I think I may have stumbled across an important, but currently largely ignored factor, which could help to explain many of the beneficial effects of caloric restriction and intermittent fasting. That key factor is bilirubin.
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