish/seafood/fowl/meat, etc)
--monounsaturated fatty acids (olive oil)
--activation of other NRs (estrogen, thyroid, testosterone, cortisol-reduction, insulin-control)


See Get Into My Genes (Part 1) -- my 50 lbs weight loss story via eliminating rice (2cups/d WOW 90g/d and juice 30g/day carbs + high carb foods), cardio/wt lifting/yoga/day-spa's/IF'ing and my love/addiction for half-marathons.




Get in My Genes (Part 2)

So... are my genes permanently improving, perfecting and modifying...?

Can we remodel our mitochondria as we have been shown that we can remodel our vasculature and regress atherosclerotic plaque? Can we spontaneously revert mitochondrial DNA mutations and nuclear DNA mutations?

I would count on it.

7 comments:

Kevin said...

Remodelling gene receptors, sounds cool. I assume I was doing that while following an Atkins-style diet. My cholesterol went up but I kept reading that cholesterol is not the cause of cardiac disease.

Now I'm trying the Ornish vegetarian diet, having read that it might control benign prostatic hypertrophy, which I now have. At the same time, I wonder if years of high saturated fat (ala Atkins) may have led to the BPH.

kevin

Dr. B G said...

Kevin,

Though I like the premise of Atkins, unfortunately, I found that the dairy content may be intolerable for many people. Dairy (casein protein) has opioidlike properties like gluten and can also trigger autoimmunity disorders.

BPH can result from insulin which is a growth hormone. Any antiinflammatory, insulin-controlled diet (like Paleo) helps BPH. Studies show vitamin D and fish oil are very benefitical in controlling BPH has well. Good luck.

-G

Kevin said...

Thanks for the note. I use VitD and fish oil. Which "Dr" are you? I'm a D.V.M.

kevin

Dr. B G said...

Hi Kevin,

That's great! Peter at Hyperlipid is a DVM as well. Have you read his thoughts? He has great analyses on clinical trials esp lipoprotein ones. LDL going up is not a bad thing necessarily. When LDL particles become more buoyant and anti-atherogenic, the LDL on calculated Freidewald may appear 'higher' when in fact the 'direct' count or NMR/VAP will show they are indeed far less.

NMR/VAP is the only accurate way to assess buoyancy and particle counts. In the US this costs about $99 to 149.

My degree is a PharmD.

Thank you,
G

theorytopractice said...

Fantastic post, G. More validation for my love of HIIT workouts and the Paleo lifestyle. And btw, I agree -- Nick Lane's book is a winner.

Dr. B G said...

Keith,

Nothing surprises me about you.

I like your inner GEEK. You're so...hot and schwingtastic...! *haah* empirically speaking of course.

-G

MCT said...

on my last question from genes part 1, I think I'm getting it now.

so I get that we can send our mitochondrial DNA to our nuclear DNA, and that our DNA can mutate daily (in fact that's part of the aging process).

If I'm understanding correctly, we can reverse our DNA mutation in our mitochondria, and then replace our nuclear DNA with (superior) mtDNA?