Question about new study by Dr Fontana

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Question about new study by Dr Fontana

Postby Adrienne » Tue Dec 24, 2013 10:44 pm

In light of your response to the question about whether or not studies on mice/rats are relevant to humans, I am curious if you have any thoughts on this new study by Dr Fontana:


Dietary protein restriction inhibits tumor growth in human xenograft models.
Oncotarget. 2013 Nov 23.
Purpose: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer. Experimental Design: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models. Results: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet. Conclusions: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.
http://www.ncbi.nlm.nih.gov/pubmed/24353195

Do you think it adds to Dr Campbell's studies on rats? Do you think it Is more relevant because they used human xenografts?

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Re: Question about new study by Dr Fontana

Postby JeffN » Wed Dec 25, 2013 9:04 am

Adrienne wrote:In light of your response to the question about whether or not studies on mice/rats are relevant to humans, I am curious if you have any thoughts on this new study by Dr Fontana:

....

Do you think it adds to Dr Campbell's studies on rats? Do you think it Is more relevant because they used human xenografts?

Thanks


Thanks.

I think the question is, does it add anything to the body of evidence on

- whether animal protein and/or casein specifically, causes cancer

- is there a difference between animal or plant protein at differing intake levels.

In that regard.

- it adds to the picture.

- it is still an animal study and a "modeling" study. Human xenografts are human tumors that are transplanted into animals so it is not truly a human study as these tissues are now part of the animals physiology and biochemistry.

- There were actually several experiments. The first few looked at the impact of total protein and compared a diet of mixed protein at either 21% protein or 7% protein. In these experiments, the lower protein intake proved superior.

- The second experiments looked at type/source/quality of protein and compared a diet of animal protein vs plant protein at both 20% of calories and at 10% of calories. In these experiments, at 10%, it did not matter as both the animal protein and plant protein diet had similar beneficial effects.

"The inhibitory effect on tumor growth exerted by the 20% and 10% plant protein diets was similar. Interestingly, there was no additive effect of switching from animal to plant proteins when dietary protein content was 10%, suggesting that a threshold exists below which the amino acid composition is less important than the protein content of the diet."

To me, while most likely disappointing to many, these results are the most informative and supports what I have been saying here about the "95%."

Also, Campbell''s early work focused on casein alone and is his main claim based on those studies. This doesn't support that as at lower total protein intakes, casein did not promote cancer more than the same amount of plant protein. His China-Oxford work looked more at total protein, which this supports, especially if the diet contains animal protein.

If we decide that this does have relevance to the bigger picture and the body of evidence, what can we learn from this?

Three things were of most interest...

- At a lower total protein intake levels (~10%), there was no difference between the effect of either animal or plant protein even if the animal protein was high in casein as the protein in the animal protein diet was ~80% casein.

- At a higher total protein intake levels (~20%), plant proteins are safer than animal proteins possibly due in part to the reduced methionine & leucine levels. The leucine may be the more important issue based on other recent data supporting this & because methionine restriction alone has not proven out. So, If you are on a diet that does contain animal protein then keep total protein intake to no more than 10%.

- There was also no difference in the impact of the 20% plant protein diet compared with the 10% plant protein diet. So, if you are on a vegan diet, reducing total protein to 10% may not be as important.

Here is a graphic from the study that puts the results of all the experiments in one graph and I think, tells the whole story.

Image

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Re: Question about new study by Dr Fontana

Postby JeffN » Mon Mar 10, 2014 4:44 pm

The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice
Cell Metabolism - 4 March 2014 (Vol. 19, Issue 3, pp. 418-430)

http://www.cell.com/cell-metabolism/ful ... %2900065-5

Highlights
- Food intake is regulated primarily by dietary protein and carbohydrate
- Low-protein, high-carbohydrate diets are associated with the longest lifespans
- Energy reduction from high-protein diets or dietary dilution does not extend life
- Diet influences hepatic mTOR via branched-chain amino acids and glucose

Summary

The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.

Image

Calorie counting off the menu
Mar 10, 2014
http://www.foodprocessing.com.au/news/6 ... f-the-menu

It looks like the theory that calorie restriction helps you live longer has been debunked. Researchers at the Charles Perkins Centre have shown that calorie restriction has no beneficial effects on life span in mice - and they say this is probably the case for humans, too.

In fact, the researchers say that not all calories are created equal: protein, fat and carbohydrate have very different effects on food intake, metabolic health, ageing and longevity.

"This research has enormous implications for how much food we eat, our body fat, our heart and metabolic health, and ultimately the duration of our lives," said Professor Steve Simpson, academic director of the University of Sydney's Charles Perkins Centre and corresponding author of the study, which was published in Cell Metabolism.

"We have shown explicitly why it is that calories aren't all the same - we need to look at where the calories come from and how they interact."

While low-carb, high-protein diets did reduce body fat and food intake in mice, the news wasn't great for their life span or health: they lived shorter lives and had poor cardiometabolic health.

In contrast, a high-carb, low-protein diet did increase body fat but had better outcomes in terms of life span and cardiometabolic health. Low-protein, high-fat diets were the worst of the lot, the researchers found, with fat content not even reducing food intake.

By examining mice fed a variety of 25 diets, the research team used a state-space nutritional modelling method to measure the interactive effects of dietary energy, protein, fat and carbohydrate on food intake, cardiometabolic health and longevity.

According to the researchers, the results suggest that the life span of animals could be extended by manipulating the ratio of macronutrients in their diet - reportedly the first evidence that pharmacology could be used to extend life span in normal mammals.

"Up until this point, most research has either concentrated on a single nutritional variable, such as fat, carbohydrate or calories, so much of our understanding of energy intake and diet balance is based on one-dimensional single nutrient assessments," said study co-author Professor David Le Couteur from the Charles Perkins Centre, who is Professor of Geriatric Medicine at Concord Hospital.

"The advice we are always given is to eat a healthy balanced diet, but what does that mean? We have some idea, but in relation to nutritional composition we don't know terribly well. This research represents an important step in finding out."

The researchers predict that a diet consisting of 15 to 20% high-quality protein, relatively low in fat and high in good-quality complex carbohydrates will result in good metabolic health and a long life span.
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Re: Question about new study by Dr Fontana

Postby JeffN » Fri May 29, 2015 9:57 am

Dietary Protein to Carbohydrate Ratio and Caloric Restriction: Comparing Metabolic Outcomes in Mice,
Cell Reports (2015), http://dx.doi.org/10.1016/j.celrep.2015.05.007

Full Text
http://www.cell.com/cell-reports/pdf/S2211-1247(15)00505-7.pdf

In Brief
Nutritional interventions improve metabolic health in mice. Solon-Biet et al. find that short-term ad libitum low- protein, high-carbohydrate (LPHC) diets improve levels of insulin, glucose, lipids, and HOMA. LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of caloric restriction without a 40% reduction in total caloric intake.

Highlights
- Ad libitum low-protein, high-carbohydrate diets (LPHC) improve metabolic health
- Caloric restriction combined with LPHC diet does not provide added health benefits
- Energy intake and energy expenditure are increased on LPHC diets

Image

SUMMARY
Both caloric restriction (CR) and low-protein, high- carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake.
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Re: Question about new study by Dr Fontana

Postby JeffN » Sat May 30, 2015 7:31 am

JeffN wrote: Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake.


This has always been my contention and the main message of my presentation, Calorie Density: How To Eat More, Weigh Less and Live Longer. Our diet, especially the MWL, automatically gives you the benefits of calorie restriction without having to formally restrict calories.

And, as the Shintani studies on his Hawaiian diet showed, when switching from the typical SAD to an ad-libitum, high carb, low fat, low calorie dense diet, calorie intake automatically drops up to 40%, without having to formally restrict.

viewtopic.php?f=22&t=10827&p=86403&#p86403

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Re: Question about new study by Dr Fontana

Postby JeffN » Mon Nov 26, 2018 11:01 am

This study in mice further supports the ones above about ad-libitum, low protein high carb diets compared to CR. No formal active restriction required

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Mainstream Article

Brain health: Low-protein, high-carb diet just as good as low-calorie diet
Published Friday 23 November 2018 By Ana Sandoiu Fact checked by Gianna D'Emilio
Medical News Today

https://www.medicalnewstoday.com/articles/323772.php


Abstract

Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice.
Wahl D, Solon-Biet SM, Wang QP, Wali JA, Pulpitel T, Clark X, Raubenheimer D, Senior AM, Sinclair DA, Cooney GJ, de Cabo R, Cogger VC, Simpson SJ, Le Couteur DG.
Cell Rep. 2018 Nov 20;25(8):2234-2243.e6. doi: 10.1016/j.celrep.2018.10.070.
PMID: 30463018
Highlights

- Calorie restriction (CR) and low-protein, high-carb (LPHC) diets improve health
- Hippocampus RNA expression is positively influenced by CR and LPHC diets
- Nutrient-sensing pathways are similarly influenced by CR and LPHC diets
- CR and LPHC diets positively influence dendritic spines and cognitive function

Summary
Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
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Re: Question about new study by Dr Fontana

Postby JeffN » Mon May 27, 2019 5:57 am

Here is an excellent overview from 2017 from Fontana that I missed posting

Calorie restriction in humans: an update
Ageing Res Rev. 2017 Oct; 39: 36–45.
Published online 2016 Aug 17. doi: 10.1016/j.arr.2016.08.005

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315691/

PMID: 27544442

Abstract
Calorie restriction (CR), a nutritional intervention of reduced energy intake but with adequate nutrition, has been shown to extend healthspan and lifespan in rodent and primate models. Accumulating data from observational and randomized clinical trials indicate that CR in humans results in some of the same metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in animal models of longevity. In particular, moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality. In this paper, we will discuss the effects of CR in non-obese humans on these physiological parameters. Special emphasis is committed to recent clinical intervention trials that have investigated the feasibility and effects of CR in young and middle-aged men and women on parameters of energy metabolism and metabolic risk factors of age-associated disease in great detail. Additionally, data from individuals who are either naturally exposed to CR or those who are self-practicing this dietary intervention allows us to speculate on longer-term effects of more severe CR in humans
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