Reflecting On The 5:2 Diet & Intermittent Fasting

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Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Mon May 13, 2013 12:15 pm

Some comments on the 5:2 diet, Intermittent Fasting (IF), Calorie Restriction (CR) and Optimal Nutrition (ON)

First, as explained in the "Eating Between Meals' thread, the single most important thing anyone can do in regard to their diet and health is to understand and apply the basic principles and guidelines.

http://www.drmcdougall.com/forums/viewt ... 22&t=26337

"Bottom line, following the recommendations here to consume a unrefined unprocessed plant based diet that is low in calorie density, high in nutrient density and high in satiety, along with the proper amount and type of physical activity may be the most important issue. Whether someone does this in 3 meals vs 5 meals vs 1 meal, may be less important than total calories and overall food choices, and a fine detail that would be up to the individual based on which method helps them incorporate the more important principles."

"Some people just can't maintain a meal plan with fewer meals and some just can't maintain a meal plan with more frequent meals. I am one of the latter, and so, I keep a more limited meal plan but would not insist on that for someone who felt more comfortable with more frequent meals as long as the overall dietary and nutritional pattern is the same."


Basing your overall diet on calorie density is a much better approach to incorporating the recommended guidelines and principles as it addresses many important issues at once...

First, it allows you to eat whenever hungry until you are comfortably full, which addresses the key issues of hunger and satiety.

Second, the recommended foods are not only low in calorie density and high in satiety, they are also the foods that are the most nutrient dense, which addresses the issue of optimal nutrition

While some people are able to do fine with occasional fasting and the skipping of meals, whether or not this is feasible for someone should not be their first and/or main priority.

In addition, we live in a toxic food environment and trying to incorporate meal skipping and intermittent fasting may prove not only difficult to many, but also detrimental. Two recent studies highlight some of these issues...

1) Caloric deprivation increases responsivity of attention and reward brain regions to intake, anticipated intake, and images of palatable foods. NeuroImage, Volume 67, 15 February 2013, Pages 322–330

http://www.sciencedirect.com/science/ar ... 1912011408

(An article on the study)

"Results imply that dieting characterized by meal skipping & fasting would be less successful than weight loss efforts characterized by intake of low energy dense healthy foods."

"The implications of this imaging study are crystal clear; if people want to lose excess weight, it would be more effective to consume healthy, low-fat/low-sugar foods during regular meals, rather than go for long periods of time without any caloric intake"

http://www.eurekalert.org/pub_releases/ ... 050213.php

2) Wansink B, Tal A "Fattening fasting: hungry grocery shoppers buy more calories, not more food" JAMA Intern Med 2013; DOI: 10.1001/jamainternmed.2013.650.

http://archinte.jamanetwork.com/article ... id=1685889

(An article on the study)

Short-term food deprivation (fasting, skipping meals) increases overall grocery shopping & leads shoppers to buy 31% more high-calorie foods.

http://www.news.cornell.edu/stories/201 ... -fattening

My concerns...

- Many people who come from the old dieting/restriction mentality still apply that thinking to this way of eating and still restrict portions & food volume, not understanding that due to the low calorie density of this food, you actually do not need to do that and often need to eat more volume. So, they restrict the consumption of the healthy recommended foods, that are low in calorie density, then end up starving and eventually binging on unhealthy regular foods or vegan/plant based junk foods.

- In an attempt to maximize the impact of this way of eating, people often shift the calorie density of their diet too low, focusing mostly on very low calorie dense foods like mostly veggies, skip healthy foods like whole grains, roots/tubers and even legumes. In doing so, they may get lots of food volume but they do not get enough calories and eventually get very hungry and also end up starving and end up binging on high fat, high sugar raw vegan things like dried fruit, nuts and date/nut treats or just vegan/plant based junk food.

- In addition, even when switching to this way of eating, people may skip meals during the day &/or make their meals very small thinking by doing this and then eating a sensible healthy dinner, they will be helping to reduce overall caloric intake. While this may often prove easy during the day when people are busy and hunger is still somewhat manageable, it usually fails in the evening when they are home and hunger has become unmanageable. So instead of a sensible healthy dinner, they eat everything not nailed down! Then, the next morning they repent and try again by skipping breakfast and/or lunch and/or making them very small and end up just repeating an unhealthy pattern, over and over.

- While these scenarios can happen to anyone trying to follow a whole food, plant based diet depending on how they interpret & apply the principles, from my personal & professional experience, it seems to be more common in the raw vegans, who end up overdoing the high fat/high sugar foods/treats (from nuts, dried fruits, juices etc), those who overly restrict any of the programs (thru portion control &/or CR), and in those who overly limit or eliminate the intact whole grains, starchy vegetables, roots & tubers (& sometimes even beans).

- Of course, we will always find the few people who are able to do IF and CR with portion control and food restriction and in whom, satiety and hunger are just not issues. However, 70% of Americans struggle with weight issues and have proven that they can not control their food intake in this toxic ad libitum food environment. And, the odds are that those who come to me for help (or these forums), this percentage is much higher. Otherwise, they would not be here.

So..

1) If one is trying to lose weight, there are only 3 studies I know of to date in the literature that directly compare the effects of IF vs CR, there is one review comparing the results from separate studies of IF and CR and these studies do not show any advantage to IF (see below). In addition, as noted above, there are several studies that show meal skipping and fasting may not work for many people.

2) If one is trying to lower IGF-1, there is no known benefit to IF over CR in this regard. Focusing on IGF-1 is missing the point. IGF-1 should be the result of our efforts and not the focus. In addition, if the reason for lowering IGF-1 is to impact cancer, then lowering IGF-1, which is only a marker, is not the same as lowering cancer risk or incidence. However, a total lifestyle program that included regular exercise and a low fat, near vegetarian diet (without IF), did lower IGF-1 levels and impact cancer cell growth and the progression of some types of cancer (breast, prostate). This does not mean it will impact cancer cell growth and the progression of all and any cancer.

http://www.ncbi.nlm.nih.gov/pubmed/12588089

http://www.ncbi.nlm.nih.gov/pubmed/16094059

It is proposed that one of the benefits of this way of life that lowers the IGF-1 is both the reduced protein intake and the amino acid profile of the protein on this program.

http://cebp.aacrjournals.org/content/11 ... 1.abstract

3) If one was interested, the best way to incorporate the potential benefits of CR & ON that also addresses the issues of satiety and hunger, is through the understanding and application of the principles of calorie density and the MWL program.

4) If one is on a CR'd version of this program and is trying to fine tune it to see if there is some potential additional benefits to incorporating IF as part of their CR'd program, then that is fine, but first, they really need to understand and implement the basics of calorie density/MWL into their lives first.

Which bring us right back to my original point....

"Bottom line, following the recommendations here to consume a unrefined unprocessed plant based diet that is low in calorie density, high in nutrient density and high in satiety, along with the proper amount and type of physical activity may be the most important issue. Whether someone does this in 3 meals vs 5 meals vs 1 meal, may be less important than total calories and overall food choices, and a fine detail that would be up to the individual based on which method helps them incorporate the more important principles."

In Health
Jeff


In all studies the outcome was the same: No significant differences in weight loss, or changes in body composition.

1) Am J Clin Nutr. 1989 Aug;50(2):248-54. Evaluation of an alternating-calorie diet with and without exercise in the treatment of obesity.

http://www.ncbi.nlm.nih.gov/pubmed/2667313

2) Int J Obes (Lond). 2011 May;35(5):714-27. doi: 10.1038/ijo.2010.171. Epub 2010 Oct 5. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women.

http://www.ncbi.nlm.nih.gov/pubmed/20921964

3) Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss? Varady KA. Obes Rev. 2011. Jul;12(7):e593-601. doi: 10.1111/j.1467-789X.2011.00873.x. Epub 2011 Mar 17. Review. PMID: 21410865

http://www.ncbi.nlm.nih.gov/pubmed/?term=21410865

4) Menopause. 2012 Aug;19(8):870-6.
Short- and long-term effects of continuous versus intermittent restrictive diet approaches on body composition and the metabolic profile in overweight and obese postmenopausal women: a pilot study.

http://www.ncbi.nlm.nih.gov/pubmed/?term=22735163
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Tue May 28, 2013 10:36 am

Benefit of a low-fat over high-fat diet on vascular health during alternate day fasting

Nutrition & Diabetes (2013) 3, e71; doi:10.1038/nutd.2013.14
Published online 27 May 2013

Abstract

Background: Alternate day fasting (ADF) with a low-fat (LF) diet improves brachial artery flow-mediated dilation (FMD). Whether these beneficial effects can be reproduced with a high-fat (HF) diet remains unclear.

Objective: This study compared the effects of ADF-HF to ADF-LF regimens on FMD. The role that adipokines have in mediating this effect was also investigated.

Methods: Thirty-two obese subjects were randomized to an ADF-HF (45% fat) or ADF-LF diet (25% fat), consisting of two phases: (1) a 2-week baseline weight maintenance period and (2) an 8-week ADF weight loss period. Food was provided throughout the study.

Results: Body weight was reduced (P<0.0001) in the ADF-HF (4.4±1.0 kg) and ADF-LF group (3.7±0.7 kg). FMD decreased (P<0.05) by ADF-HF relative to baseline (7±1 to 5±2%) and increased (P<0.05) by ADF-LF (5±1 to 7±2%). Blood pressure remained unchanged in both groups. Adiponectin increased (P<0.05) in the ADF-HF (43±7%) and ADF-LF group (51±7%). Leptin and resistin decreased (P<0.05) in the ADF-HF (32±5%; 23±5%) and ADF-LF group (30±3%; 27±4%). Increases in adiponectin were associated with augmented FMD in the ADF-LF group only (r=0.34, P=0.03).

Conclusion: Thus, improvements in FMD with ADF may only occur with LF diets and not with HF diets, and adipokines may not have a significant role in mediating this effect.
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Sun Mar 09, 2014 12:57 pm

The Latest Research On (Meal Frequency &) Intermittent Fasting - The Diane Rehm Show

http://thedianerehmshow.org/shows/2014- ... -fasting-0

Dr. Michael Mosley physician, science journalist and author. (5/2 Diet - Fasting 2 Non Consecutive Days Per Week Fasting)

Dr. Mark Mattson researcher, National Institute on Aging. EOD (Every Other Day or Alternate Day Fasting)

Dr. Valter Longo director, University of Southern California Longevity Institute. (4-5 Consecutive Days Per Month Fasting)

On their plans (Dr Fontana & Dr Varady are two other researchers in the field)

Luigi Fontana:
Advocates fasting (within the context of 24 hours) for as long as possible. He suggests that if you have to consume 5/600 calories then they should be consumed as one meal, very early in the morning so as to maximise the length of the fast.

Valter Longo:
With regard to IGF-1 reduction it is better to do 4 days of (consecutive) fasting every few months and then skip meals during the week to maintain weight and try to adopt a plant based low protein diet. An alternative to the 4 days fasting is just to fast on 2 days at a time as in the 5-2 plan but you must also try to move to a healthy diet, plant based and low protein.

Krista A. Varady:
With regard to how you should eat (if at all), on a fast day: So far, we have performed studies permitting people to eat 600 kcal bethween 12pm-2pm. We find that this strategy works well for most people (whereas a complete fast for 24 h does not). We have yet to run a study where we allow people to consume the 600 kcal as 6x100kcal (or 3 x 200 kcal) smaller meals throughout the day. However, we are planning to run this study within the next year. Krista Varady says ‘eating the 500 calorie allowance throughout the day would prevent a persons body going into a fasted state’. Since it is the fasted state that is so beneficial to us, this information is critical.

Mark P. Mattson:
1. A complete fast (no food) with hydration maintained with non-caloric beverages will be superior to consuming 600 calories on the fasting days.
2. Eating the 600 calories at one meal will be superior to eating several smaller meals spread throughout the day. By eating only one meal, the body goes essentially 24 hours with no food. This results in adaptive cellular stress responses which we believe is particularly good for the brain.
3. In the case of the 5:2 diet, we do not know whether better health benefits are realized with two consecutive days of fasting versus any two days of fasting during the week.

What I found most interesting is..., (all of which reinforce my comments in this thread)...

- all the versions worked with fasting being defined as a either a period of eating ~500 calories per day or total abstinence

- whichever routine implemented, the subjects adapted in about 2 weeks and rarely experienced hunger, though this was hardest on the 5 days per month plan.

- as Dr Mosley said, the most important thing is for each individual to find the regime within the basic guidelines that works best for them.

I agree.

In Health
Jeff
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Sun Mar 09, 2014 1:01 pm

*** Update ***

Fasting: Molecular Mechanisms and Clinical Applications
Valter D. Longo and Mark P. Mattson,
Cell Metabolism 19, February 4, 2014

From the study...

"Fasting has been practiced for millennia, but, only recently, studies have shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism, and bolster cellular protection. In lower eukaryotes, chronic fasting extends longevity, in part, by reprogramming metabolic and stress resistance pathways. In rodents intermittent or periodic fasting protects against diabetes, cancers, heart disease, and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma, and rheumatoid arthritis. Thus, fasting has the potential to delay aging and help prevent and treat diseases while minimizing the side effects caused by chronic dietary interventions."

Conclusions and Recommendations

Based on the existing evidence from animal and human studies described, we conclude that there is great potential for lifestyles that incorporate IF or PF during adult life to promote optimal health and reduce the risk of many chronic diseases, particularly for those who are overweight and sedentary. Animal studies have documented robust and replicable effects of fasting on health indicators including greater insulin sensitivity and reduced levels of blood pressure, body fat, IGF-I, insulin, glucose, atherogenic lipids, and inflammation. Fasting regimens can ameliorate disease processes and improve functional outcome in animal models of disorders that include cancer, myocardial infarction, diabetes, stroke, AD, and PD. One general mechanism of action of fasting is that it triggers adaptive cellular stress responses, which result in an enhanced ability to cope with more severe stress and counteract disease processes. In addition, by protecting cells from DNA damage, suppressing cell growth, and enhancing apoptosis of damaged cells, fasting could retard and/or prevent the formation and growth of cancers.

However, studies of fasting regimens have not been performed in children, the very old, and underweight individuals, and it is possible that IF and PF would be harmful to these populations. Fasting periods lasting longer than 24 hr, and particularly those lasting 3 or more days, should be done under the supervision of a physician and preferably in a clinic. IF- and PF-based approaches toward combating the current epidemics of overweight, diabetes, and related diseases should be pursued in human research studies and medical treatment plans. Several variations of potential ‘‘fasting prescriptions’’ that have been adopted for overweight subjects revolve around the common theme of abstaining from food and caloric beverages for at least 12–24 hr on 1 or more days each week or month, depending on the length, combined with regular exercise. For those who are overweight, physicians could ask their patients to choose a fasting-based intervention that they believe they could comply with based upon their daily and weekly schedules. Examples include the ‘‘5:2’’ IF diet (Harvie et al., 2011), the alternate day modified fasting diet (Johnson et al., 2007; Varady et al., 2009), a 4–5 day fast (Lee et al., 2012; Safdie et al., 2009), or low-calorie-but high- nourishment fasting-mimicking diets once every 1–3 months fol- lowed by the skipping of one major meal every day if needed (V.D.L., unpublished data). One of the concerns with unbalanced alternating diets, such as those in which low calorie intake is only observed for 2 days a week, are the potential effects on circadian rhythm and the endocrine and gastrointestinal systems, which are known to be influenced by eating habits. During the first 4–6 weeks of implementation of the fasting regimen, a physician or registered dietitian should be in regular contact with the patient to monitor their progress and to provide advice and super- vision.

Fasting regimens could also be tailored for specific diseases as stand-alone or adjunct therapies. Results of initial trials of IF (fasting 2 days per week or every other day) in human subjects suggest that there is a critical transition period of 3–6 weeks dur- ing which time the brain and body adapt to the new eating pattern and mood is enhanced (Harvie et al., 2011; Johnson et al., 2007). Though speculative, it is likely that during the latter transition period brain neurochemistry changes so that the ‘‘addiction’’ to regular consumption of food throughout the day is overcome. Notably, the various fasting approaches are likely to have limited efficacy, particularly on aging and conditions other than obesity, unless combined with high-nourishment diets such as the moderate calorie intake and mostly plant-based Mediterranean or Okinawa low-protein diets (0.8 g protein/kg of body weight), consistently associated with health and longevity.

In the future, it will be important to combine epidemiological data, studies of long-lived populations and their diets, and results from model organisms connecting specific dietary components to proaging and prodisease factors, with data from clinical studies, to design large clinical studies that integrate fasting with diets recognized as protective and enjoyable. A better under- standing of the molecular mechanisms by which fasting affects various cell types and organ systems should also lead to the development of novel, FDA-approved prophylactic and preventive and therapeutic interventions for a wide range of disorders.
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Sat Sep 20, 2014 2:49 pm

The health pros and cons of continuous versus intermittent calorie restriction: More questions than answers
Malgorzata E. Skaznik-Wikielemailemail, Alex J. Polotsky
University of Colorado Anschutz Medical Campus, Department of Obstetrics and Gynecology, 12631 E 17th Avenue, B198-3, Aurora, CO 80045 United States
Received: August 2, 2014; Received in revised form: August 7, 2014; Accepted: August 9, 2014; Published Online: August 22, 2014
DOI: http://dx.doi.org/10.1016/j.maturitas.2014.08.007

http://www.maturitas.org/article/S0378-5122(14)00268-0/fulltext#sec0010

Highlights

•The two most popular diets include caloric restriction and intermittent fasting.

•Both may be beneficial for overall health and wellbeing.

•The research investigating their efficacy and long-term influence on general health is limited and mostly in animal models.

•Currently there are no properly designed clinical studies to formulate evidence-based practice recommendations.

Beneficial effects on health of limiting food intake for certain periods of time have been recognized for a long time. While many diets can produce short-term weight loss, most fail to result in a long-lasting impact. Current data suggest that intermittent fasting may be beneficial for overall health and wellbeing. However, the lack of properly designed clinical studies makes it challenging to formulate evidence-based practice recommendations. Potential health risks of drastic changes in food intake are often ignored and might only be revealed after extensive follow-up. This review summarizes the popular intermittent dieting methods and their potential impact on fertility and reproduction.
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Sun Oct 12, 2014 5:46 am

Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance.
Free Radic Biol Med. 2011 Oct 1;51(7):1454-60. doi: 10.1016/j.freeradbiomed.2011.07.006. Epub 2011 Jul 21.
PMID:21816219

Free Article
http://www.sciencedirect.com/science/ar ... 4911004473
http://ac.els-cdn.com/S0891584911004473 ... 5fa4ec3fff

Abstract

Calorie restriction is a dietary intervention known to improve redox state, glucose tolerance, and animal life span. Other interventions have been adopted as study models for caloric restriction, including nonsupplemented food restriction and intermittent, every-other-day feedings.

We compared the short- and long-term effects of these interventions to ad libitum protocols and found that, although all restricted diets decrease body weight, intermittent feeding did not decrease intra-abdominal adiposity. Short-term calorie restriction and intermittent feeding presented similar results relative to glucose tolerance. Surprisingly, long-term intermittent feeding promoted glucose intolerance, without a loss in insulin receptor phosphorylation. Intermittent feeding substantially increased insulin receptor nitration in both intra-abdominal adipose tissue and muscle, a modification associated with receptor inactivation. All restricted diets enhanced nitric oxide synthase levels in the insulin-responsive adipose tissue and skeletal muscle. However, whereas calorie restriction improved tissue redox state, food restriction and intermittent feedings did not. In fact, long-term intermittent feeding resulted in largely enhanced tissue release of oxidants.

Overall, our results show that restricted diets are significantly different in their effects on glucose tolerance and redox state when adopted long-term. Furthermore, we show that intermittent feeding can lead to oxidative insulin receptor inactivation and glucose intolerance.
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Tue Nov 18, 2014 6:40 am

Study

Meal timing during alternate day fasting: Impact on body weight and cardiovascular disease risk in obese adults.
Hoddy KK, Kroeger CM, Trepanowski JF, Barnosky A, Bhutani S, Varady KA.
Obesity (Silver Spring). 2014 Sep 24. doi: 10.1002/oby.20909. [Epub ahead of print]
PMID:25251676

http://www.ncbi.nlm.nih.gov/pubmed/25251676/?

Abstract

OBJECTIVE: Alternate day fasting (ADF; 24-h feeding/24-h 25% energy intake at lunchtime), is effective for weight loss, but diet tolerability is questionable. Moving the fast day meal to dinnertime, or dividing it into smaller meals, may improve tolerability. Accordingly, this study compared the effects of ADF with three meal times on body weight and heart disease risk.

METHODS: Obese subjects (n = 74) were randomized to 1 of 3 groups for 8 weeks: 1) ADF-L: lunch, 2) ADF-D: dinner, or 3) ADF-SM: small meals.

RESULTS: Body weight decreased similarly (P < 0.001) in all groups (ADF-L: 3.5 ± 0.4 kg, ADF-D 4.1 ± 0.5 kg, ADF-SM 4.0 ± 0.5 kg). Reductions (P < 0.001) in fat mass and visceral fat were also comparable. Plasma lipids remained unchanged, and low density lipoprotein (LDL) particle size increased (P < 0.05) in all groups (1.3 ± 0.5 Å). Systolic blood pressure decreased (P < 0.05) by ADF-SM only. Fasting glucose, insulin, and HOMA-IR remained unchanged.

CONCLUSION: Thus, allowing individuals to consume the fast day meal at dinner or small meals produces similar weight loss and cardio-protection as consuming the meal at lunch. This flexibility in meal timing may increase tolerability and long-term adherence to ADF protocols



Mass Media Article

Alternate Day Fasting Effectiveness Not Affected By Meal Timing
By Kari Oakes, PA-C | November 09, 2014

http://www.hcplive.com/conferences/ow-2 ... eal-Timing
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Mon Nov 24, 2014 1:29 pm

Meal frequency and timing in health and disease.
Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, Mosley M, Notterpek L, Ravussin E, Scheer FA, Seyfried TN, Varady KA, Panda S.
Proc Natl Acad Sci U S A. 2014 Nov 17. pii: 201413965. [Epub ahead of print]
PMID:25404320

Abstract

Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, the frequency and circadian timing of meals, and potential benefits of intermittent periods with no or very low energy intakes.

The most common eating pattern in modern societies, three meals plus snacks every day, is abnormal from an evolutionary perspective.

Emerging findings from studies of animal models and human subjects suggest that intermittent energy restriction periods of as little as 16 h can improve health indicators and counteract disease processes. The mechanisms involve a metabolic shift to fat metabolism and ketone production, and stimulation of adaptive cellular stress responses that prevent and repair molecular damage.

As data on the optimal frequency and timing of meals crystalizes, it will be critical to develop strategies to incorporate those eating patterns into health care policy and practice, and the lifestyles of the population.
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Sat Jan 17, 2015 5:46 pm

NIH videocast on the topic

Eating Patterns and Diseases

http://videocast.nih.gov/summary.asp?Live=13746&bhcp=1

In Health
Jeff
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Wed Jan 28, 2015 2:41 pm

An Interview with Valter Longo on Intermittent Fasting
Posted by Reason
23 Jan 2015

https://www.fightaging.org/archives/201 ... asting.php

Researcher Valter Longo is presently working on, among other things, packaging up intermittent fasting as a treatment with the sort of rigor needed to get it through clinical trials with the FDA. The work leading up the clinical trials involved putting numbers to the short term term benefits provided by fasting: how often and how long must someone fast in order to achieve specific changes in biomarkers of health, and how long do those effects last? The data will be useful for people who practice intermittent fasting as a health strategy, moving the state of scientific support for this strategy closer to that existing for the practice of calorie restriction with optimal nutrition.

Quote:

Calorie restriction is a very wide-ranging word. We focus more on periodic fasting - we're not really big believers in having people be on special diets or restrictions all the time. We just believe in interventions that are short and lasting, that can last a long time and protect from aging and age-related diseases. But also the use of these in improving disease treatment.

It has been very effective. Originally we did this in simple organisms to understand the molecular basis for it, and then moved to mice, and now we're finishing a number of clinical trials. The effects have been very, very promising. Most of it is not published in humans yet but a lot of it is already finished. So in the next year or so we're going to have at least 3 papers and clinical trials showing normal subjects, cancer subjects and also other diseases, showing the efficacy of these techniques, but also the high compliance that we get in doing this. So it's really something that we've found that most people can do.

As soon as the clinical trial is over basically that's it - people can start doing it. Now for the cancer one people could do it, but not to treat the cancer, only to reduce the side effects of chemotherapy. The cancer itself is regulated by the FDA so we'll have to continue our trials until these are FDA approved if we want to have the treatment included in therapy for delaying cancer progression. But of course people will do it anyway, because if you can use it with chemo obviously you're already using it to treat cancer but you just can't say.

The reduction of IGF-1 is really key in the anti-aging effects of some of the interventions. Both the dietary ones and the genetic ones. We've been putting a lot of work into mutations of the growth hormone receptor that are well established now to release IGF-1 and also cause a record life span extension in mice. So we know for example with chemotherapy resistance if you fast mice and inject IGF-1 you reverse a lot of the protective effects of fasting. So it's important; it's not the only factor, but it's certainly one of the key ones.

In Health
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Thu Jan 29, 2015 10:34 am

IGF-1 & Intermittent Fasting: Discussion with Dr. Valter Longo
2014/12/26
Christopher Edward Jones

http://michelsonmedical.org/2014/12/26/ ... ter-longo/

Groundwork

Valter Longo is Professor of Gerontology and Professor of Biological Science at the University of Southern California. He also serves as director of the USC Longevity Institute.

¦Dr Longo has established himself as an eminent and prolific researcher in the field of gerontology, recently being awarded the “Rising Star” Award in Aging Research from the American Federation for Aging Research (AFAR) in recognition of his work.

¦His research has so far revolved around the biology of aging, with a particular focus on the effects of fasting on the process of aging and the onset/progression of age-related disorders.

We were fortunate enough to have the opportunity to interview Dr Longo regarding his past research, upcoming publications and long-term plans.

A lot of your work has been into the effects of calorie restriction on age-related disorders, is this a deliberate area of focus for you?

Calorie restriction is a very wide-ranging word. We focus more on periodic fasting – we’re not really big believers in having people be on special diets or restrictions all the time. We just believe in interventions that are short and lasting, that can last a long time and protect from aging and age-related diseases. But also the use of these in improving disease treatment.

Are you surprised at how effective your research has shown periodic fasting to be?

It has been very effective. Originally we did this in simple organisms to understand the molecular basis for it, and then moved to mice, and now we’re finishing a number of clinical trials. The effects have been very, very promising. Most of it is not published in humans yet but a lot of it is already finished. So in the next year or so we’re going to have at least 3 papers and clinical trials showing normal subjects, cancer subjects and also other diseases, showing the efficacy of these techniques, but also the high compliance that we get in doing this. So it’s really something that we’ve found that most people can do.

So are you hopeful that down the line we will get treatments out of this research?

Not so much down the line but actually now. As soon as the clinical trial is over basically that’s it – people can start doing it. Now for the cancer one people could do it, but not to treat the cancer, only to reduce the side effects of chemotherapy. The cancer itself is regulated by the FDA so we’ll have to continue our trials until these are FDA approved if we want to have the treatment included in therapy for delaying cancer progression. But of course people will do it anyway, because if you can use it with chemo obviously you’re already using it to treat cancer but you just can’t say.

So would you advise someone undergoing chemotherapy to try cyclical fasting?

We can advise them to do it with their oncologist. You couldn’t advise them to do it for the sake of the cancer, jut for the sake of protecting their normal organs and cells from the effects of chemotherapy.

How about in healthy individuals? What would you expect to observe in disease-free individuals undergoing cyclical fasting?

We have finished all that, in both mouse and humans. So I can tell you we expect a lot. I can’t really talk about the results because they’re not published yet, but I will say yes, there’s a remarkable range of effects which is hardly matched by anything else I’ve ever seen.

2 to 5 Days Fasting
(A) In both mice and humans, fasting for 2 or 5 days, respectively, causes an over 50% decrease in IGF-I, a 30% or more decrease in glucose, and a 5–10-fold increase in the IGF-1 binding protein and inhibitor IGFBP1 (Cahill, 2006; Lee et al., 2012; Raffaghello et al., 2008; Thissen et al., 1994a, 1994b).

Endocrinological
(A) In both mice and humans, fasting for 2 or 5 days, respectively, causes an over 50% decrease in IGF-I, a 30% or more decrease in glucose, and a 5–10-fold increase in the IGF-1 binding protein and inhibitor IGFBP1 (Cahill, 2006; Lee et al., 2012; Raffaghello et al., 2008; Thissen et al., 1994a, 1994b).

Tumor Prevention
(A) In both mice and humans, fasting for 2 or 5 days, respectively, causes an over 50% decrease in IGF-I, a 30% or more decrease in glucose, and a 5–10-fold increase in the IGF-1 binding protein and inhibitor IGFBP1 (Cahill, 2006; Lee et al., 2012; Raffaghello et al., 2008; Thissen et al., 1994a, 1994b).

These and other endocrinological alterations affect the expression of hundreds of genes in many cell types and the consequent reduction or halting of growth and elevation in stress resistance, which may be dependent in part on FOXO and other stress resistance transcription factors. These periodically extreme conditions can promote changes, which are long lasting and delay aging and disease independently of calorie restriction, although the cellular mechanisms responsible for these effects remain poorly understood. In the presence of chemotherapy drugs, fasting can promote the protection of normal, but not cancer, cells (differential stress resistance [DSR]), since oncogenic pathways play central roles in inhibiting stress resistance, and therefore, cancer cells are unable to switch to the stress response mode.

(B) The extreme changes caused by fasting, and particularly the very low IGF-1 and glucose levels and high IGFBP1, also generate a tumor prevention environment that promotes cancer cell death, since transformed cells have acquired a number of mutations that progressively decrease their ability to adapt to extreme environments (differential stress sensitization [DSS]) (Guevara-Aguirre et al., 2011; Lee et al., 2010, 2012).

These and other endocrinological alterations affect the expression of hundreds of genes in many cell types and the consequent reduction or halting of growth and elevation in stress resistance, which may be dependent in part on FOXO and other stress resistance transcription factors. These periodically extreme conditions can promote changes, which are long lasting and delay aging and disease independently of calorie restriction, although the cellular mechanisms responsible for these effects remain poorly understood. In the presence of chemotherapy drugs, fasting can promote the protection of normal, but not cancer, cells (differential stress resistance [DSR]), since oncogenic pathways play central roles in inhibiting stress resistance, and therefore, cancer cells are unable to switch to the stress response mode.

These and other endocrinological alterations affect the expression of hundreds of genes in many cell types and the consequent reduction or halting of growth and elevation in stress resistance, which may be dependent in part on FOXO and other stress resistance transcription factors. These periodically extreme conditions can promote changes, which are long lasting and delay aging and disease independently of calorie restriction, although the cellular mechanisms responsible for these effects remain poorly understood. In the presence of chemotherapy drugs, fasting can promote the protection of normal, but not cancer, cells (differential stress resistance [DSR]), since oncogenic pathways play central roles in inhibiting stress resistance, and therefore, cancer cells are unable to switch to the stress response mode.

(B) The extreme changes caused by fasting, and particularly the very low IGF-1 and glucose levels and high IGFBP1, also generate a tumor prevention environment that promotes cancer cell death, since transformed cells have acquired a number of mutations that progressively decrease their ability to adapt to extreme environments (differential stress sensitization [DSS]) (Guevara-Aguirre et al., 2011; Lee et al., 2010, 2012).

The hormone IGF-1 comes up a lot in your research; it seems to be a big factor in mediating the effects of calorie restriction and fasting. How big of a role do you think IGF-1 is playing overall in aging?

I think it’s a pretty big role, though it’s not the only thing that’s important. The reduction of IGF-1 is really key in the anti-aging effects of some of the interventions. Both the dietary ones and the genetic ones. We’ve been putting a lot of work into mutations of the growth hormone receptor that are well established now to release IGF-1 and also cause a record life span extension in mice. So we know for example with chemotherapy resistance if you fast mice and inject IGF-1 you reverse a lot of the protective effects of fasting. So it’s important; it’s not the only factor, but it’s certainly one of the key ones.

So could we expect drugs targeting IGF-1 to work in humans?

We’re working on that both with the diet but also with drugs. So we’ve been working on that for a while and we’re getting closer to it. Of course the pharmacological part is much more complicated and expensive and so eventually we need to have big pharma partnered to do it – and that may occur very soon. But yes the growth hormone receptor/IGF-1 pathway is going to be our first target. And in fact we just organised a conference about a year ago on this, on an intervention to extend the human health span in targeting the growth hormone/IGF-1 pathway. We brought 30 of the leading experts in the world on this to Sicily and at the end everybody voted and the growth hormone IGF-1 came out most likely to be active in extending human lifespan.

So is that the direction your research will be heading in over the next few years?

Yes. And of course we are even more interested in regeneration and rejuvenation now. We just published a paper on that, showing how fasting and IGF-1 can cause stem cell based regeneration and rejuvenation of the immune system. So half of my lab has now switched to understanding how this can regenerate systems – and not just regenerate in an unsophisticated way, but regenerate in a very sophisticated way which is reminiscent of what you see during early development.

IGF-1: Insulin-like growth factor 1

IGF-1

Protein

Insulin-like growth factor 1 (IGF-1) is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a “sulfation factor” and its effects were termed “nonsuppressible insulin-like activity” (NSILA) in the 1970s. IGF-1 is a hormone similar in molecular structure to insulin and consists of 70 amino acids in a single chain with three intramolecular disulfide bridges.

Hormone

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B.

Lifetime

IGF-1 is produced throughout life: it plays an important role in childhood growth and continues to have anabolic effects in adults. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Influence

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption. Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.

Reduction

Fasting, including intermittent fasting, can reduce IGF-1 levels rapidly and dramatically

Insulin-like growth factor 1 (IGF-1) is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a “sulfation factor” and its effects were termed “nonsuppressible insulin-like activity” (NSILA) in the 1970s. IGF-1 is a hormone similar in molecular structure to insulin and consists of 70 amino acids in a single chain with three intramolecular disulfide bridges.

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B.

IGF-1 is produced throughout life: it plays an important role in childhood growth and continues to have anabolic effects in adults. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption. Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.

Fasting, including intermittent fasting, can reduce IGF-1 levels rapidly and dramatically

Do you have any predictions for where you’ll be in 10 years’ time?

In 10 years’ time we hope that a lot of what we’ve been doing is actually out there. I don’t think it is going to be used by everybody, but judging by the success of Michael Mosley’s 5:2 diet, which is in part taken from our work and the work of Michelle Harvie and others, and is now one of the best-selling books – in fact the best-selling book – in England for the past two or three years, and also one of the best-selling books in the US. So these diets are now making it into the, not mainstream, but certainly are getting exposure. So we hope that we get to a point where maybe 10-20% of the population are using these on a regular basis so that they in some ways, stay away from medicine and drugs and doctors.

I suppose that may be especially beneficial in the UK where we have the NHS; there will be less pressure placed on the service. Maybe these non-pharmacological approaches are the way forward.

Yes I think so. I was surprised at England and the people there – just how supportive it was. Maybe more than any place else in the world. It was interesting how that happened. So I don’t know if there’s something special about England in that sense, but it’s interesting. I was very surprised that that would be two years in a row the best-selling book out of all books – you would think there would be fiction books or something that people would be more interested in than a book on fasting.

It’s good that it’s having an impact. It’s good that people are listening.

Yes. It’s important for us. I can see in my lab – and I have a lab both here and in Europe – that when they can see people – when they feel that people are doing it and the media is interested – they are much more excited about what we’re going to do next and what problem we are going to solve next. I think that’s absolutely important.


Valter Longo’s fields of study include the understanding of the fundamental mechanisms of aging in yeast, mice and humans by using genetics and biochemistry techniques, identifying the molecular pathways conserved from simple organisms to humans that can be modulated to protect against multiple stresses and treat or prevent cancer, Alzheimer’s Disease and other age-related diseases. The focus is on the signal transduction pathways that regulate resistance to oxidative damage in yeast and mice. Photo Credit: Michelson Medical Research Foundation [MMRF].
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Mon Apr 06, 2015 3:23 pm

5) Effects of intermittent compared to continuous energy restriction on short-term weight loss and long-term weight loss maintenance. Keogh JB, Pedersen E, Petersen KS, Clifton PM. Clin Obes. 2014 Jun;4(3):150-6. doi: 10.1111/cob.12052. Epub 2014 Mar 6. PMID:25826770

http://onlinelibrary.wiley.com/doi/10.1 ... 2/abstract

Abstract

Effective strategies are needed to help individuals lose weight and maintain weight loss.

The primary aim of this study was to investigate the effect of intermittent energy restriction (IER) compared to continuous energy restriction (CER) on weight loss after 8 weeks and weight loss maintenance after 12 months. Secondary aims were to determine changes in waist and hip measurements and diet quality.

In a randomized parallel study, overweight and obese (body mass index [BMI] =/> 27 kg m(-2) ) women were stratified by age and BMI before randomization. Participants undertook an 8-week intensive period with weight, waist and hip circumference measured every 2 weeks, followed by 44 weeks of independent dieting. A food frequency questionnaire was completed at baseline and 12 months, from which diet quality was determined.

Weight loss was not significantly different between the two groups at 8 weeks (-3.2 ± 2.1 kg CER, n = 20, -2.0 ± 1.9 kg IER, n = 25; P = 0.06) or at 12 months (-4.2 ± 5.6 kg CER, n = 17 -2.1 ± 3.8 kg IER, n = 19; P = 0.19). Weight loss between 8 and 52 weeks was -0.7 ± 49 kg CER vs. -1 ± 1.1 kg IER; P = 0.6. Waist and hip circumference decreased significantly with time (P < 0.01), with no difference between groups. There was an increase in the Healthy Eating Index at 12 months in the CER compared with the IER group (CER 8.4 ± 9.1 vs. IER -0.3 ± 8.4, P = 0.006).

This study indicates that intermittent dieting was as effective as continuous dieting over 8 weeks and for weight loss maintenance at 12 months. This may be useful for individuals who find CER too difficult to maintain.
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Sun May 10, 2015 6:24 pm

Safety of alternate day fasting and effect on disordered eating behaviors.
Hoddy KK, Kroeger CM, Trepanowski JF, Barnosky AR, Bhutani S, Varady KA.
Nutr J. 2015 May 6;14(1):44. [Epub ahead of print]
PMID:25943396
http://www.nutritionj.com/content/14/1/44
http://www.nutritionj.com/content/pdf/s ... 0029-9.pdf

Abstract

BACKGROUND: Alternate day fasting (ADF; ad libitum intake "feed day" alternated with 75% restriction "fast day"), is effective for weight loss, but the safety of the diet has been questioned. Accordingly, this study examined occurrences of adverse events and eating disorder symptoms during ADF.

FINDINGS: Obese subjects (n = 59) participated in an 8-week ADF protocol where food was provided on the fast day. Body weight decreased (P < 0.0001) by 4.2 ± 0.3%. Some subjects reported constipation (17%), water retention (2%), dizziness (<20%), and general weakness (<15%). Bad breath doubled from baseline (14%) to post-treatment (29%), though not significantly. Depression and binge eating decreased (P < 0.01) with ADF. Purgative behavior and fear of fatness remained unchanged. ADF helped subjects increase (P < 0.01) restrictive eating and improve (P < 0.01) body image perception.

CONCLUSIONS: Therefore, ADF produces minimal adverse outcomes, and has either benign or beneficial effects on eating disorder symptoms
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Fri Jun 19, 2015 2:48 am

This may be the most interesting work to date on the topic. It included a pilot test in humans of 3 cycles. As noted in the above Diane Rehm interview.....

viewtopic.php?f=22&t=36724&p=499823#p431231

... Longo's belief is that longer fasts periods of 3-5 days, done less often (about 1x per month) are the most effective form of Intermittent Fasting.

In a pilot clinical trial (in humans), three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

It is interesting to note that maximal lifespan, a benefit of CR, was not extended in this study.

In Health
Jeff

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan
Cell Metabolism. Volume 22, Issue 1, p86–99, 7 July 2015
http://dx.doi.org/10.1016/j.cmet.2015.05.012


Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00224-7

http://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(15)00224-7
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Re: Reflecting On The 5:2 Diet & Intermittent Fasting

Postby JeffN » Wed Jul 22, 2015 6:33 pm

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity.
CALERIE Study Group. J Gerontol A Biol Sci Med Sci. 2015 Jul 17. pii: glv057. [Epub ahead of print]
PMID: 26187233

Abstract

BACKGROUND:
Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR.

METHODS:
To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change ("RMR residual") and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.

RESULTS:
Body mass index averaged 25.1 (range: 21.9-28.0kg/m2). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean±standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.

CONCLUSIONS:
Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.






Two-Year Trial of Human Caloric Restriction.
J Gerontol A Biol Sci Med Sci. 2015 Jul 17. pii: glv100. [Epub ahead of print]

PMID: 26187232
Calorie restriction (CR) retards aging and extends mean and maximal life span in most species tested (1). However, whether prolonged CR increases life span in long-lived species (such as primates) is still controversial. Although two independent studies addressing the effects of CR in monkeys have shown different outcomes on life span, both converge into the fact that CR delays the onset and impact of age-related diseases (2,3). In humans, the evidence of beneficial effects of CR derives from observational studies in longer-lived population in Okinawa, Japan (4) and from individuals who self-impose CR (5,6). In the latter, severe food restriction causes several metabolic and molecular changes associated with CR in animals that protect against age-related pathologies, including changes in markers for type 2 diabetes, hypertension, cardiovascular disease, cancer, and dementia (7). However, only a limited number of people have the discipline to follow the duration and severity of the CR regimen that is required for optimal benefits. In light of this, it became an important research objective to assess the feasibility, safety, and health-related outcomes of prolonged CR in a well-controlled human clinical trial.

In this edition of the Journal of Gerontology, Ravussin and colleagues (8) report the results obtained from the CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy) research program. This is the first systematic investigation of CR in nonobese human beings. The hypothesis being tested was that 2 years of sustained CR, involving a 25% reduction of ad libitum energy intake, results in beneficial effects similar to those observed in model organisms. This study was a three-site control trial of 218 nonobese men and women aged 21–51 years, randomized to a 2-year intervention designed to achieve 25% CR or to ad libitum diet. The two primary outcomes were selected to test the hypothesis whether CR would induce metabolic adaptations proposed to slow aging in laboratory animals, a decrease in resting metabolic rate, and a decrease in core body temperature. Other secondary outcomes were serum triiodothyronine (T3) and tumor necrosis factor-alpha, based on evidence suggesting relationships of the thyroid axis and inflammatory mediators of longevity and health span (9–11).

The authors report high level of compliance, 82% of CR completed the study, albeit with a lower than expected reduction in caloric intake (12%), resulting in 10.4% sustained weight loss over the 2 years. Residual resting metabolic rate decreased significantly more in CR than ad libitum diet at 12 months but not at 24 months. Core temperature differed little between the groups. T3 decreased more in CR at 12 and 24 months, whereas tumor necrosis factor-alpha decreased significantly more only at 24 months. Overall, CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.

The authors conclude that this level of sustained CR (12%) is both feasible and had no adverse effects in the quality of life of the participants. Because the intervention affected some, but not all, potential proposed mediators of longevity induced by CR in laboratory animals, further studies are needed to expand on the potential impact of greater levels of CR on human quality of life, health, and survival. As clearly stated by the authors, CALERIE involves a highly motivated population and very intensive behavioral intervention, thus caution is taken regarding the feasibility of CR in broader nonobese populations. Another recent study, a meta-analysis of randomized controlled trials of long-term weight loss (greater than 18 months), yielded further evidence that intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality (12).

Nonetheless, CALERIE has important implications for the design of a longer-term follow-up comprising a longer portion of the human life span than 2 years. This would permit a more meaningful comparison between the impact of CR in human populations and laboratory animal studies. Clinical trials in humans are unlikely to use life span as an initial primary outcome. Thus, there is an urgent need to develop a consensus for validated biomarkers of aging, optimally across species that can be objectively measured and evaluated in longitudinal studies (13).
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