The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 5 No.
5 • October 2002
"I have yet to see any problem, however complicated, which,
when you looked at it in the right way, did not become still more complicated."
- Poul Anderson
New Scientist, September 25, 1969
"A committee is a cul-de-sac down which ideas are lured and
then quietly strangled."
- Sir Bennett Cocks
New Scientist, 1973
"In a democracy, it's hard to get turkeys to vote for
- John Lawton, chief executive of Britain's Environmental Research Council
Nature 418:813-4 (2002)
He was complaining about how hard it is to get voters to
spend huge sums of money now for alleged environmental benefits that will not be
apparent for decades (if ever). Well, Mr. Lawton, you reveal (perhaps
unwittingly) a rather low opinion of taxpayers by calling them "turkeys,"
but they may not be stupid enough to vote for Christmas.
"According to a cable dispatch from Vienna, a newspaper for
nervous persons is projected, which will handle startling occurrences in such an
unexciting way as to permit sensitive individuals to keep au courant with the
times without the needless shock liable to be produced by usual chronicles."
- From the Journal of the American Medical Association
October 25, 1902
Sounds good, but on the basis of the popularity of
newspapers and TV news, most people prefer their news to be startling and even
frightening. Years ago, we hypothesized that people have what we call a
"conservation of paranoia," meaning that people have an innate urge to
search for and focus on dangers (we wouldn't be here if we didn't) and that
when a major danger, such as war, suddenly vanishes, there is a swift shift of
people's focus to some other alleged danger.
Preventing Cancer, Atherosclerosis, and Obesity Through
Angiogenesis, the growth of new blood vessels, is known to
be a major basis for the growth of cancers, and considerable research, including
human clinical trials, is being done to discover effective antiangiogenic
agents. A 1998 paper reported that the hormone leptin, released largely by
adipocytes (fat cells), acts as an angiogenic factor. Leptin is known to affect
fat mass by regulating food intake and energy expenditure; it modulates lipid
metabolism, hematopoiesis, pancreatic beta-cell function (these are the cells
that release insulin), ovarian function, thermogenesis, and wound repair.
The authors of the 1998 paper showed that the leptin
receptor (OB-Rb) that is expressed primarily in the hypothalamus is also
expressed in human vasculature and in primary cultures of human endothelial
cells. In vitro and in vivo assays revealed that leptin has angiogenic activity.
They reported that leptin caused cultured endothelial cells to aggregate and
form tubes that resemble early-stage blood vessels. Leptin also caused new blood
vessels to form in the corneas of rats. The authors proposed that leptin
stimulates an angiogenic response that maintains an appropriate balance between
blood supply and fat depot size.
In an interview (Reuters, Sept. 11, 1998), the lead author,
Dr. M. Rocio Sierra-Honigmann, suggested that "Tumors make angiogenic factors,
so it's not at all remote to think that they may be making leptin." Although
the second article in reference 1 mentioned that Judah Folkman's team "is
checking to see if any tumors make leptin," we haven't seen anything
published on this.
In a 1999 paper, researchers report that human
umbilical-vein endothelial cells, which express leptin receptors, are subject to
oxidative stress in response to leptin. They showed that reactive oxygen species
act as second messengers to carry leptin-induced signals in endothelial cells.
Increased JNK activity and AP-1 DNA binding in the cells were sensitive to
antioxidant treatment with N-acetylcysteine. Leptin-increased NF-kappaB DNA
binding activity was also prevented in nuclear extracts from cells pretreated
Moreover, leptin led to an upregulation of MCP-1. MCP-1,
the authors explained, belongs to the class of chemotactic cytokines shown to
elicit the direct migration of monocytes to inflammatory sites and is increased
in response to mitogenic signals (which includes oxidative stress) in a variety
of cells, including smooth muscle cells and endothelial cells. The MCP-1
upregulation was suppressed in the presence of antioxidants. The authors
speculate that the actions of leptin that lead to MCP-1 expression in
endothelial cells may play a key role in the inflammatory process linked to
Another paper reported that leptin regulates
proinflammatory immune responses. The study indicated that leptin enhances the
synthesis of proinflammatory cytokines, such as tumor necrosis factor-alpha and
IL-6, by cultured macrophages when the cells are treated with LPS, a bacterial
lipopolysaccharide. Inflammation is associated with cellular proliferation, such
as occurs in cardiovascular disease (smooth muscle cell proliferation in
plaques) and cancer.
A recent paper proposes that adipose tissue mass is
regulated by vasculature. This tissue is highly vascularized and depends upon
growth of blood vessels in order to increase in mass. The authors hypothesized
that "adipose tissue growth is angiogenesis-dependent and, therefore, may be
inhibited by antiangiogenesis agents."
The researchers used a fat (ob/ob) mouse model. This animal
lacks the hormone leptin (which regulates appetite and metabolism), overeats,
expends less energy, and rapidly accumulates adipose tissue, becoming morbidly
obese. Fat loss in these mice can be induced by treating them with leptin.
However, rather than using leptin, the researchers treated the ob/ob mice with
various angiogenesis inhibitors, such as angiostatin, endostatin, TNP-470,
Bay-12-9566, and thalidomide. The body and adipose tissue weights of treated
mice were significantly less than those of controls. In fact, loss of adipose
tissue mass was similar to that resulting from leptin treatment. (This supports
the hypothesis that leptin may act on adipose tissue mass largely via its
angiogenic effects.) There was decreased endothelial cell proliferation and
increased apoptosis of adipose tissue cells compared to controls. These results
suggest that fat tissue is angiogenesis-dependent, as the researchers predicted.
This is a very exciting finding. Although the specific
angiogenesis inhibitors used by the researchers in this study are either not
available or, in the case of thalidomide, may not be suitable for general use in
obese people (also, the antiangiogenic mechanism of thalidomide is not known),
there is a large number of nutritional antiangiogenic substances, as well as
NSAIDs (nonsteroidal anti-inflammatory drugs, including aspirin), which inhibit
various steps in the angiogenic pathway, such as COX-2 and VEGF (vascular
endothelial growth factor).
Angiogenesis has been reported to be inhibited by tea,
especially green tea, resveratrol (a natural compound found in red wine and
grapes), N-acetylcysteine, epigallocatechin-3-gallate (a constituent of
green tea), genistein, flavonoids, silymarin, selenium, phytoestrogens,
lignans, vitamins B3, D, and E, capsaicin, and curcumin, among others, and
possibly glucoraphanin (found in broccoli), arginine, and omega-3 fatty acids
Rather than a calorie-restricted diet that leaves you
hungry, we would suggest that you alter your diet to include more of these
antiangiogenic foods and food constituents. Although we do not know how well any
particular combination of antiangiogenic foods will perform in a weight-loss (to
be more precise, fat-loss) program, it is something that is well suited to safe
self-experimentation. Please let us know how your personal program works out.
- Sierra-Honigmann et al. Biological action of leptin as an angiogenic
factor. Science 281:1683-6 (1998). Barinaga. Leptin sparks blood vessel growth.
Science 281:1582 (1998).
- Bouloumie et al. Leptin induces oxidative stress in human endothelial
cells. FASEB J 13:1231-8 (1999). See also Maulik, Das. Redox signaling in
vascular angiogenesis. Free Rad Biol Med 33(8):1047-60 (2002).
- Loffreda et al. Leptin regulates proinflammatory immune responses. FASEB
J 12:57-65 (1998).
- Rupnick et al. Adipose tissue mass can be regulated through the
vasculature. Proc Natl Acad Sci 99(16):10730-5 (2002).
- Trends in Pharmacological Sciences 19 (June 1998).
- Cao, Cao. Angiogenesis inhibited by drinking tea. Nature 398:381 (1999).
- Brakenhielm et al. Suppression of angiogenesis, tumor growth, and wound
healing by resveratrol, a natural compound in red wine and grapes. FASEB J (June
- Tosetti et al. "Angioprevention": angiogenesis is a common and key
target for cancer chemopreventive agents. FASEB J 16:2-14 (2002).
- Losso. Preventing degenerative diseases by anti-angiogenic functional
foods. Food Technol 56(6):78-88 (2002). Many other food substances were
mentioned in this article.
- CAUTION: N-acetylcysteine can inhibit blood clotting by increasing
prothrombin time. If you are taking a prescription "blood thinner," do not
use N-acetylcysteine without having your physician check your prothrombin time.
Be cautious if you are taking low-dose aspirin, ginkgo, or both (and also,
possibly, fish oil), all of which inhibit blood clotting. Sandy was taking
ginkgo along with low-dose aspirin and fish oil and had to discontinue ginkgo
(and reduce her dose of fish oil) when she developed nosebleeds at night. Pol,
Lebray. N-acetylcysteine for paracetamol poisoning: effect on prothrombin.
Lancet 360:1115 (2002).