Ran into this while researching breast cancer.

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"J Nutr Health Aging. 1999;3(2):92-101. Related Articles, Links

Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction.

Kari FW, Dunn SE, French JE, Barrett JC.

Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

This paper focuses on the role of insulin-like growth factor-1 (IGF-1) and its associated regulatory apparatus as a key endocrine, autocrine, and paracrine signalling system involved in mediating the anti-carcinogenic activity of dietary restriction. Literature is reviewed showing that the inhibitory action of dietary restriction on carcinogenesis is global and pervasive--it is effective in several laboratory species, for a variety of tumor types, and for both spontaneous tumors and tumors caused by different types of tumor-inducing agents. Evidence is presented showing the IGF-1 pathway responds appropriately to nutritional interventions including diet restriction. Recent evidence points to an obligatory role for the IGF-1 receptor in the establishment and maintenance of the transformed phenotype and reveals that IGF-1 in concert with insulin-like binding protein 3 and p53 is involved in autocrine/paracrine growth signaling pathways as adaptive responses to environmental stimuli. Considered together these works show that the IGF-1 pathway is uniquely poised to influence cellular transformation leading to the malignant phenotype by modulating the balance of cellular proliferation and cell death (apoptosis) in precancerous and cancerous cells and by influencing metastasis of nascent tumors. We evaluated these hypotheses directly using animal models of mononuclear cell leukemia, bladder transitional cell carcinogenesis, and breast cancer. Our studies demonstrate that manipulation of IGF-1 level through dietary intervention influences tumor growth and metastasis. Upregulation of this pathway demonstrated that increased IGF-1 stimulates tumor proliferation, progression and metastasis. Conversely, downregulation of this pathway in vivo as a consequence of dietary restriction results in antitumorigenic activity. We found that the functional disruption of IGF-1R markedly influences breast cancer metastasis in nude mice by suppressing cellular adhesion, invasion, and metastasis of breast cancer cells to the lung, lymph nodes, and lymph vessels. Epidemiological observations and clinical oncology results support the involvement of IGF-1 in carcinogenesis and anticarcinogenesis. This leads to the hypothesis that factors such as IGF-1 which regulate body size and composition may be related to human cancer incidence or prognosis. Additional understanding of this pathway and its interactions with other signaling pathways will advance our ability to develop new interventions towards decreased cancer risk in humans.

Publication Types:
Review
Review, Tutorial

PMID: 10885804 [PubMed - indexed for MEDLINE] "

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We know that caloric restriction has a number of favorable effects in terms of life span, cancer prevention, etc... This being due to multiple factors; the general trend of decreased metabolic and hormonal actions, general catabolism, decreased protein synthesis, and so on which accompanies a hypocaloric state. We also know that IGF-1 and related growth factors play powerful roles in many common carcinomas (such as many breast cancer lines).

My question, regarding the abstract, is why does a downregulation of IGF-1 [action] correlate with caloric restriction? It was my understanding that in the general diet model, GH output increases. Would this not be opposite of what is proposed? Am I misreading the study and/or attributing IGF-1 with GH incorrectly? If I'm not, then one explanation I can think of would be since we know that in a fed/hypercaloric state, a general upregulation of many metabolic and hormonal actions occurs; such as increased estrogen induced GH/IGF-1 elevation (systemicly--liver). Maybe such an increase is cumulatively greater than the hypocaloric induced GH increase? Does that make sense? I'm gonna dig through the 'related articles' link at PubMed and see if I can find the flaw in my thinking here.

Also just curious for any related general or specific thoughts on caloric restriction and its anti-cancer effects... is interesting to me.

The anti-cancer properties of caloric restriction is in part due to reduced IGF-I and increased corticosteroid, which work though different mechanisms to attenuate pathways of cell division. Of course it's much more complicated, but it distills mostly down to that.


Increased GH and downregulated IGF-I can go hand in hand though. It's bio 101

Simple analogy of increase hormone but decreased target receptors is insulin resistance. BTW, Insulin resistance could, I suppose, be thought of as the antithesis to caloric restriction -- consider the hormonal milieu surrounding this state, and all the diseases/cancers that tend to accompany it.

As much as we may not like it, I think one theme that repeats itself is: bb is anti-thetical to longevity and healthful (cancer-free) lifestyle.

This has been discussed elsewhere in another thread. I summarized the influence of caloric restriction and low-carb diets on systemic IGF-1: both decrease circulating IGF-1 through redundant and separate mechanisms. Insulin and amino acids influence hepatic IGF-1 gene expression and over ride GH-mediated regulation of hepatic IGF-1 expression during caloric and carb restriction. I offered explanations for this as an adaptive response during fasting/famine or nutritional restriction. You can search? the GH/IGF-1 threads for more details.

Calorie restriction and increased longevity are well documented, although the exact mechanisms involved are still not well understood. I suspect that it is multifactorial instead of just one factor. The prevailing hypothesis is reductions in insulin and IGF-1, and decreased cellular and DNA turnover. The research supports this, but there are other influences as well, such as decreases in inflammatory cytokines, etc.

If you think about this from a cell cycle perspective, an arrested cell cycle or reductions in cell turnover obviously reduce DNA turnover. This means several things: reductions in DNA damage, proliferation of cells with damaged DNA (related to cancer), etc. Think about the role of IGF-1 as anti-apoptotic (and the role of TNF-alpha as apoptotic). In other words, IGF-1 has been implicated as a role player in cancer growth because it inhibits cell apoptosis and stimulates proliferation. Although this per se will not CAUSE cancer, it can increase the proliferation of damaged and cancerous cells.

Now, think about what happens at the cellular level as we age. Increased DNA replication, reductions in DNA damage repair, these DNA-damaged cells tend to slip by the intrinsic repair and check points, they increase in number, causing glitches in our cellular machinery or even unchecked cell cycle. Reduced function of cellular proteins (such as enzymes involved in metabolism, gene regulation, etc) and possibly malfunction of housekeeping cellular function. Wallah: things break down, dysfunctional cells proliferate.

The latter two are not always simultaneous. Many people grow and die without any cancerous growth; their cellular machinery slows or dysfunctions ultimately leading to functional failure of one or several organs. On the other hand, young people can die from cancer which overtakes one or more organs, leading to systemic failure and death.

It's complex. But there is an association between caloric restriction and longevity that remains to be fully explained. A researcher which whom I had a wonderful chat during my vacation verified the association of insulin and longevity based on his extensive genomic and proteomic reserach. We briefly discussed the association of IGF-1, to which he agreed there is probably a strong relationship. Some of the preliminary research supports this.

Coincidentally, in trying to catch up with the literature during my absence, I came upon this review which you may find interesting. "Is growth hormone deficiency a beneficial adaptation to aging? Evidence from experimental animals."

The full article is available on BioMedNet, but you have to sign in to access it.
http://reviews.bmn.com/journals/atoz/lates...4%4007%40014_07

In our lifestyle, yes. i.e. rampant uncontolled fuel availability. Our intrinsic regulatory systems can't handle it.

However, consider that famine and severe or longterm caloric restriction are also associated with insulin resistance. It is an adaptive response to protect the brain. Insulin resistance in target tissues means that more glucose is available to fuel the brain.

Target receptors are only one coin in a hand of plenty. Downstream signal transduction is another issue which is often neglected. For instance, we now know that TNF-a and free fatty acid excess dysrupt the downstream signaling cascade of insulin regardless of membrane receptor density and extracellular ligand levels. This leads to decreased insulin sensitivity of target tissues.

I thought this was an interesting attempt to quantify to what extent the lifespan extension seen during caloric restriction was due to suppression of the GH-IGF-1 axis (1). The authors bred transgenic rats heterozygous for GH antisense RNA in certain tissues, and compared their lifespans to normal rats subjected to caloric restriction. The main result was that

"Transgenic rats had a life span similar to that of control CR [caloric restriction] rats, but CR exhibited not only a greater effect in life span extension but also an additive effect on life span in the transgenic rats
Life span was extended in tg/- (AL) [fed ad libitum] rats by 10.0% at 25th and 10th percentile survival points and 10.7% and 17.8% in -/- (CR) rats compared with those in -/- (AL) rats. The survival curve in tg/- (AL) rats did not statistically differ from that in -/- (CR) rats by a log-rank test. However, multivariate analysis with Cox proportional hazards models estimated that the hazard ratios for mortality were 0.40 (95% confidence interval (CI), 0.27 to 0.59; P<0.0001) for CR and 0.59 (CI, 0.40 to 0.85; P<0.005) for the transgene, indicating a greater life-prolonging effect of CR. Life span was extended in tg/- (CR) rats by 20.7% and 29.5% at 25th and 10th percentile survival points compared with those in -/- (AL) rats, indicating the life-prolonging effect of CR in tg/- (AL) rats was simply additive."

So to a simple person who hated statistics in college it looks like at the 10th percentile survival point there was a 7% greater extension in lifespan in the CR rats vs the transgenic rats. The authors concluded that

"The present findings of food intake, body weight, and plasma IGF-1 indicated that the transgenic rats manifested a dwarf phenotype similar, although not completely equivalent, to that of CR rats. The present findings of life span and pathologies, however, indicated that the effect of CR was slightly greater than that of the reduced GH-IGF-1 axis and that there was an simply additive effect on life span extension when long-lived tg/- rats were subjected to CR. The present pathologic analyses support this notion. These imply that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effect partly through the reduced GH-IGF-1 axis."


(1) FASEB J. 2003 Jun;17(9):1108-9. Epub 2003 Apr 08.

Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction.

Shimokawa I, Higami Y, Tsuchiya T, Otani H, Komatsu T, Chiba T, Yamaza H.

The most frequently used phrase in contemporary scientific literature!

Ironically, the more we learn the more we use that phrase.

Coincidentally, there was a newspaper article this morning that talked about a compound in red wine called Resveratrol, which is believed to mimic the effect of caloric restriction, and is thought to be the prevailing avenue through which red wine reduces cancer and heart disease.

The researchers speculated a connection between this and the longer life-span of the French despite their high-fat diets.

It is an interesting compound that seems to have several different proposed modes of action. I've seen research showing that it antagonizes the so called dioxin receptor, to which cigarette smoke tars bind. Its antioxidant properties also prevent the epoxidation of a number of compounds, which once epoxidized would otherwise be highly reactive and easily form DNA adducts. Reading up about this latter property of resveratrol led me to some intriguing research suggesting that tamoxifen might work the same way to prevent breast cancer, rather than simply blocking the proliferative effects of estrogen in breast tissue:

http://www.cuttingedgemuscle.com/Forum/sho...18085#post18085

Sir2 Gene

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I think resveratrol is related more to activating Sir2 gene (silencing gene) which Guarente studied.

Glycolysis involves utilization of NADH molecules. When we are well fed, it is thought that NAD molecules are mostly involved in glycolysis. Unfortuantely, the use of NAD molecules for glycolysis prevent them from being used to stimulate a particular gene, when activated, begins DNA cleansing process (thus repairing them).

The particular gene is known as Sir2 gene. Research has shown, at least for yeasts, that supplying cells with extra NAD molecules increased lifespan. NAD is nicotinamide adenine dinucleotide.

I think one's body can be stimulated to produce more NAD from niacin, which is nothing more than vitamin B3.


EDIT:

(1) I wanted to add that consumption of niacin does result in elevated level of NAD in cells. I have read pubmed studies that show this, even though I no longer have their citations.

(2) There seems to be some evidence that raw nicotinamide (a variant of nicotinic acid) in cells may _accelerate_ aging process. See http://www.ncbi.nlm.nih.gov/entrez/query.f...2&dopt=Abstract

An interesting review in the recent AJCN
"Calorie restriction and aging: review of the literature and implications in humans"

Check it out.

Sorry, I started this thread just before moving back to school and just now have my internet account working.

Thanks everyone for the info and discussion; very helpful. Will respond if/when I have time soon.

Resveratrol is a very powerful antioxidant. It also has antiinflammatory properties, and, interestingly, it may mimic as a muscle relaxant (sipping on a glass of Shiraz with ice). It is being used more and more in cellular studies, but I don't think they have yet arrived at clinical trials. Last I heard two years ago, a team was considering synthesizing and administering it for clinical trials. I don't know if that has moved forward.

I'm sure that red wine may be associated with decreased cardiovascular disease in Mediterranean diets, but also remember that their lifestyles are also very different. When I was there, we ate large lunches with wine and ate small dinners (again with wine), ate lots of fish and vegetables, and we walked/biked/danced alot more than we do here. Oh, we laughed alot more, too.

http://www.washingtonpost.com/wp-dyn/artic...-2003Aug24.html

here is the article in question.

discusion was on the ability of compounds to stimulate sirtuins.

sirtuins are Sir2-like proteins.

How about the gene 2SirWL?

Perhaps tweezer? Dunno -- I am stumped.

An off-color reference to an old movie: To Sir With Love. Poor pun, but I was punchy.

We have to be cautious in the extrapolation of associations of the sir genes/proteins and correlations with longevity in yeast and fly models. We still don't know if these models apply to humans.

Also, consider the recent study that demonstrated longevity in insulin receptor knockout mice who ate eucaloric diets. This suggests that caloric restriction per se may not be necessary, or at least is not the only modality for extending longevity. This was another issue I discussed with the researcher during my vacation. He's done some fantastic genomic and proteomic work on aging and associations with insulin and IGF-1.

......

IGF-1 is also vital for neurogenesis and low levels in the elderly is linked to cogntive dysfunction, lower BMR and less LBM.

So you do some calorier estriction get small, cranky and stupid - but you live longer...

I´m hoping that CR mimetics will get the effect without the bad shit. Oh btw RESV which has been shown to increase lifespan in some species
lowers IGF-1 but it also lowers aromatase so it might be bodycomp "neutral".

This answers the confusion of GH/IGF-1 relationship



Carnitine could lead to a reduction in free IGF-1: