August 09, 2009
Calorie Restriction Cuts Breast Cancer Risk In Mice
Even Intermittent Calorie Restriction (CR) cuts breast cancer risk in mice.
Previous studies have shown that intermittent calorie restriction provided greater protection from mammary tumor development than did the same overall degree of restriction, which was implemented in a chronic fashion. The researchers compared changes of a growth factor (IGF-1) in relationship to these two calorie restriction methods chronic and intermittent and tumor development beginning in 10-week old female mice at risk to develop mammary tumors. Their hope was to explain why intermittent restriction is more effective.
The overall degree of restriction was 25 percent reduction compared to control mice. Mammary tumor incidence was 71 percent in the control mice who ate the amount of food they wanted, 35 percent among those who were chronically restricted and only nine percent in those who intermittently restricted calories.
If one does not want to do intermittent or constant calorie restriction how best to lower insulin-like growth factor (IGF-1) and insulin in the blood? A lower glycemic index and lower carbo diet probably helps. But I wonder if any reader knows of some good tricks for lower IGF1. Maybe some dietary compound lowers it?
For the guys: It is worth noting that IGF-1 also appears to boost prostate cancer growth. Most of the dietary advice that applies to cutting breast cancer risk also applies to cutting prostate cancer risk. Couples would do well to keep that in mind.
The researchers were surprised intermittent calorie restriction helped since they expected a big IGF1 surge after calorie restriction would cancel out the benefit of brief IGF1 reduction.
The researchers were initially surprised by these findings for several reasons. First, the prevailing wisdom is that the degree of protection from calorie restriction is proportional to the degree of mammary tumor prevention. Second, they originally thought that intermittent calorie restriction might enhance tumor growth due to growth factors being secreted in response to re-feeding, Cleary said.
I did some searching on compounds that'll lower IGF-1. One study reports resveratrol lowering IGF-1 in mice on a high calorie diet. But a paper in Plos One found that while resveratrol delivered many of the benefits of calorie restriction (CR) it didn't lower IGF-1 in mice.
Some of the phenotypes that are observed in animals with altered IGF-1 or insulin signaling are also observed in CR mice, such as reduced levels of IGF-1, insulin and glucose . To investigate if resveratrol inhibits transcriptional profiles of aging and mimics CR through an endocrine mechanism, we measured glucose, T3, insulin, IGF-1 and GH in five month-old control, CR and resveratrol fed mice. Following two months of dietary intervention, we observed reduced IGF-1 levels in CR mice, but not in resveratrol treated mice (Figure 2B). We did not observe significant alterations in any other hormones examined. Surprisingly, because we observed a large overlap of transcriptional shifts induced by resveratrol and CR in all organs examined, our findings also suggest that a large component of the transcriptional program induced by CR may be independent of CR-mediated alterations in plasma IGF-1, or insulin. This conclusion is supported by the finding that dwarfism and CR may impact lifespan through independent mechanisms , and the finding that GH deficiency and CR display minimal overlap at the gene expression level .
Can any flavonoids lower IGF-1?
Update: Cancers can mutate to become insensitive to CR.
Our findings indicate that each tumor cell bears a signature that determines whether or not that cell will be affected by dietary restriction, says Nada Kalaany, first author of the paper and a postdoctoral researcher in the lab of Whitehead Member David Sabatini. We think that mutations in the PI3K pathway are a major determinant of the sensitivity of tumors to dietary restriction.
Do not wait until late in life to clean up your diet. By then the damage has already accumulated.
Even selective restriction of essential amino acids depresses IGF-1 levels, mRNA translation and protein synthesis. See:
"Dietary Restriction of Single Essential Amino Acids Reduces Plasma Insulin-Like Growth Factor-I (IGF-I) but Does Not Affect Plasma IGF-Binding Protein-1 in Rats"
"Regulation of Global and Specific mRNA Translation by Amino Acids"
However, these diets may be hard to stick to (but maybe [as cited above] intermittent restriction suffices). See:
"Rats Rapidly Reject Diets Deficient in Essential Amino Acids"
BTW, as you probably already know, a 1-2 day fast prior to chemo therapy appears to significantly increase its effectiveness. Restricting dietary amino acids (prior to chemo) is also being investigated.
Should we eat less protein to lower our IGF-1 or less carbo to lower our insulin? Or less carbo and less protein and more fat?
I find it far easier to tell people to eat more fruits and vegetables than to tell them what ideal ratio of fats versus protein versus carbohydrates to eat.
I read fructose implicated in weight gain. But that only seems to happen with corn syrup. I do not read evidence of this with fruit consumption. Am I wrong on this point?
Also, then there's the supposed big baddie fat. Leaving aside some saturated fats it seems to me fats are good overall. Should we be eating more fats to displace carbo and protein? It is not clear to me.
What's the fat:protein:carbo ratio in the Mediterranean diet? My impression is less protein that the standard American diet. Also, lower glycemic index.
Do you have a good sense on this one? I mostly focus on fruits and veggies. I also feel on firm ground arguing for lower glycemic index. Beyond that I try to avoid some obviously naked calories and meats cooked in ways that increase carcinogens (e.g. grilling and processed meats). Between the three main calorie sources I'm less clear. You got a good way to approach this?
The article below is suggestive that taking acetaminophen (Tylenol) might allow CR to duplicate the benefits of IF in reducing cancer development. IF most likely works better than CR for this due to lowering S-nitrosylation better. Tylenol duplicates this effect.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17291990 (table five) has more on IF and nitrosylation.
PLoS One. 2009 Jul 29;4(7):e6430
Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.
Wu M, Katta A, Gadde MK, Liu H, Kakarla SK, Fannin J, Paturi S, Arvapalli RK, Rice KM, Wang Y, Blough ER.
Department of Biological Sciences, Marshall University, Huntington, West Virginia, United States of America.
BACKGROUND: Aged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s) underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB) is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention. PRINCIPAL FINDINGS: Compared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308) was higher in soleus muscles of very aged rats (33-months). Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR) phosphorylation, along with decreased levels of insulin receptor beta (IR-beta), phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1) (Ser241). In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS). Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month) animals with acetaminophen (30 mg/kg body weight/day) for 6-months. CONCLUSIONS: These data demonstrate that Akt dysfunction and increased S-nitrosylation of Akt may contribute to age-associated disorders in skeletal muscle and that acetaminophen may be efficacious for the treatment of age-related muscle dysfunction.
I don't know the risk/reward ratio of lowering IGF-1 - probably depends on age, gender, weight, insulin resistance, cardiac and bone health, ... For many people, I expect it's harmful.
For some cautionary notes, see -
"Aging, IGF-1, and diet"
As you probably already know, caloric restriction without protein restriction doesn't reduce IGF-1 in humans.
"Diet details may influence longevity: cutting protein may be as important as cutting calories"
If I had to guess, I'd guess (without a lot of confidence) that the best way for humans to reduce IGF-1 is to selectively and intermittently reduce dietary level of at least one essential amino acid. I didn't see much data on the effect of fats.
Intriguing. Maybe the new acetaminophen variant without liver toxicity will have some new uses.
Green tea extract and high doses of lycopene reduce IGF-1. Zinc supposedly increases the number by 5 ng/ml for each milligram of zinc intake. Cat's Claw will also increase it.