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.

What To Do After You've Lost 50 # ? Get Into My Genes...

What To Do After You've Lost 50 lbs:

1. Get rid of your larger-sized jeans -- donate 'em, burn 'em, give them away, t-h-r-o-w them away so you don't get any ideas
2. Buy new hot jeans, preferable anything that makes you look hotter
3. Get rid of your larger-sized undies b/c they will peak out of your sexy new(low rise) jeans.
4. Welcome the customer service you'll get (sad but true) -- the better you look the better service (even though you're the s-a-m-e cranky consumer).
5. The better the service, the bigger the spending. Get a larger wallet!

About 5yrs ago I started on a 'health' kick which started when I couldn't fit into my size 10-12 jeans. Everyone reaches their own personal 'rock bottom' at some point which starts the process of life-altering new change. My rock bottom occurred when my bottom couldn't fit. *sigh* Wish I could say it was for improving my 'fitness' or 'golf' or 'longevity' or 'primary coronary prevention'. Nope.

You wanna get into my genes?

After losing 50 lbs (low carb, working out, yoga, eliminating juice/cereal/rice) and achieving the ultimately best health ever, I would say my genes ROCK now. Can we alter our genes and genetics? (Clinton was once clobbered for saying he changed his 'genes' and after making adjustments to his diet and weight after his multiple-vessel CABG .... we wondered what (??!) was he was talking about) *heh*

It certainly is possible to optimize and out-maneuver genetic polymorphisms (and other DNA curses). With a semi-Paleo diet, inadvertently fasting intermittently (cheating with chocolate and coffee), exercise (both low and high intensity), the weight went from originally 158 to finally 108 lbs... (115 lbs now after growing 7 lbs of muscle/mammaries/hair ... they're real... and spectacular... J/K (!!)... miss my Seinfeld). My BMI is 19.4 (size 1). I started at 38% body fat (wow -- more than 1/3 of the initial weight) and now I'd estimate 19-22%. Was it hard? Let me tell you... it wasn't always easy. But it wasn't difficult once the process started. Like a rock rolling down a hill. At some point, natural laws of gravity kick in -- with big enough kicks(and other physics, such as smaller masses require shopping for smaller jeans). Psychologists say that change takes 2 weeks to occur and be reinforced.

Randomness in workouts helps me -- mixing up the intensity and varying the lengths. Boredom can't set in when the routine is constantly changing, setting new bars of achievement (instead of 2 miles, 4 miles), finding friends to join in the fun, or attending classes where you can share camaraderie (and accountability).

French culture have taught us yet another lesson (other than croissants, butter, wine, cheese and other good foods can be good for us). By consuming the right balance of foods and right portions for our specific genetics, we can extend health, longevity, and vitality to the maximum. Make the most of the interplay between personal genetics and diet. As certain genes can be turned on for optimization of health, many genes can be down-regulated and shut OFF to stop and control chronic diseases.

As Hippocrates once said "Let thy food be thy medicine, and thy medicine thy food."

No pain-au-chocolat, no gain!

(Food was probably high-carb 50-80% of daily calories-- the context would not apply necessarily to TYP-ers and therefore dietary fat effects may not extrapolate out)Features of the metabolic syndrome (MetSyn) are modulated by an interaction between the peroxisome proliferator-activated receptor-delta -87T>C polymorphism and dietary fat in French-Canadians. Robitaille J, et al. J Obes (Lond). 2007 Mar;31(3):411-7. (More on PPAR-delta later... what a fascinating receptor)

OBJECTIVE: We verified whether genetic variants in this gene are associated with the MS and whether dietary fatty acids interact with the -87TC polymorphism.

METHODS: By direct sequencing, we identified 15 variants in the PPAR-delta gene and analyses were pursued with the -87TC polymorphism for 340 subjects.

RESULTS: Metabolic variables were comparable among each genotype group. The -87TC polymorphism, fat intake and the interaction accounted, respectively for 2.2, 1.9 and 1.5% of the variance in high-density lipoprotein cholesterol (HDL-C) levels (P less than 0.05) (age, sex and energy intake were included into the model). The total cholesterol/HDL-C ratio was also modulated by a gene-diet interaction and by the -87TC polymorphism (P less than0.05). No gene-diet interaction effects were observed for other features of the MS. The age- and sex-adjusted odds ratio (OR) of exhibiting three or more features of the MS when carrying the -87C allele was 0.62 (P=0.04) compared to -87T/T. However, in subjects consuming less than 34.4% of energy from fat (median of fat consumption), the OR in carriers of the -87C allele was of 0.42 (P=0.008).

CONCLUSION: These data suggest that the PPAR-delta -87TC polymorphism may be associated with a lower risk to exhibit the MS and this association is influenced by dietary fat intake.The metabolic syndrome (MS) is influenced by genetic and environmental factors. Peroxisome proliferator-activated receptor delta (PPAR-delta), a transcription factor involved in lipid metabolism, is a candidate gene for the MS. PMID: 16953259


A certain genetic type (polymorphism) determines whether saturated fat increases apo B (and Metabolic Syndrome and thus small dense atherogenic LDL and plaque-progression) or protects against elevated apo B (et cetera). I wish I could get into my genes... but I would bet that my genes exhibit the apo B/MetSyn/atherogenic type... like the great majority of the global human population (insulin resistant with age, sedentary lifestyle, and excessive carb intake). The A94 type is impressive (A++) but unfortunately my genes probably wouldn't be so lucky. I wish I had A++ genes... but I more than make it up with A++ physical activity and food. Robitaille J, et al. Mol Genet Metab. 2004 Aug;82(4):296-303.

Plasma concentrations of apolipoprotein B are modulated by a gene--diet interaction effect between the LFABP T94A polymorphism and dietary fat intake in French-Canadian men.
Hyperapobetalipoproteinemia is a common feature of the metabolic syndrome and could result from the interaction between genetic and dietary factors. The objective of this study was to verify whether dietary fat intake interacts with the T94A polymorphism of the liver fatty acid-binding protein (LFABP) gene to modulate plasma apolipoprotein (apo) B levels. Dietary fat and saturated fat intakes were obtained by a dietitian-administered food frequency questionnaire and the LFABP T94A genotype was determined by a PCR-RFLP based method in 623 French-Canadian men recruited through the Chicoutimi Lipid Clinic (279 T94/T94, 285 T94/A94, and 59 A94/A94). The LFABP T94A polymorphism was not associated with plasma apo B levels when fat intake was not taken into consideration. However, in a model including the polymorphism, fat intake expressed as a percentage of total energy intake, the interaction term and covariates, the variance in apo B concentrations was partly explained by the LFABP T94A polymorphism (5.24%, p = 0.01) and by the LFABP T94A*fat interaction (6.25%, p = 0.005). Results were similar when saturated fat replaced fat intake in the model (4.49%, p = 0.02 for LFABP T94A and 6.43%, p = 0.004 for the interaction). Moreover, in men consuming more than 30% of energy from fat, the odds ratio for having plasma apo B levels above 1.04 g/L for A94 carriers was of 0.40 (p = 0.02) compared to T94/T94 homozygotes. Results were similar for carriers of the A94 allele consuming more than 10% of energy from saturated fat (OR: 0.32, p = 0.005).

In conclusion, T94/T94 exhibit higher apo B levels whereas carriers of the A94 allele seem to be protected against high apo B levels when consuming a high fat and saturated fat diet. These findings reinforce the importance to take into account gene-diet interactions in the prevention and management of the metabolic syndrome. PMID: 15308127