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Original Investigation |

Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality ONLINE FIRST

Mingyang Song, MD, ScD1,2; Teresa T. Fung, ScD2,3; Frank B. Hu, MD, PhD2,4,5; Walter C. Willett, MD, DrPH2,4,5; Valter D. Longo, PhD6,7; Andrew T. Chan, MD, MPH1,5,8; Edward L. Giovannucci, MD, ScD2,4,5
[+] Author Affiliations
1Clinical and Translational Epidemiology Unit, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
2Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
3Department of Nutrition, Simmons College, Boston, Massachusetts
4Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
5Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
6Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles
7FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milano, Italy
8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge
JAMA Intern Med. Published online August 01, 2016. doi:10.1001/jamainternmed.2016.4182
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Importance  Defining what represents a macronutritionally balanced diet remains an open question and a high priority in nutrition research. Although the amount of protein may have specific effects, from a broader dietary perspective, the choice of protein sources will inevitably influence other components of diet and may be a critical determinant for the health outcome.

Objective  To examine the associations of animal and plant protein intake with the risk for mortality.

Design, Setting, and Participants  This prospective cohort study of US health care professionals included 131 342 participants from the Nurses’ Health Study (1980 to end of follow-up on June 1, 2012) and Health Professionals Follow-up Study (1986 to end of follow-up on January 31, 2012). Animal and plant protein intake was assessed by regularly updated validated food frequency questionnaires. Data were analyzed from June 20, 2014, to January 18, 2016.

Main Outcomes and Measures  Hazard ratios (HRs) for all-cause and cause-specific mortality.

Results  Of the 131 342 participants, 85 013 were women (64.7%) and 46 329 were men (35.3%) (mean [SD] age, 49 [9] years). The median protein intake, as assessed by percentage of energy, was 14% for animal protein (5th-95th percentile, 9%-22%) and 4% for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was weakly associated with higher mortality, particularly cardiovascular mortality (HR, 1.08 per 10% energy increment; 95% CI, 1.01-1.16; P for trend = .04), whereas plant protein was associated with lower mortality (HR, 0.90 per 3% energy increment; 95% CI, 0.86-0.95; P for trend < .001). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors. Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59-0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat, 0.88 (95% CI, 0.84-0.92) from unprocessed red meat, and 0.81 (95% CI, 0.75-0.88) from egg.

Conclusions and Relevance  High animal protein intake was positively associated with mortality and high plant protein intake was inversely associated with mortality, especially among individuals with at least 1 lifestyle risk factor. Substitution of plant protein for animal protein, especially that from processed red meat, was associated with lower mortality, suggesting the importance of protein source.

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Risk for Mortality Associated With Replacement of 3% Energy From Various Animal Protein Sources With Plant Protein

Protein intake from plant sources and from all the animal food items considered were included in the multivariable model that was also adjusted for total caloric intake and percentage of energy from saturated fat, polyunsaturated fat, monounsaturated fat, and trans-fat (all continuous), multivitamin use (yes or no), smoking status (never, past, or current [1-14, and ≥15 cigarettes/d]), pack-years of smoking (in women, ≤15, 16-25, 26-45, and ≥46; in men, <10, 11-24, 25-44, and ≥45), body mass index (calculated as weight in kilograms divided by height in meters squared; <23.0, 23.0-24.9, 25.0-26.9, 27.0-29.9, 30.0-34.9, and ≥35), physical activity (quintiles), alcohol consumption (in women, 0, 0.1-5.0, 5.1-15.0, and >15.0 g/d; in men, 0, 0.1-10.0, 10.1-20.0, and >20.0 g/d), history of hypertension diagnosis (yes or no), glycemic index (in quintiles), and intake of whole grains, total fiber, fruits, and vegetables (all in quintiles). CVD indicates cardiovascular disease; HR, hazard ratio. Error bars indicate 95% CIs.

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Submit a Comment
How come India has lot of CAD?
Posted on August 2, 2016
Anant Rao
Conflict of Interest: None Declared

As a life-long vegetarian, this is good news to me (and those who take it up now thanks to this article), I'd like to share an interesting contradictory information.

Being from India, I know that millions of families, including mine, are vegetarian for generations. However, India has some of the highest cases of diabetes (DM) and coronary artery disease (CAD).

Agreed there're environmental factors like pollution, lack of exercise. Still, I feel if some peoples are genetically predisposed to certain diseases in spite of being consuming a plant-based diet.
Need for an edit in the abstract's conclusion section?
Posted on August 2, 2016
John Well
Conflict of Interest: None Declared
In the abstract section, the conclusion ends with \"Substitution of plant protein for animal protein, especially that from processed red meat, was associated with lower mortality, suggesting the importance of protein source.\"

After reading the rest of the article, I imagine that there might have been an error in that sentence and that its proper edit should likely be \"Substitution of animal protein, especially that from processed red meat, for plant protein was associated with lower mortality, suggesting the importance of protein source.\"

Best regards.
Clarifications on Statistical information
Posted on August 2, 2016
MN Nicolosi
Conflict of Interest: None Declared
I've combed through your statistical methods section and I would like to inquire about the following:

With such a large sample, you probably have too much power, hence the results of your research might be blown out of proportion. Why haven't you reported your effect sizes?

Also, medical sciences usually work with more stringent p-values, .001, specifically. Why have you chosen this cut-off value (i.e. .05)?

Finally, your confidence intervals for cause of death by protein illustrate, at best, marginally significant values for consumers of unprocessed meats, poultry, eggs and dairy products and no significant relationship with cancer, even for processed meats:

(1) Why haven't you added the CIs for plant protein as well;
(2) Don't you think your conclusions were somewhat stretched? There's really nothing new here. It has been known that processed meats are highly associated with CVD. That seems t be the only major finding I see here.
RE: Clarifications on Statistical information
Posted on August 4, 2016
Mingyang Song
Massachusetts General Hospital
Conflict of Interest: None Declared
I thank MN Nicolosi for the comments, and would like to provide some response.

First, we have reported the hazard ratio as effect size throughout the manuscript.

Second, our use of p<0.05 as the threshold for statistical significance is consistent with the standard of the epidemiologic literature.

Third, it is true that some of the confidence intervals are marginally significant. But as the reader pointed out, statistical significance should be interpreted in the context of the effect size. Also, we did report the confidence intervals for plant protein throughout the manuscript.

Finally, our conclusions were drawn based on our findings, which I believe go well beyond the well-known relationship between processed red meat and CVD.
Something is missing
Posted on August 8, 2016
Zoltan Sandor
Research Centre for Natural Sciences, Hungarian Academy of Sciences
Conflict of Interest: None Declared
As John Well, I find a strange contradiction, and something is missing or wrong.

On the end of the abstract (in Conclusions and relevance:) I see:
\"Substitution of plant protein for animal protein, especially that from processed red meat, was associated with lower mortality, suggesting the importance of protein source.\"

And in the article:
\"These results UNDERSCORE THE IMPORTANCE of protein sources FOR RISK ASSESSMENT AND SUGGEST THAT OTHER COMPONENTS in protein-rich foods (eg, SODIUM [45], NITRATES, and NITRITES [46] in processed red meat), in addition to protein per se, MAY HAVE A CRITICAL HEALTH EFFECT.\"

And in the press release of the Massachusetts General Hospital:
And on scientific media - for example:
And also on a Hungarian (a little country in Europe) news portal:

Nothing about the critical health effect of added sodium (NaCl), nitrates and nitrites. Why? Since, the real conclusion is that not the protein source (animal or plant) is important and have health risks, but the added sodium salts have health risks (critical health effect). That is not public? The danger of the sodium-induced disorder is a taboo?

Some important references:
Sodium-Induced Disorder Syndrome. Where have all the sciences gone?
BMJ Online (13 April 2016)

Re: The scientific report guiding the US dietary guidelines: is it scientific?
BMJ Online (25 September 2015)

Entropy and sodium intakes, the wicked problems of health sciences
Science 2.0 (9. 9. 2013.)

Sincerely: Zoltan Sandor
Research Centre for Natural Sciences,
Hungarian Academy of Sciences
Is it necessary to choose between 2 protein sources?
Posted on August 6, 2016
George Henderson
Human Potential Centre AUT
Conflict of Interest: None Declared
The highest quintile of plant protein intake only has median intake of 6.6% of energy, which is probably not enough to sustain life. The mortality HR for animal protein is minimal and non-significant at the highest quintile. The substitution analysis uses a mere 3%E of plant protein.
Given the benefits noted from high protein, low carbohydrate diets, is there any reason from this data not to add some plant protein to a diet high in animal protein? For example, the \"paleo\" diet supplements high quality animal protein from various sources with plant protein from nuts and seeds. Low carbohydrate high fat and Mediterranean diets are similar, with dairy and legumes as possible additional protein sources.
If the HRs for highest quintiles of animal and plant protein combined were presented, this might be of use to those considering higher protein diets. Health conscious people today eat protein from a variety of sources, but may not consciously limit meat.
It is notable that processed meats such as sausage meats of the frankfurter type can be a source of plant protein, and I wonder whether this was factored into the analysis.
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