Thursday, August 29, 2013

Ketones, without the side order of Danish Pastry please

Here is a discussion paper from Denmark. It is a deeply satisfying read, well worth overcoming the slight oddities of grammar which seem to have come from it being written in Danish as a first language. What they are doing is taking the concept discussed by Nick Lane (which they cite) about the intracellular selection of mitochondria under bioenergetic stress and putting a testable molecular framework in place. Obviously, from the Hyperlipid perspective, just look what they place at the top of the list as one of their factors for mitochondrial health. Here's the whole conclusion section:


Conclusions

This perspective deals with the notion that adaptive stress responses to respiratory challenges and stimulation drive natural selection of genetically and epigenetically inherited properties of mitochondria:
  • When brain energy turnover increasingly depends on ketone body or fatty acid metabolism rather than on glucose, sparing of complex I and proliferation of mitochondria is beneficial to overall mitochondrial health.
  • High glucose availability for oxidative phosphorylation, on the other hand, establishes a state of low selection pressure with increased accumulation of lesions.
  • Intermittent non-chronic insults with increased ROS production benefit mitochondrial health and promote healthy aging and increased longevity.
  • In healthy tissue, transient non-lethal insults such as chemotherapy, hypoglycemia, or hypoxic challenges, select mitochondria that are more resilient to subsequent challenges. These mitochondria are better adapted and more numerous.
  • Stressful challenges with increased ROS levels, followed by subsequent recovery and treatment with biogenesis-promoting agents, yield mitochondria with greater respiratory capacity than mitochondria treated with biogenesis-promoting agents alone.
These claims have specific and testable implications, the resolution of which can revise the general understanding of the role of mitochondrial challenges in healthy aging.




OK, 6.06am here, time to fry some egg yolks in butter. No taters for me.

Peter

17 comments:

Miguel said...

Hi Peter,

looking at the last of the points, what could be the strategy then for a correct stressful ROS attack followed by treatment with biogenesis-promoting agents?

Of course, which are those "agents"? Apart from a LCHF diet... CoQ10 and PQQ maybe?

Best regards.

Chip Spitter said...

Excellent stuff lately, Peter. I think I even understand most if it, which is nice.

I've been reading a bit of stuff from a bloke named Samuel T Henderson lately with a view to Ketones helping Alzheimer's. Fascinating, even if the papers are a little limited in their view. Example - http://www.biomedcentral.com/1471-2350/12/137

But down to the really important stuff - do your chooks produce eggs with bright yellow yolk? If I understand correctly the brightness depends, in part, to the amount of carotenes in the diet. Sources also say the yolk colour doesn't necessarily mean better nutritional value. Any expert comments? Not so keen on changing my chook's diet for no good reason. At the moment they're yellow, but not particularly bright/dark.

Jimmy Gee said...

OK, question not about the post, but about your breakfast. I've read this a couple of times in your blog now - egg yolks only. Why do you exclude the whites? Just curious.

Peter said...

Hi Miguel, not sure. Paraquat makes a perfectly good stressor in C elegans and there is no need for the promoters for life extension via oxidative stress to be achieved. Not suggesting humans use paraquat, not so good if you use lungs to oxygenate!

Chip, I spend ££££ on carrots, sweetcorn and cabbages for the chooks. Nice yolks. I get embarrassed that people and Tesco Clubcard software think that I eat the veggies!!! Regards to the chooks from my chickens BTW!

Jimmy, I limit protein as far as practical. mTOR signalling and all that. More when we get back to Cynthia Kenyon at some time and the evolve-ability of longevity via signalling pathways.

Peter

daveizmir said...

does the stress of chemo on cancer create more hardy lesion mitochondria? Seems like when it returns it does with a vengeance

O Numnos said...

Hi Peter, first a thank-you for responding to my question on BPH on a previous posting.

Whilst researching the possibility of selectively restoring liver glycogen without the use of Fructose I found this concerning depleted liver glycogen as a trigger for SNS mediated lipolysis in adipose tissue.

I've recently been upping my cycle mileage in order to ride a couple of centuries (100 milers). I find that after a couple of hours I start to get slightly hypo which worsens as time goes on, so at least I hope my neural mito's are getting a good work-out.

I mention this as the linked paper gave me a "hmmm..." moment as I've noticed very perceptible fat loss after only a couple of these longer rides. Although there is of course the increased volume confounder but it "feels" disproportionate.

Anyway hypoglycaemic work-outs for fat loss, could be on to something big here :-D

I see pairing this with some patentable franken-carb that selectively replenishes hepatic glycogen without the nasty steatosis or other fructose-like issues.

Might need some help with that one though.

JohnN said...

O Numnos: what are your ideas of franken carbs, may I ask?
Have you tried acetic acid, citric acid and other metabolites of the Kreb's cycle?
I am experimenting with boosting endurance at high altitude and there seems to be no substitute for mito-biogenesis of the good kind, beta-oxidation.

Chip Spitter said...

blogger ate my homework/response the other day.

Thanks for the chook feed tips. I live in the tropics so they have a plentiful supply of cockroaches to fight over. I never knew chickens were so pet-like - mine squat next to you and expect a pat.

Carry on with the ketone discussion...

Evangelista Nick said...

Thanks. Great info

George Henderson said...

For biogenesis, PQQ looks good. Also consider fulvic acid and co, and oligomeric catechins.

Would supplementing ubiquinone in ketosis enhance ROS?

Paeonia is TCM anti-aging herb that activates heat-shock protein:

"Paeoniflorin inhibited mitochondrial membrane potential dissipation, ATP loss, inactivation of complexes I and IV, cytochrome c release, and cardiolipin oxidation induced by antimycin A. In addition, paeoniflorin prevented antimycin A-induced ROS release and nitrotyrosine increase. These results imply that paeoniflorin protects osteoblasts from antimycin A-induced cell death via improved mitochondrial function."

Ryne said...

I too was very curious about the mention of "biogenesis-promoting agents". The key line in the Danish study is "Although much remains to be learned about the complex mechanisms of biogenesis...the mechanisms are believed to be regulated by interplay with the nuclear genome, involving hormonal regulators, transcriptional factors and co-activators, sirtuins, and the fusion-fission cycles of mitochondria (Lopez-Lluch et al., 2008)."

If you follow over to the 2008 Spanish study they idiotically waste time in the abstract mentioning resveratrol and starvation (to increase AMPK), but luckily the full-text is free.

For me the goodies of the paper are probably less trendy than the CR/red wine/exercise jumk found in the conclusion, but much more practical:

"Both thyroid and steroid hormones such as glucocorticoids regulate the expression of most of the nuclear genes encoding mitochondrial proteins. Sex hormones have been shown to exert differential effects on the expression of various mitochondriogenic molecules.For example, in brown adipose tissue progesterone promotes while testosterone inhibits mitochondriogenesis by differentially modulating the expression of several transcription factors involved in this process (Rodriguez-Cuenca, et al., 2007). Other hormones, like adrenal steroids, play an important role in perinatal mitochondrial maturation and biogenesis in a tissue-specific manner (Prieur, Bismuth & Delaval, 1998).

In mammals, the most important factors involved in mitochondrial biogenesis are the thyroid hormones (Mutvei, et al., 1989). Treatment of rats with the thyroid hormone T4 produces hyperplasia and increases the number and mass of mitochondria in both liver (Wooten & Cascarano, 1980) and cardiac muscle (Goldenthal, Weiss & Marin-Garcia, 2004). Levels of T3 and T4 hormones have been regarded as important factors in the maintenance of proper mitochondriogenic rates during aging (Mutvei, et al., 1989). The effectiveness of thyroid hormones on specific tissues depends on the amount of receptors present at the site of action, and receptor levels can vary under different physiological conditions. For instance, T3 is able to increase mitochondrial biogenesis in oxidative rat muscle but not in glycolytic muscle, and this differential response correlates with lower amounts of TH receptor in the glycolytic tissue (Bahi, et al., 2005)."

Any quick read of Emma's old PP&RS blog, Broda Barnes threads, Stop the Thyroid Madness forums, RP forums, etc. will show that most doctors world wide fall right into step with the Spaniards here and will recommend things like exercise, starvation and resveratrol pills (if the wine itself has too many calories) rather than risk putting a person on T3 or T4 and actually improve their health.

I would personally try thyroid hormone before putting my faith in "the secret of Eternal Youth found on a grapeskin" as Peter described it awhile back, haha!

Paraquat is good for suicides and I would feel much cooler buying it than a shopping cart full of vegetables!

One thing I am wondering is that if NO activates PGC-1a and promotes mitochondria, will vitamin B12 in high doses have a negative effect the way C&E do by interfering with adaptive signaling???

I'm currently experimenting with a supply of thirty 1250 mcg B12 injections, so...

ARosvere said...

For a biogenesis promoting activity how about cold exposure?

Miguel said...

Thank you very much Peter, George & Ryne.

George Henderson said...

Ryne,
I thought hydroxycobalamin (like creatine) quenched peroxynitrite, not NO.
In fact, superoxide that escapes from the cell quenches NO in forming peroxynitrite (superoxide is a reducing radical).

Here Goji berries stimulate retinal mitochondrial biogenesis
http://www.ncbi.nlm.nih.gov/pubmed/23505020

Retinoic acid is the thyroid messenger that activates mitochondria.
http://onlinelibrary.wiley.com/doi/10.1080/15216540214316/pdf
And retinol
http://www.ncbi.nlm.nih.gov/pubmed/19812372
These results illuminate a hitherto unsuspected role of vitamin A in mitochondrial bioenergetics of mammals, acting as a nutritional sensor. As such, retinol is of fundamental importance for energy homeostasis. The data provide a mechanistic explanation to the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action.

George Henderson said...

I got this on the wrong thread - but maybe aspirin is the simple fix:
Thyromimetic Action of the Peroxisome Proliferators Clofibrate, Perfluorooctanoic Acid, and Acetylsalicylic Acid Includes Changes in mRNA Levels for Certain Genes Involved in Mitochondrial Biogenesis

http://www.sciencedirect.com/science/article/pii/S0003986196900132

"These effects are in some ways similar to those obtained with thyroid hormone."

George Henderson said...

Here's a bit of mito biogenesis from a familiar suspect:
http://www.ncbi.nlm.nih.gov/pubmed/16205884
Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat.

If the first part is correct, then occasional high exposure to DHA, i.e. catching the occasional salmon or trout, might be enough.

Peter said...

Hi George, passing citations in the ethernet! Also as per the omega 3 post there is something out there which looks at the lipoxides of DHA as the mitochondrial biogenesis signal...

Peter