Bilirubin - The overlooked key to caloric...
Jason Williams
14 Jun 2010
Here's brief rundown of some of the major evidence suggestive of the possible role of bilirubin in caloric restrictionand intermittent fasting:
- serum bilirubin levels are significantly elevated(doubled to tripled) in humans and other mammals(monkeys, horses, rats) during fasting and caloric restriction. (REF. 1, 2)
- bilirubin is "a potent antioxidant" which has "major physiological cytoprotectant qualities." (REF. 3)
- serum bilirubin levels in humans are inversely correlated with rheumatoid arthritis, psoriatic arthritis, lupus erythematosus, atherosclerosis, cardiovascular disease, cardiovascular mortality, coronary artery disease, myocardial infarction, myocardial infarction mortality, cancer mortality and all-cause mortality. (REF. 4, 5, 6, 7)
- bilirubin is "a powerful immunomodulatory agent" which has been shown to suppress experimental autoimmune encephalomyelitis in mice, and may more generally "protect mammals against autoimmune diseases." (REF. 8)
- artificially increasing serum bilirubin concentrations has recently been proposed as a method to prevent oxidative and inflammatory diseases. (REF. 9)
- approximately five percent of the population have a harmless genetic mutation called Gilbert's Syndrome which leads to lifelong abnormally high levels of bilirubin(comparable to every-other-day intermittent fasting levels.) These people provide a very large sample for testing the longterm effects of elevated bilirubin concentrations in humans. A large scale study showed that those with Gilbert's Syndrome had a six-fold reduction in risk for ischemic heart disease. (REF. 10)
I think that there is now strong experimental and theoretical support for the claim that bilirubin has a host of beneficial effects. Beneficial effects which seem to overlap with and replicate the benefits seen in caloric restriction and intermittent fasting. Further, there also appears to be no question that, at least in the short term, caloric reductions(including intermittent fasting) significantly increase bilirubin levels in humans and other mammals.
What has really surprised me in my review of the current and past research in these areas, is that there so far seems to have been no attention paid, and no link made, betweem calorie restriction, intermittent fasting and bilirubin levels. I have no formal training in the relevant areas of study, but eveything I have read thus far strongly suggests to me that there probably exists some links here. I'm hoping that by posting my thoughts and the results of my reviews of research, I can further the awareness and investigation into possible links. I would be most happy and interested in discussing these subjects and ideas further.
REFERENCES
1. The effect of fasting on total serum bilirubin concentrations. B H Meyer, H E Scholtz, R Schall, F O Müller, H K Hundt, and J S Maree
http://www.ncbi.nlm....les/PMC1364954/
2. Inactivation of Digestive Proteases by Deconjugated Bilirubin and the Physiological Significance of Fasting Hyperbilirubinemia. Xiaofa Qin
http://www.gastrores...ewArticle/59/55
3. Biliverdin reductase: A major physiologic cytoprotectant. David E. Barañano,* Mahil Rao,* Christopher D. Ferris,† and Solomon H. Snyder*‡§¶
http://www.pnas.org/...9/25/16093.full
4. Bilirubin tests as risk predictors for cancer mortality, rheumatoid arthritis, Gilbert's syndrome and all-cause mortality. Schwertner, Harvey A;Fischer, Jr., Joseph R.
http://patft.uspto.g.....ry=PN/6720189
5. Combined cholesterol and bilirubin tests as risk predictors for coronary artery disease. Schwertner; Harvey A., Fischer, Jr., Joseph R.
http://patft.uspto.g.....ry=PN/6869802
6. Bilirubin tests as risk predictors for systemic lupus erythematosus and psoriatic arthritis. Schwertner; Harvey A.
http://patft.uspto.g.....ry=PN/6905880
7. Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle. Thomas W. Sedlak, MD, PhD*, Solomon H. Snyder, MD*,{ddagger}
http://pediatrics.aa...full/113/6/1776
8. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis. Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M.
http://www.jimmunol....ract/181/3/1887
9. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Schwertner HA, Vítek L.
http://www.atheroscl...0053-1/abstract
10. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P.
http://www.ncbi.nlm....pubmed/11849670
health_nutty
14 Jun 2010
dehbleh
14 Jun 2010
Being chronically tired with persistent jaundice is not life extending!
openeyes
14 Jun 2010
Edited by openeyes, 14 June 2010 - 05:30 AM.
Jason Williams
14 Jun 2010
I have gilbert's syndrome and it ain't no CR mimic.
Being chronically tired with persistent jaundice is not life extending!
What are your measured bilirubin levels?
There is definitely some ongoing debate, but as far as I'm aware, the conventional medical stance is that Gilbert's Syndrome is asymptomatic. Some studies have been done on this, for instance:
http://www.ncbi.nlm..../pubmed/3264448
http://www.ncbi.nlm....ov/pubmed/67389
How do you know that your chronic tiredness is related to having Gilbert's? Persistent jaundice, is, as far as I know, more often associated with higher levels of bilirubin such as are found in Crigler-Najjar Syndrome, not the more mild increases seen in Gilbert's. There are some treatments available to potentially reduce bilirubin levels, like phenobarbital, maybe you could investigate that?
JLL
14 Jun 2010
CobaltThoriumG
14 Jun 2010
Some posts here also: 141, 145, 149.
This interests me as I have Gilbert's Syndrome. I only learned of it in 2008. I'm asymptomatic for the most part but sometimes have fatigue. I attribute that to not enough sleep, though, the obvious cause. My bilirubin is usually 2-3 times high normal. I also do mild intermittent fasting of at least 16 hours/day. I'm having bloodwork soon and am interested to see how bilirubin has changed. I only recently started the IF. I'll have the blood drawn toward then end of a fasting window. I would think it would be up some.
Given bilirubin's potent antioxidant activity, I have cut back on supplemental antioxidants and use only a small amount of vitamin C, 500 mg, four days/week. Whether Gilbert's results in life extension or not, I can't remember any specific study on this, it certainly seems to have a lot of other favorable health effects as noted above. And I think in time it will be considered among the so-called longevity genes.
kismet
14 Jun 2010
Hypotheses at this stage to be exact.There are lots of theories why CR works...
Take care not to mix quality of life with the retardation of aging.I have gilbert's syndrome and it ain't no CR mimic.
Being chronically tired with persistent jaundice is not life extending!
That being said I think your hypothesis is interesting (not necessarily right). Very good first (second?) post. However, I would like you to refine it a little: there is a considerable gap in your data. Refs 1,2 do not show that CR leads to or is correlated with hyperbilirubinemia AFAICS from the abstracts. Fasting apparently is, but CR does not have to involve fasting and the benefit of CR-IF over CR is probably non-existent in experimental models (and IF non-CR does not seem to replicate CR much at all). E.g. and as per the abstract (ref 1): "A clinically relevant rise in TSB took place after 12 h into the fasting period"
Jason Williams
15 Jun 2010
That being said I think your hypothesis is interesting (not necessarily right). Very good first (second?) post.
Thankyou. I agree that my hypothesis may not be right. The title I tried to give to this thread was "Bilirubin - The overlooked key to caloric restriction and intermittent fasting benefits?" - emphasis on the question mark. But the forum cut off the last part of the title, making it appear more like I was making a statement, instead of suggesting a tentative possibility, which was my intent.
However, I would like you to refine it a little: there is a considerable gap in your data. Refs 1,2 do not show that CR leads to or is correlated with hyperbilirubinemia AFAICS from the abstracts. Fasting apparently is, but CR does not have to involve fasting and the benefit of CR-IF over CR is probably non-existent in experimental models (and IF non-CR does not seem to replicate CR much at all). E.g. and as per the abstract (ref 1): "A clinically relevant rise in TSB took place after 12 h into the fasting period"
Yes, you're right. Good catch! I intentionally kept my initial post and data brief. There is so much potentially relevant data and studies out there, and I'm still trawling through it. I have, however, come across several studies that do indeed show that reduced calorie diets still raise bilirubin levels. The following study shows that complete fasting is not necessary to elevate bilirubin levels in humans:
http://www.ncbi.nlm....les/PMC1586818/
Diagnosis of Gilbert's Syndrome: Role of Reduced Caloric Intake Test. D. Owens and S. Sherlock
Subjects were tested with a 3 day duration 400 calorie/day diet, which resulted in a 60% mean increase in bilirubin levels in normal subjects and a 110% mean increase of bilirubin in Gilbert's Syndrome subjects.
So far, all the other data I have reviewed involves relatively short duration(less than a week) caloric restriction and fasting regimes. One of the many things I'm searching for now is data on the relationship between longer-term caloric restriction and/or intermittent fasting and bilirubin levels in human and/or animals.
Jason Williams
15 Jun 2010
Does bilirubin increase lifespan in mammals?
There are claims that it lowers risk of all-cause mortality in humans (ref.3), which may not be quite the same thing.
Does fasting increase bilirubin in, say, rats and mice? Because intermittent fasting does not seem to extend lifespan in them.
I have yet to see fasting bilirubin data on mice, but it could be out there. As I noted in my first post, rats do show elevated levels of bilirubin after fasting(ref.2). I don't currently have detailed data for the rats though.
If, however, the bilirubin elevation trend in rats is similar to the more detailed data I have seen in humans(ref.1), then there is a chance that fasts that are greater than 24 hours in duration may confer more noticeable advantages. Greater duration fasts may raise bilirubin levels in normal subjects to a degree that more closely mimics the baseline bilirubin levels(and correlated effects) seen in Gilberts Syndrome.
Have >24 hour duration fasting periods been tested with longterm I.F. in animals?
REFERENCES
1. The effect of fasting on total serum bilirubin concentrations. B H Meyer, H E Scholtz, R Schall, F O Müller, H K Hundt, and J S Maree
http://www.ncbi.nlm....les/PMC1364954/
2. Inactivation of Digestive Proteases by Deconjugated Bilirubin and the Physiological Significance of Fasting Hyperbilirubinemia. Xiaofa Qin
http://www.gastrores...ewArticle/59/55
3. Bilirubin tests as risk predictors for cancer mortality, rheumatoid arthritis, Gilbert's syndrome and all-cause mortality. Schwertner, Harvey A;Fischer, Jr., Joseph R.
http://patft.uspto.g.....ry=PN/6720189
Edited by Jason Williams, 15 June 2010 - 03:06 AM.
Matt
15 Jun 2010
on the day i had my tests done i had developed gastritis on that day, hence why some of my markers are unlike CR =/
http://www.matthewla...com/results.htm
Edited by Matt, 15 June 2010 - 08:40 PM.
Skötkonung
16 Jun 2010
For Asians - Gilbert's syndrome:
http://www.snpedia.c...x.php/Rs4148323
Overview:
http://www.snpedia.c...bert's_syndrome
Indicative of high bilirubin:
http://www.snpedia.c....php/Rs34815109
You can check Rs28934877 © or Rs4148323 (A), and Rs4124874 (G). I'm AA, GG, and GT and don't have the condition. Other than that here are some links:
http://www.snpedia.c...bert's_syndrome
http://www.nature.co...l/6500221a.html
http://www.pharmgkb....ne#tabview=tab2
For Rs4124874, the UGT1A1:-3279T>G variant linked to Gilbert's syndrome among the Japanese.
This SNP is related to a gene that metabolizes estrogen and detoxifies carcinogens. For Africans, GG is the most common genotype (GG), but for Europeans is about 17%, Asians 9%. For Africans it's been linked to breast cancer, the risky allele for them is the T.
http://cbcs.med.unc......erase 1A1.pdf report abuse
Edited by Skötkonung, 16 June 2010 - 11:55 PM.
Jason Williams
18 Jun 2010
Prior thread on topic.
http://www.imminst.o...o...8013&st=140
Thanks for those links.
This interests me as I have Gilbert's Syndrome. I only learned of it in 2008. I'm asymptomatic for the most part but sometimes have fatigue. I attribute that to not enough sleep, though, the obvious cause. My bilirubin is usually 2-3 times high normal. I also do mild intermittent fasting of at least 16 hours/day. I'm having bloodwork soon and am interested to see how bilirubin has changed. I only recently started the IF. I'll have the blood drawn toward then end of a fasting window. I would think it would be up some.
After 16 hours of fasting, the following study showed a mean increase in bilirubin levels of approximately 35% in Gilbert's Syndrome subjects:
The effect of fasting on total serum bilirubin concentrations. B H Meyer, H E Scholtz, R Schall, F O Müller, H K Hundt, and J S Maree
Some other relevant extracts from that study, with my comments in brackets:
"Minimum TSB (total serum bilirubin) concentrations were obtained 4 h after supper..."
(I believe "supper" here is probably synonymous with any nutritionally balanced meal.)
"A clinically relevant rise in TSB took place after 12 h into the fasting period..."
(This is when the elevations in bilirubin start to become noticeable.)
"TSB concentrations at 24h(into the fast) were about 2.5 time higher after a fast compared with non fasting treatment."
(The difference between a 16 hour fast and a 24 hour fast on bilirubin levels is large: ~35% vs ~250% increase. This is due to the fact that there is a close to linear increase in bilirubin levels during fasting beyond the 12 hour mark. The increase after 12 hours fasting is approximately 2.5 micromol/l per hour in Gilbert's subjects.)
-
Another interesting study which may have relevance is: Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome. Gollan JL, Bateman C, Billing BH.
The results here showed that the elevated levels of bilirubin seen in fasting can be maintained with a normal calorie intake, so long as those calories are obtained from glucose with lipids eliminated from the diet(or at least severely reduced.) They suggest that there is evidence that a diet consisting entirely of carbohydrates(however glucose is the only one tested) may maintain hyperbilirubinaemia for those with Gilbert's Syndrome.
Edited by Jason Williams, 18 June 2010 - 02:12 AM.
Jason Williams
18 Jun 2010
My bilirubin went to high normal after CR =) but then went back down =/
on the day i had my tests done i had developed gastritis on that day, hence why some of my markers are unlike CR =/
http://www.matthewla...com/results.htm
Did you follow any specific pattern as regards meal-timing and blood collection times? To get more comparable blood tests results, controlling for meal timing may be necessary. For instance, four hours after a meal bilirubin could be at its lowest, but soon after breakfast(following the overnight "fast" that occurs during sleeping hours) bilirubin might be at its highest point.
Jason Williams
22 Jun 2010
"The effects of long-term caloric restriction on the hepatic phase II drug metabolizing enzymes were investigated in the male Fischer 344 rat. Rats that had been restricted to 60% of their pair-fed control consumption from 14 weeks post-partum exhibited altered conjugating enzyme activities at 22 months. Caloric restriction significantly reduced the age-related decrease in glutathione-S-transferase activity towards 1,2-dichloro-4-nitrobenzene, but did not significantly alter the age-related changes in UDP-glucuronyltransferase or sulfotransferase activities towards hydroxysteroids. Caloric restriction appeared to increase hepatic microsomal UDP-glucuronyltransferase activity toward bilirubin and gamma-glutamyltranspeptidase activities. These observations suggest that caloric restriction has multiple effects on the hepatic phase II drug metabolizing enzymes in the rat. Such effects may alter hepatic metabolism and activation or detoxification of drugs and carcinogens."
Effects of aging and caloric restriction on hepatic drug metabolizing enzymes in the Fischer 344 rat. II: Effects on conjugating enzymes.
Leakey JA, Cunny HC, Bazare J Jr, Webb PJ, Lipscomb JC, Slikker W Jr, Feuers RJ, Duffy PH, Hart RW.
Edited by Jason Williams, 22 June 2010 - 02:05 AM.
JLL
22 Jun 2010
I have yet to see fasting bilirubin data on mice, but it could be out there. As I noted in my first post, rats do show elevated levels of bilirubin after fasting(ref.2). I don't currently have detailed data for the rats though.
If, however, the bilirubin elevation trend in rats is similar to the more detailed data I have seen in humans(ref.1), then there is a chance that fasts that are greater than 24 hours in duration may confer more noticeable advantages. Greater duration fasts may raise bilirubin levels in normal subjects to a degree that more closely mimics the baseline bilirubin levels(and correlated effects) seen in Gilberts Syndrome.
Have >24 hour duration fasting periods been tested with longterm I.F. in animals?
If they have, I'm not aware of them. I don't think there is lifespan data in mammals for >24 hour IF, at least.
Is CR more effective in increasing bilirubin in the long term than 24 hour IF? If not, and if bilirubin is the key to longevity, then animals on IF should see extended lifespans -- but they don't. If yes, however, then a closer look at bilirubin and different fasting scenarios is in order.
Jason Williams
23 Jun 2010
Is CR more effective in increasing bilirubin in the long term than 24 hour IF? If not, and if bilirubin is the key to longevity, then animals on IF should see extended lifespans -- but they don't. If yes, however, then a closer look at bilirubin and different fasting scenarios is in order.
I don't know the answers to these questions yet. I'm still searching through and reviewing studies to try to find the answers. I will post relevant evidence if and when I find it.
Of all the studies and data I have reviewed thus far, there are very few cases of bilirubin measurements being taken in conjunction with longterm CR or IF feeding protocols. So, there's a general lack of data on this subject, but there may still be relevant data that I have yet to find.
I currently have no data on long term IF and bilirubin levels. I have data on single episode fasting and bilirubin, and I believe there is considerably more data on single episodes fasts out there which I am yet to review. I may have to try to extrapolate from these single episode fasts.
The best data I currently have on long term CR and bilirubin is the study that I quoted in my previous post. But, unfortunately, that only dealt with bilirubin levels in liver assays, which whilst very suggestive, and strengthening the case for bilirubin in general, are not ideal. Serum bilirubin levels are probably what I need to make the best comparisons between CR and IF regarding bilirubin levels.
Jason Williams
07 Jul 2010
This interests me as I have Gilbert's Syndrome. I only learned of it in 2008. I'm asymptomatic for the most part but sometimes have fatigue. I attribute that to not enough sleep, though, the obvious cause. My bilirubin is usually 2-3 times high normal. I also do mild intermittent fasting of at least 16 hours/day.
I'd urge caution with this. You may be at a particularly increased risk of gallstone formation - both Gilbert's Syndrome and fasting have been linked to gallstones.
Gilbert's syndrome as a predisposing factor for idiopathic cholelithiasis in children.
Gallstone disease: Primary and secondary prevention"
leha
26 Aug 2010
So do you think there could be some connection between the CR/bilirubin effect ala changes in liver metabolism and the cytochrome P450-altering effects of Resveratrol?
JohnD60
15 Nov 2010
Billirubin has been recognized as an extremely powerful antioxident, and I believe that I do obtain some protective benefit from my chronically high levels of bilirubin. But I don't believe that that antioxidant benefit is the same as the health benefit I get from intermittent fasting. (and I too experience a jaundice problem on high bilirubin days).
It is no surprising that bilirubin increases after and during fasting. The primary health benefit of fasting is that it up regulates autophagy (if you doubt this read the September issue of Nature: Cell Biology). Bilirubin is merely the product of Heme destruction, which would of course occur during a fast.
I found the study you referenced fascinating (The effect of fasting on total serum bilirubin concentrations). Making some assumptions, one could use Bilirubin levels as a proxy to measure total effective autophagy. Making those assumptions, the study helped validate my hypothesis that there is a world of difference in total autophagy between a 16 hour fast and a 24 hour fast.
Jason Williams
17 Nov 2010
So do you think there could be some connection between the CR/bilirubin effect ala changes in liver metabolism and the cytochrome P450-altering effects of Resveratrol?
I have no idea, I haven't looked into that area.
Jason Williams
17 Nov 2010
I have Gilbert's Syndrome (range 1.0-2.4 mg/dL, which is slightly higher than the average Gilbert Syndrome person, but not freakishly high) and I fast two days a month.
My bilirubin serum levels have consistently measured around 3.0mg/dL, but I've never noticed any jaundice.
Billirubin has been recognized as an extremely powerful antioxident, and I believe that I do obtain some protective benefit from my chronically high levels of bilirubin.
According to one researcher "So potent an anti-oxidant is bilirubin that it displaces glutathione, the molecule believed for 80 years to be the most important cellular anti-oxidant."(1)
It is no surprising that bilirubin increases after and during fasting. The primary health benefit of fasting is that it up regulates autophagy (if you doubt this read the September issue of Nature: Cell Biology).
I've been reading through a lot papers on autophagy; a fascinating subject and it looks like it might be intimately connected with caloric restriction and anti-ageing mechanisms more generally.
There's another very interesting link I've found between autophagy, bilirubin and Gilbert's Syndrome.
An anti-lipolytic drug(nicotinic acid) can be be used to quickly induce increased levels of bilirubin and this response has been proposed as an alternate method to test for Gilbert's Syndrome(2,6,7,8). In addition, anti-lipolytic drugs have also been used to intentionally upregulate autophagy. Some researchers have even proposed that anti-lipolytic agents might be useful as pharmacological anti-ageing interventions(4,5.)
There's a nice summary of some of the research here: http://morelife.org/...s/acipimox.html
Making those assumptions, the study helped validate my hypothesis that there is a world of difference in total autophagy between a 16 hour fast and a 24 hour fast.
Keep in mind that the bilirubin response to fasting can be variable between individuals. I've seen studies(which I can't find right now) that suggest there may be two quite different populations amongst Gilbert's Syndrome subjects, one of which show very blunted bilirubin increases in response to fasting. You might want to consider having your levels tested before and during fasting to see how you personally respond, which might be useful in helping to tune the length of the fast based on your own response.
Also, if you haven't already, I suggest you read my post about gallstones above, as Gilbert's Syndrome might put you at increased risk of developing them with fasting possibly increasing the risk further.
(1) Little Yellow Molecule Comes Up Big: Hopkins Scientists Solve Paradox Of Bilirubin, Identify It As Cells' Major Antioxidant
(2) Reduced caloric intake and nicontinic acid provocation tests in the diagnosis of Gilbert's syndrome. A R Davidson, A Rojas-Bueno, R P Thompson, and R Williams. PMCID: PMC1673423
(3) Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Kang HT, Hwang ES. PMID: 19473119
(4) Anti-aging effects of anti-lipolytic drugs. Donati A, Cavallini G, Carresi C, Gori Z, Parentini I, Bergamini E. PMID: 15236765
(5) The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically. Bergamini E, Cavallini G, Donati A, Gori Z. PMID: 12888255
(6) Nicotinic acid test in the diagnosis of Gilbert's syndrome: correlation with bilirubin clearance. W Röllinghoff, G Paumgartner, and R Preisig
(7) Effect of nicotinic acid administration on serum levels of bilirubin and iron in patients with porphyria cutanea tarda. Gentile S, Ayala F, Orlando C, Santoianni P, Budillon G. PMID: 3201096
(8) Dose dependence of nicotinic acid-induced hyperbilirubinemia and its dissociation from hemolysis in Gilbert's syndrome. Gentile S, Tiribelli C, Persico M, Bronzino P, Marmo R, Orzes N, Orlando C, Rubba P, Coltorti M. PMID: 3944496
Edited by Jason Williams, 17 November 2010 - 02:45 AM.
JohnD60
17 Nov 2010
I could not find the Gallstone post you made reference to.
Some questions related to your bilirubin levels:
1. Do you drink much alcohol?
2. Do you eat a lot of green foods?
3. Do you take Resveratrol?
rwac
08 Apr 2011
albedo
16 Oct 2011
It is an area i did not study and any comment is appreciated. These are my last results (hinting to Gilbert's?)
Total bilirubin (TBIL) 18 mcmol/l (ref 3.4-20.5) or 1.05 mg/dl (ref 0.2-1.2) (conversion 17.1)
Direct bilirubin (conj.) 3.7 mcmol/l (ref <8.6)
Indirect bilirubin (free) 14.3 mcmol/l (ref <13)
Edited by albedo, 16 October 2011 - 10:51 AM.


