Tuesday, February 16, 2010

Lipoprotein(a) and ascorbate

OK, ascorbate and Lp(a).

There are some posts which are quite hard to write. I really like the "Lp(a) is a surrogate for ascorbate" hypothesis. It's neat and elegant, so the more information I read which undermines it, the more depressing I find it.

We humans are members of the sub order haplorrini of the order primates. Haplorrhini, that is humans and apes, Old World Monkeys and New World monkeys, have all lost function of that gene for the last enzyme in the formation of ascorbate from glucose.

Of course the crucial species are the tarsiers.

Tarsiers are quite interesting as they have been batted back and forth from the haplorrhini, ie us lot, to the prosimians, ie the rest of the primates. It's a very very close call genetically as to whether tarsiers are haplorrini or not.

There is one isolated report that tarsiers cannot make vitamin C. This should put them firmly in to the haplorrini but geneticists still argue the exact grouping.

It matters because the loss of ascorbate synthesis appears to have occurred in haplorrhini very soon after the split between our sub order and the rest of the primates.

Now, there is this concept that humans lost the ability to synthesise ascobate because a common ancestor to all of us haplorrini sat around all day eating melons and nectarines. Of course it's quite hard to say exactly what the ancestor of the tarsiers actually ate, but it's quite simple to say what current tarsiers eat. They eat insects, lizards and small snakes. I've seen at least one textbook entry which suggest that tarsiers are about as close to anything resembling the common ancestor of we haplorrhini as anything alive today.


Perhaps tarsiers use Lp(a) as an ascorbate replacement? No one has checked this, but what they have checked is whether the New World monkeys make Lp(a). They don't. Or, if they do, it is unrecognisable using human Lp(a) sensing antibodies. If tarsiers can make an Lp(a) like substance it puts them firmly down with the Old World monkeys and apes. They're certainly not an Old World monkey or an ape.

To summarise: Only Old World monkeys and apes make recognisable Lp(a). All haplorrhini have lost ascorbate. The haplorrhini are probably derived from an ascorbate-less near carnivore. New World monkeys are doing fine without Lp(a) or ascorbate. Modern tarsiers are doing fine as pure carnivores without ascorbate....

Of course the guinea pig is a fascinating little beast too. As far as I am aware, it does not make Lp(a) (Pauling and Rath appear to have made a mistake here), it doesn't make ascorbate and it doesn't eat much fruit either. OK, guinea pigs never ever, ever eat fruit in the wild. They live in the high Andes where the year round fruit availability is probably as good as it is in Antarctica.

They eat grass. And guinea pig pooh. That puts ascorbate intake down at very low, but not zero, levels. Like rabbits, they actually live primarily on volatiile fatty acids produced by hind gut fermentaion of cellulose. The minute you feed them cr@pinabag they will immediately become either hyperglycaemic, hyperinsulinaemic or both compared to living on short chain saturated fats. That's not exactly how they are designed to run and their ascorbate requirement rockets. BTW they become obese too. Feed them rabbit cr@pinabag and they die. It's a bit like feeding sailors or tarsiers on dried salt beef and ships biscuits, but probably doesn't taste as good. Doesn't have the weevils either.

Then there is that fruit bat which has also lost its ability to synthesise ascorbate because, well, it eats fruit. This sounds quite convincing as a reason for losing ascorbate until you realise that it seems as if all bats have lost their ability to synthesise ascorbate. Most ascorbate-less bats are pure carnivores. Insects are where it's at. Insects don't synthesise or supply much ascorbate. Fruitbats are the oddballs among bats and it's probably not why they don't make ascorbate. That's just a bat-thing.

Now, I hate to mention hedgehogs again but, here I go, we all know that they not only do make ascorbate, but they also make an Lp(a)-like substance too. As an aside to pointing out that this doesn't go along with Lp(a) as a surrogate for ascorbate, I'd just like to mention kringles III and IV to clear up a minor point:

Humans repeat kringle IV from plasminogen in their Lp(a). Hedgehogs repeat kringle III. How convergent is that? Not very. But in hedgehogs it is kringle III of plasminogen which binds to fibrin, in humans it is kringle IV. So hedgehog Lp(a) seems to be markedly convergent with human Lp(a). This makes me happy as it suggests Lp(a) is not some idiotic mistake only made by humans and their kin. It's worth evolving by non related species. That just leaves the big unknown of whether hedgehogs are also using Lp(a) to deliver oxidised lipids to where they are most needed (guess yes!).... And what we are both doing with those lipids. And their kringles in addition to binding to fibrin.

Anyway, the simple concept that humans and guinea pigs make Lp(a) as an ascorbate substitute seems to be so full of holes that I can't see it. Sigh.

Mega dosing on C in the attempt to put the clock back 40 million years and so reduce Lp(a) and heart disease does not hold water. Whether there is a pharmacological benefit of mega dosing ascorbate, along the lines of using niacin to mimic beta hydroxyburytate, seems possible. But if this is the case it's an accidental benefit derived from faulty logic...

Oh, a last comment on bats. None of them make ascorbate. Some, but not all, are VERY long lifespan species. Not in the league of Naked Mole rats of course, but some certainly live far longer than the same sized mouse.

Never mind mega dosing on ascorbate, that's without making any ascorbate and living on insects.

Peter

15 comments:

Jay said...

I understand that members of the cat family in the wild avoid carrion and eat almost exclusively their freshly killed prey, especially the stomach and its contents, the liver, blood and other ascorbate rich parts.
If a pure carnivore could do without making their own ascorbate, I would expect the felines to be among them.

Pål Jåbekk said...

Doesn't the simple fact that us haplorrini have lost the ability to synthesize ascorbate, suggest that this is not a vital function? If this mutation way back in time had in any way been detrimental, or somehow negatively affected fertility we wouldn't be her today not producing ascorbate. Cant see how this ads up with good old Linus' advice to eat grams of vit C.

Nostril Damus said...

What do you boffins make of Vitamin C supplementation ?

Do I get enough of the stuff eating a moderate protein / high fat / low carb diet ?

Or should I pop it alongside my D3 ? Or do I need to give you more info before you can answer this ?

All the best
J

Ned Kock said...

Very interesting post Peter! I guess there is a lot more we can learn from bat physiology.

Peter said...

Hi J,

Yes, you would have thought so, but evolution is random and Jukes felt that ascorbate loss was neutral. It may be slightly disadvantageous as many primates use uric acid by loss of uricase, possibly as a replacement. It gets complex. Obviously cats have a uricase, but their daily ascorbate production is cited by Irwin Stone as low. I'll bet it goes up on grain based cr@pinabag!

Pål,

Scurvy in humans is undoubtedly associated with diets based on salt pork and grains. Whatever criticisms might be levelled at relying on Stephansson, he did do a year on meat only... And then there was Shackleton too, no scurvy if you are dependent on eating penguins!

Nostril, I don't megadose. I make sure I get a few milligrams now and then from food sources but I personally feel better without the 10g/d I tried for a year. I just got more colds but didn't feel as unwell when I had them! I'll keep my free radicals.

Ned, it was the going back 40MY that I find hard. We can adapt to hypoascorbataemia, especially if we are evolved from something that gave us the tarsier!

Peter

Greg said...

Thanks for that. I just happened across Matthias Rath and Linus Pauling's original theory last night and was intrigued.

http://www.pnas.org/content/87/16/6204.full.pdf

Peter said...

Hi Greg,

I think Lp(a) could be a sort of add on to healing but not a replacement for ascorbate. Uric acid is similarly an add on after the loss of ascorbate. There may well be other tweaks to help repair, but simple mega dose C does not convince me. And I was initially very comfortable with the concept...

Peter

Aaron said...

High levels of uric acid are not desirable either. I'm interested in the fact that vitamin c in amounts as low as 200mg seem to lower uric acid a bit. I'm sure we don't need more vitamin c than we get from food if we include vegetables. No way I'm going 100% carnivore.

Ken said...

Pauling gave the water soluble vitamin C content of 110 raw natural plant foods in an amount giving 2500 Kcals of food energy. The average for 110 foods was 2300mg while peppers gave 14200 -16500mg, salmon would be the peppers. Even the lowest group of foods gave 600- 1200mg. It was known at the time that at a small dailly intake of vitamin C - up to about 150mg - the concentration in the blood is nearly proportional to the intake. 5mg per litre for an intake of 50 mg, 10mg for an intake of 50mg, 10mg per litre for an intake of 1000mg Above an intake of 150mg a day the concentration in the blood increases much less with increasing intake , reaching about 30mg per litre for an intake of 10 GRAMS a day.


(Compare Vieth's data on D, the dose response is significant.
Quote:
"Two studies showed that in response to a given set of ultraviolet light treatment sessions, the absolute rise in serum 25(OH)D concentration was inversely related to the basal 25(OH)D concentration. In the study by Mawer et al (34), the increase in 25(OH)D in subjects with initial 25(OH)D concentrations <25 nmol/L was double the increase seen in subjects with initial concentrations >50 nmol/L. Snell et al (27) showed that in subjects with initial 25(OH)D concentrations <10 nmol/L, ultraviolet treatments increased 25(OH)D by 30 nmol/L, but in those with initial 25(OH)D concentrations approaching 50 nmol/L, the increase was negligible."(Vieth 99))

Anyway back to C another interesting animal Dalmations



POINTING out the structural similarity between uric acid and the stimulant purines caffeine and theophylline, Orowan1 first proposed that the emergence of intelligence in the primate line might arise from a single evolutionary event, the loss of the enzyme uricase, with the result that uric acid became the end product of purine metabolism. The only non-primate mammalian strain whose final purine metabolite is uric acid is the Dalmatian dog".

Dalmations were supposed to be keeping strange dogs away from the horses so they had to have stamina to keep up.



Uric acid
"The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid."

Why Apples are Healthful
"Based on our data, it is conceivable that the presumed antioxidant role of flavonoids in plasma after fruit consumption reported in numerous previous studies may have been confounded by uric acid. The potential, specific beneficial effect of these transient increases in uric acid after fruit consumption remains uncertain but deserves further investigation. On the other hand, we continue to explore the mechanism by which low concentrations of flavonoids and their metabolites may exert health benefits. Clearly, our apple study has demonstrated that the consumption of fruit may have a greater impact on human health and potential health benefits for more reasons than we expected."

donny said...

http://www.ajcn.org/cgi/reprint/27/3/310.pdf

"Low ascorbate status in the Masai of Kenya"

I'm not sure what this study tells us about the theory that carbohydrate increases vitamin c requirements; there's a lot of fermentation going on, for one. But anyways, it's a population with low blood abscorbate and low intake, but no signs of scurvy. It's not a very big study, but it's interesting. Is walking a scurvy-preventative?

Bernstein claims that high dose vitamin c gives deceptively low Hba1c (did I get that right? glycated hemoglobin, anyways) that does not correlate properly to actual blood glucose control.

I wonder how gut bacteria feel about twenty grams or so of vitamin c? Could you get some of the benefits of Orlistat?

al said...

I fail to see how the tarsier or any single evolutionary ancestor of humans has the last word on appropriate levels of vitamin c consumption in humans.

Anyway, Pauling's argument in favor of augmented vitamin c intake did not rest solely on the role, however putative, of Lp(a).

Peter said...

That's fine al, we each have different views of the world.

Peter

Peter said...

Cracking link donny, Ta

Peter

Craig said...

I've read that meat contains hydroxylysine and hydroxyproline, which vitamin C is used to make in combination with lysine and proline. If that's true, it would reduce the requirement for ascorbate.

Craig said...

I've read that meat is a source of hydroxylysine and hydroxyproline. If this is true, it would reduce the requirement for Vitamin C as we wouldn't need it to make these connective tissues in-body.