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Showing posts with label calorie restriction. Show all posts
Showing posts with label calorie restriction. Show all posts

Tuesday, 21 October 2014

Can we count on counting calories?

reposted from: http://www.nhs.uk/news/2014/10October/Pages/Can-we-count-on-counting-calories.aspx
crabsallover highlightskey pointscomments / links.

It's a concept at the cornerstone of most diets: counting the calories of your food intake so you don't go over the limit.
But just how accurate are calorie labels? And are some calories more "equal" than others?
There is a seemingly endless stream of media articles focusing on the latest diet wonder, whether it involves intermittent fasting or feasting on fats.
Although they protest otherwise, most miracle weight loss programmes come down to calorie restriction.
Behind the Headlines takes a look at the science behind calorie counting, examining why it may be only one aspect of healthy, sustainable weight loss.

Systematic review

This article is not asystematic review, where a team carries out a synthesis of the relevant medical research on a given subject

What's in a calorie?

A calorie is a unit of measurement of how much energy is stored in a mass of food.
Confusingly, the "calories" we talk about in daily life are officially described as kilocalories, or kcals, and this is how they appear on food labels. One calorie equals one kilocalorie.
A single calorie is defined as having approximately the amount of energy needed to raise the temperature of one kilogram of water by 1C. 

Calorie allowances

An average man needs around 2,500kcal a day. For an average woman, that figure is around 2,000kcal a day.
These values can vary widely depending on levels of physical activity. For example, some Olympic swimmers have reported eating as many as 12,000 calories a day when they are competing.

How the laws of the universe affect your weight

When we're dealing with energy, there is one law we always have to consider – the first law of thermodynamics.
The first law is one of the immutable laws of the universe, up there with death, taxes and how you can't travel faster than the speed of light.
It states that energy can never be destroyed, only changed from one form to another. Most of the energy in the universe is in the form of mass: solid objects.
It's easy to underestimate how much energy is stored in mass. For example, the energy contained in a single apple is enough to boil a litre of water.
The complex chemical processes whereby the energy in food is transformed into energy in our bodies makes up part of the metabolism. Metabolism is all the chemical processes that go on continuously inside the body to keep you alive and well, such as breathing, repairing cells and digesting food.
Even when you're having a snooze, your body requires energy for automatic processes such as breathing and keeping your heart beating. This minimal energy requirement is known as your basal metabolic rate (BMR).
Your BMR accounts for anything between 40% and 70% of your body's daily energy requirements, depending on your age and lifestyle.
Any extra energy you consume above your BMR will either be used by your body when you perform any physical activity, or will be stored as mass.
If you regularly do anaerobic activities (high-intensity activities that make use of physical strength, such as sprinting and weight lifting), any extra energy should be stored as muscle (or more specifically, in the form of glycogen, a converted form of glucose found in muscle tissue).
But if, like many of us, you are not exercising enough, any excess energy will be stored as fat.

The inventor of calorie counting

Much of what we know about the calorie content of different foods is down to one man: Wilbur Olin Atwater.
Atwater was a 19th century American nutritionist who spent most of his career measuring the calorie content of different foods. He used a variety of methods that became known as the Atwater system.
Key to this system was a device he invented called the respiration calorimeter.
The body needs oxygen from the air we breathe to release energy from the food we eat. In the process, carbon dioxide is released, which we breathe out.
Atwater's respiration calorimeter was a chamber that measured the use of oxygen and the production of carbon dioxide when people were placed inside the chamber after eating certain foods.
By measuring this, the calorimeter was able to estimate the heat and metabolic activity different foods produced.
As well as using the evidence provided by calorimeters, the Atwater system also used mathematical equations to take into account factors such as energy lost through urine, faeces and various gases.

How accurate is the Atwater system?

Atwater was essentially working blind. But with no previous body of research to build on and using Victorian-era technology, his work is surprisingly (but not entirely) accurate.
And while flaws in his original techniques have been widely discussed, no credible alternative methods of measuring calorie contents have been produced.
Calorimeters – albeit more advanced versions – are still used by dietitians and food makers to estimate the calorie content of foods today.
But there is evidence that some of the underlying mathematics of the Atwater system fails to take into account certain vagaries of the human digestive system.
For example, in a 2012 study researchers had the unenviable task of picking through faeces samples from 18 healthy adult volunteers to check for undigested food stuffs.
They found the body has difficulty digesting almonds. The Atwater system failed to take this into account, so, according to the study, wrongly overestimated the energy content of almonds by 32%. The researchers argued a similar overestimation of energy content could apply to other nuts.
According to biochemist Professor Richard Feinman, this flaw in the Atwater system is the result of a failure to appreciate the second law of thermodynamics.

Calories and metabolic efficiency

The Atwater system, and calorie counting in general, is based on the principle of "a calorie is a calorie". What you eat, whether it is honey, hummus or haddock, is unimportant. It's the amount you eat, right?
Feinman argued that this approach, while seemingly logical, is flawed because it does not take the second law of thermodynamics into account.
This law states any complex system will experience increasing disorder over time. All systems have an ingrained inefficiency. The energy that drives organisms, machines and processes will always "leak out", usually in the form of heat.
Our digestive systems, as marvellous as they are, cannot overcome this ingrained inefficiency. Some energy will always leak out.
The level of inefficiency varies depending on the type of food being eaten – a concept known as metabolic efficiency. The higher the metabolic efficiency, the more energy you receive from food.
Foods with poor metabolic efficiency are known as having a "metabolic advantage" – they make your metabolism work harder, so you are less likely to gain weight from eating them.
There are many things that can affect metabolic efficiency, not least cooking. As a 2009 anthropological paper argued, it was the discovery of fire – and, by extension, cooking – that probably kept the human race from dying out during the last ice age.
Cooked foods, especially cooked carbohydrates, have a far superior metabolic efficiency compared with raw fruit and vegetables.
Cooking may also have been responsible for the rapid development in brain power that occurred over the past 100,000 years (our brains use 20% of the body's total energy intake).
This is great if you are trying to survive in your cave through the winter. But it's not so great if you are tying to lose weight.

Calories in processed foods

In industrialised countries, much of our diet is made up of processed foods such as crisps, biscuits, burgers and ready meals. Processed foods have been found to have a very effective metabolic efficiency.
2010 US study bears this out. In the study, a small group of volunteers were assigned to eat one of two cheese sandwiches:
  • a processed-food sandwich – made up of white processed bread and processed cheese "products"
  • a "whole-food" sandwich – made up of multigrain bread and cheddar cheese
The interesting part of the experiment is that both sandwiches had roughly the same nutrition content:
  • 20% protein
  • 40% carbohydrate
  • 40% fat
A spirometer (a device used to measure airflow in and out of the lungs) was then used to estimate how much energy the body used (in terms of calorie consumption) when digesting the sandwiches.
The whole-food sandwich took around 137 calories to digest, which accounted for 19.9% of the total energy provided by the meal. The processed-food sandwich only took 73 calories to digest, which accounted for 10.7% of the total energy provided by the meal.
Imagine we took two identical twin brothers – Alan and Bob – and made them stick to different diets over the course of a year, but did not allow them to exercise.
Bob – eating the processed food sandwich – would theoretically put on around twice the amount of weight as Alan, even though the nutritional content of their diet was identical in terms of protein, carbohydrates and fats.
Another concern about processed foods is that they tend to have a high sugar content. Even foods you would never suspect, such as pizza, yoghurt and cheese, are often fortified with sugar.
Campaigners have warned that added sugar increases the risk of developing type 2 diabetesmetabolic syndrome and fatty liver disease. Read more about the potential dangers of sugar.

Why a balanced diet is as important as calories

Focusing solely on the calorie content of your food at the expense of its nutritional value could lead to health problems further down the line.
Interestingly, a 2014 study looked at a series of the more fashionable diets and found they were all pretty similar in terms of achieving weight loss.
Many of these diets are based on the idea that excluding certain types of food can essentially "hack" the metabolism, causing it to burn off weight at an increased rate and increase your metabolic advantage.
For example, the Atkins diet is based on the principle that by cutting carbohydrates out of your diet, the body is forced to look elsewhere to find glucose so it starts burning fat – a process known as ketosis.
Attempting to "cheat" the metabolism comes at a cost. In the short term, ketosis resulting from a low-carb diet can lead to symptoms such as nausea and bad breath. But in the long-term, it may cause kidney problems such as kidney disease and kidney stones.
Keeping your carbohydrate intake at around the recommended levels, where they make up around a third of your dietary intake, has been shown to lower heart disease risk and reduce body weight.
Ultimately, there is no such thing as an inherently "bad" type of food. It is common for certain types of food to be demonised in the press and by the diet industry: one month it's carbohydrates, the next sugars, and the month after that saturated fats. The truth is we need all three to function properly. The important thing is to get the balance right.
Current recommendations say the main staples of your diet should be fruit and vegetables, as well as starchy foods such as rice and pasta. We should also include a moderate amount of protein, such as meat and eggs, and a moderate amount of dairy products such as milk and cheese. And then just a small amount of saturated fats and sugars completes a balanced diet.
For more detailed information, see the Eatwell plate.

Can you think your way thin?

As well as focusing on the physical aspects of your diet, it may also be beneficial to look at your emotional and psychological attitudes towards diet, eating and the role of food as a reward or addiction.
Focusing on only the physical issue of calories and ignoring the psychological aspect of your eating habits will probably not lead to sustainable, long-term weight loss.
There is a growing body of research to suggest that combining a calorie-controlled diet with a talking therapy known as cognitive behavioural therapy (CBT) can be effective in helping people lose weight.
CBT is based on the principles of identifying unhelpful and unrealistic patterns of thinking and behaviour, and then trying to replace them with more helpful and realistic patterns to improve health outcomes.
Many researchers are now combining elements of CBT with traditional calorie-controlled diets in an approach known as "behavioural weight loss".
2011 study looked at how well behavioural weight loss fared when compared with the standard CBT programme. It found people treated with CBT were more likely to have remissions from bingeing behaviour, but also lost a little weight.
Those treated with behavioural weight loss had a lower rate of remission (36% compared with CBT's 51%), but experienced a statistically significant drop in BMI.
And over the course of 2014 there have been three interesting studies covered by Behind the Headlines about the impact of psychology on eating habits:
If you think you could benefit from CBT or behavioural weight loss, your GP or the doctor in charge of your care should be able to provide more information.
Even if you are not a binge eater, you may find there are certain triggers that cause you to throw your good intentions out the window and have a sudden splurge.
These triggers may be emotional, such as feeling stressed, anxious or bored. They can also be environmental, such as going to the cinema, the local pub or dining out with friends.
Environmental "cues" that can trigger overeating shouldn't be overlooked. A study from August 2014 found people who ate in "posh" restaurants consumed just as many calories as those who ate fast food. Learning to spot these "diet danger zones" is a useful exercise  being forewarned is to be forearmed.
Many psychologists with an interest in weight loss have warned against adopting an extremely rigid attitude towards calorie consumption. The more rigid the rules of your diet, the more likely it is you will just give up on the whole thing if you find yourself breaking the rules.
Rather than setting a strict daily limit on calories, it may be a better idea to set weekly limits. So if you do find yourself slipping up one day, you can always make up for it over the rest of the week.

Do calories matter?

Calories do matter. There is no getting away from that fact. If you repeatedly eat more calories than you burn off, you will put on weight. It's the first law of thermodynamics.
But is obsessively focusing on the calorie content of everything you put in your mouth a healthy and sustainable way to achieve weight loss and improve your health? Possibly not.
Emerging evidence (summarised in recent NICE guidelines on managing overweight and obese adults) suggests a structured and holistic plan to change behaviour, and not just calorie intake, is the most effective way to achieve healthy, sustained weight loss.
Calories do count, but exercise and being more active, learning more about nutrition, and eating a balanced diet are also important.
An evidence-based weight loss plan that incorporates a combination of all the factors listed above can be downloaded free from the NHS Choices website. 

Links to the science

Bleich SN, Wolfson JA, Vine S, Wang YC. Diet-beverage consumption and caloric intake among US adults, overall and by body weight. American Journal of Public Health. Published online March 2014
Carmody RN, Wrangham RW. The energetic significance of cooking. Evolutionary Anthropology. October 2009
Daumit GL, et al. A Behavioral Weight-Loss Intervention in Persons with Serious Mental Illness. New England Journal of Medicine. April 25 2013
Feinman RD, Fine EJ. 'A calorie is a calorie' violates the second law of thermodynamics. Nutrition Journal. July 28 2004
Frost G, Sleeth ML, Sahuri-Arisoylu M, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nature Communications. Published online April 29 2014 
Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA. September 3 2014
National Institute for Health and Care Excellence. Managing overweight and obesity in adults – lifestyle weight management services. May 2014
Nguyen BT and Powell LM. The impact of restaurant consumption among US adults: effects on energy and nutrient intakes. Public Health Nutrition. Published online July 30 2014
Novotny JA, Gebauer SK, Baer DJ. Discrepancy between the Atwater factor predicted and empirically measured energy values of almonds in human diets. American Journal of Clinical Nutrition. July 3 2012 

Tuesday, 12 March 2013

Resveratrol increases sirtuins.

reposted from: NHS Choices
crabsallover highlightskey pointscomments / links.

Further to the article by David Stipp in Scientific American blog, reviewed by me a few days ago...

Drugs that could help people 'to live to 150' could soon be a reality, according to headlines in The Daily Telegraph and the Daily Mail.
The news comes from molecular-level research into the compound resveratrol, which is found in red wine and dark chocolate, and has been shown to increase the activity of proteins called sirtuins.
These proteins are able to increase the lifespan of yeast, worms and flies, and it has been suggested that they may also play a role in human age-related diseases such as Alzheimer's disease.
This laboratory study looked at whether a synthetic version of resveratrol could stimulate the activity of sirtuins to such an extent that it could theoretically improve human life expectancy.  
Although the researchers found that these compounds directly activated the sirtuin proteins, it is far too early and optimistic to claim that a pill could be created that would allow people to live to 150.
This study was interested in biological processes in a laboratory, not the development of an anti-ageing pill. No pill has been made to improve life expectancy in humans, and the '150-year' claim seems to have been manufactured by the headline writers. Dreams of a pill that will allow you to live to 150 remain just that: dreams.

Red wine and resveratrol

Red wine only contains tiny amounts of resveratrol. Any hopes that a bottle of red will extend your lifespan are unfounded.

Where did the story come from?

The study was carried out by researchers from Harvard Medical School, the Massachusetts Institute of Technology, the US National Institutes of Health, the pharmaceutical company GlaxoSmithKline, and other institutions in Portugal and Australia.
The research was funded by research organisations throughout the US and Portugal. No funding support was reported for GlaxoSmithKline (GSK), although a GSK company (Sirtris) employs several of the researchers involved in the project, and one author is an inventor on patents licensed to this company.
Patents have also been filed by Harvard Medical School on the tests developed in their study, as well as by Sirtris and another company for some of the compounds tested.
The study was published in the peer-reviewed journal Science.
Headlines proclaiming that a pill has been developed that will help us live to 150 are highly flawed. It is also unclear what evidence these claims are based on, such as the Daily Mail stating that a pill could be "available within five years". Indeed, it is nearly two years since the last time the Mail ran a story on very similar news.
This laboratory research tested whether, and how, a class of compounds can increase the activity of a particular enzyme previously identified as being involved in a range of age-related diseases.
The research did not assess whether these compounds have the same effect when given to humans in a pill, if there is any effect on human disease or lifespan, or whether such a pill would be safe.
Much more research is needed before we know if these compounds could show any effect on human lifespan.

What kind of research was this?

This was a laboratory study that examined the ways that molecules called sirtuin-activating compounds (STACs) may increase the activity of the protein sirtuin-1 (SIRT1). 
Previous research has found that activating sirtuin proteins leads to a longer lifespan in yeast, flies and worms. It has been suggested that SIRT1 plays a role in many age-related conditions, including cancerAlzheimer's disease, and type 2 diabetes.
Researchers report that SIRT1 has been shown to be involved in several processes surrounding these conditions, including controlling DNA repair and natural cell death, insulin secretion and inflammatory pathways, among others.
These findings make it an attractive drug target, as researchers hope that drugs that safely activate this protein could improve human health and extend our lifespan.
Previous research has shown that both synthetic and naturally occurring STACs (including resveratrol) can activate SIRT1 in the laboratory.
However, there has been debate as to whether this activation was a real, direct effect of STACs, or if it was caused by fluorescent chemical compounds called fluorophores, which are used to monitor the effects of STACs during experiments.
Fluorophores are widely used in laboratory research, as they make it easier to measure chemical changes to these proteins. However, they do not occur naturally in the human body and they may change what naturally happens in the reactions being tested.
There is the risk of a kind of biological Heisenberg Uncertainty principle: the act of observation could change the system you are trying to observe. This means that if the STACs cannot really directly activate SIRT1 in the body, and only do so in the laboratory due to the presence of the fluorophores, they would no longer be potential candidates for treating age-related diseases or extending lifespan.
The set of experiments described in the current study were designed to determine whether STACs were able to directly activate SIRT1, and to identify the precise way that such activation occurs.

What did the research involve?

The researchers carried out a series of complex laboratory experiments to determine whether a range of STACs were able to activate SIRT1. They developed a new way of measuring SIRT1 activation that did not require the use of fluorophores, so that these compounds could not affect the reactions.
The SIRT1 protein acts by modifying a range of different proteins, and the researchers tested whether the STACs enhanced the effect of SIRT1 across this range of proteins, or only on certain proteins. They also assessed how STACs might be having this effect.

What were the basic results?

The researchers found that STACs could activate SIRT1 in the laboratory, even if fluorophores weren't present.
They found that this increase in SIRT1 activity only affected proteins that had a specific type of amino acid in a particular position in the protein.
They found similar findings for all of the 118 STACs tested, including resveratrol.

How did the researchers interpret the results?

The researchers felt that their results meant that a range of STAC compounds can activate SIRT1, and that this process "remains a viable therapeutic intervention strategy for many diseases associated with ageing".

Conclusion

As yet, there is no pill that allows us to live to 150 years old. The research these claims are based on actually aimed to resolve debate about whether STACs, such as the resveratrol found in red wine, can activate the ageing- and disease-related SIRT1 protein. The results suggest that these compounds do in fact directly activate this protein.
Compounds that can activate the SIRT1 protein are of great interest to longevity researchers. This is because they have found that activating similar sirtuin proteins in yeast, flies and worms extends their lifespan. It remains to be seen whether or not producing these compounds can increase the human lifespan. 
Researchers have pointed out that the amount of resveratrol in red wine is significantly lower than the amounts fed to mice in previous research. The lead researcher said that, "at least 100 glasses [of red wine] would be needed each day to get the levels shown to improve health in mice". Research is also being conducted into similar synthetic chemicals, as some of these seem to have greater effects in the laboratory.
This type of study is a necessary and useful early step in the development of drugs. On its own, however, it is certainly not sufficient evidence for us to be able to say that STAC compounds can reverse human ageing or help us live for 150 years.
Media claims that such a pill is five years around the corner are ludicrously optimistic. While researchers suggest that pre-clinical studies in mice have been initiated, these studies would need to prove effective and safe, and then be followed by furtherrandomised control trials in humans.
It is important to note that the media coverage of this research failed to highlight the fact that the best way to reap the benefits of sirtuins is to take regular exercise.
Rather than waiting for scientists to develop a wonder drug, why not go for a walk in your local park, go for a swim or have a leisurely bike ride? Read more about the importance of exercise for older adults.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links to the headlines

Pill to live to 150. The Daily Telegraph, March 10 2013

Links to the science

Hubbard BP, Gomes A, Dai H, et al. Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Science. Published online March 8 2013

Saturday, 9 March 2013

Sirtuin mechanism, resveratrol & calorie restriction by David Stipp

reposted from: Scientific American Blogs
crabsallover highlightskey pointscomments / links.


What is it about sirtuins? Few research topics have engendered fiercer controversy in recent years than these enzymes, channels through which the famous red-wine ingredient resveratrol appears to exert effects like those of calorie restriction, a reduction of food intake known to slow ageing in many species.

The most basic bone of contention is whether resveratrol really activates sirtuins. The idea that it revs up the enzymes dates from the first study that suggested it has anti-ageing power—a 2003 investigation led by Harvard University’s David Sinclair. Two years later, other researchers published studies suggesting that resveratrol only stimulates sirtuins in misleading test-tube assays—and probably not in living cells. The skeptics’ findings put a cloud over Sinclair’s research and raised questions about work at Sirtris Pharmaceuticals, a biotech he cofounded.

But now Sinclair’s group has marshalled evidence that sirtuin activators really do stimulate the enzymes as originally proposed—at least in certain situations. Their new findings are reported in the March 8 issue of Science in a study coauthored by Sirtris researchers. A second study led by Clemens Steegborn at the University of Bayreuth in Germany, published this week in Aging, supports the Harvard group’s analysis.

Together the studies “appear to elegantly resolve” the mechanism controversy, according to a commentary in Aging by Sita Kugel and Raul Mostoslavsky, researchers at Massachusetts General Hospital in Boston. Mostoslavsky is a member of Sirtris’s scientific advisory board.

The new data won’t end the sirtuins debate, which concerns issues besides the mechanism question—the most hotly contested one is whether sirtuins are centrally involved in calorie restriction’s anti-aging effects. But the studies should restore lost luster to Sinclair’s work on sirtuins. They’re also good news for GlaxoSmithKline, which bought Sirtris in 2008 for a hefty $720 million—the skeptics’ reports had suggested that Glaxo’s effort to develop sirtuin activators as drugs was based on a cracked foundation.

The mechanism debate began after Sinclair and colleagues discovered in 2003 that resveratrol sped up the action of SIR2, a yeast sirtuin thought to mediate calorie restriction’s effects, and of SIRT1, a mammalian version of SIR2, in test-tube assays. Using a fluorescent molecule called Fluor-de-Lys to flag the enzyme’s activity, their experiments indicated that resveratrol interacted with the sirtuins in a way that accelerated their normal function. (SIR2 and SIRT1 regulate the activity of various “substrate” molecules in cells by removing pieces from them called acetyl groups.) The sirtuin stimulation extended yeast cells’ lifespans by up to 60%, according to the report.

But in 2005, skeptics reported that resveratrol failed to boost sirtuins’ action without the presence of Fluor-de-Lys. (Attached to substrates, the fluorescent molecules generated a telltale glow when acetyl groups were removed by sirtuins.) That suggested Fluor-de-Lys inadvertently had played a central role in producing the sirtuin-boosting effect—and that the effect didn’t occur outside the test tube. 
In 2009 and 2010, respectively, researchers at Amgen and Pfizer reported similar findings.

Meanwhile, many studies in living organisms were reported that indicated resveratrol and other sirtuin activators induce calorie-restriction-like effects by stimulating the enzymes. But many observers found them suspect. Indeed, soon after the Pfizer report, a scientist tracking the debate emailed me that it seemed “sirtuins and resveratrol and the entire Sirtris enterprise are a house of cards that is in the process of crumbling badly.”

It appeared to the skeptics that purported sirtuin activators, at most, might indirectly boost the enzymes via unknown knock-on effects in cells. That led many to conclude that Glaxo had made a costly blunder when it bought Sirtris in hopes of turning its compounds into drugs targeting SIRT1 and other sirtuins.

But Sinclair theorized that the fluorescent molecules may have acted a lot like naturally-occurring parts of sirtuin substrates in the test-tube assay. If so, his team’s apparently misleading experiments with Fluor-de-Lys could have pointed, fortuitiously, to a correct conclusion: That resveratrol can rev up sirtuins in living cells.

The new studies support this theory. Both indicated that the fluorescent molecules, which are hydrophobic (repelling water molecules), mimic hydrophobic amino acids found at two locations in certain SIRT1 substrate molecules. In fact, sirtuin activators appear to rev up SIRT1 only when it is interacting with a limited number of substrates that contain hydrophobic molecules at one or both of the two locations.

By a twist of fate, the substrate used by both Sinclair and his critics in their early test-tube experiments lacked the critical hydrophobic amino acids. That’s why resveratrol’s sirtuin-revving effect only occurred, as the skeptics reported, when that substrate was gussied up with Fluor-de-Lys—the fluorescent molecules substituted for the missing hydrophobic amino acids.

Importantly, according to the Sinclair group’s new data, substrates with such amino acids include ones thought to help induce some of calorie restriction’s key health-promoting effects, such as the “stress response,” which hardens cells against damage by DNA-mangling molecules.

In its latest study, Sinclair’s group also went beyond test-tube experiments to probe SIRT1’s action in living cells. This step was based on their discovery that the SIRT1 protein includes a single amino acid that’s critical for the boosting of the enzyme’s activity by resveratrol and other activators—when another amino acid is substituted for it, SIRT1 does its normal enzymatic thing but can’t be artificially revved up.
That enabled a revealing experiment: Sirtuin activators added to cells containing normal SIRT1 were found to enhance the cells’ mitochondrial function in a way reminiscent of calorie restriction’s effect. (Mitochondria, cells’ energy dynamos, are spruced up by calorie restriction.) But when the activators were added to cells whose SIRT1 lacked the critical amino acid, the mitochondrial boost didn’t occur. The results imply that SIRT1 serves as a key channel for inducing the mitochondrial effect, which the Sirtris compounds can amplify in cells.

Besides clearing up the mechanism issue, said Mostoslavsky, the new findings should aid drug development since they’ve illuminated how different sirtuin activators exert selective effects on SIRT1 substrates. That promises to lead to sirtuin-boosting medicines that confer specific therapeutic benefits, with few side effects, by targeting certain SIRT1 substrates and not others.



References:

Hubbard B.P. et al. (2013). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science, 339, 1216-1219.

Kugel S., Mostoslavsky R. (2013). SIRT1 Activators: The Evidence STACKs Up. Aging, 5.
Lakshminarasimhan M., et al. (2013). SIRT1 activation by resveratrol is substrate sequence-selective. Aging, 5.

Yuan H., Marmorstein R. (2013). Red Wine, Toast of the Town (Again), Science, 339, 1156-1157.

Saturday, 11 August 2012

Eat, Fast and Live Longer by BBC Horizon with Michael Mosley

reposted from: http://www.bbc.co.uk/iplayer/episode/b01lxyzc/hd/Horizon_20122013_Eat_Fast_and_Live_Longer/ (view until 17th September 2012) or thereafter on http://documentaryheaven.com/eat-fast-and-live-longer/ (accessed August 21st, 2017)

my comments and links in blue. 

Summary


Michael J. Mosley (wikipedia) fasted for two days every week
Michael Mosley says 'Scientists are uncovering evidence that short periods of fasting if properly controlled, could achieve a number of health benefits, as well as potentially helping the overweight.'


The Horizon editor assured me there was great new science and that I might see some dramatic improvements to my body. So, of course, I said, "yes".

I am not strong-willed enough to diet over the long-term, but I am extremely interested in the reasons why eating less might lead to increased life span, particularly as scientists think it may be possible to get the benefits without the pain. 


How you age is powerfully shaped by your genes. But there's not much you can do about that.

Calorie restriction, eating well but not much, is one of the few things that has been shown to extend life expectancy, at least in animals. We've known since the 1930s that mice put on a low-calorie, nutrient-rich diet live far longer. There is mounting evidence that the same is true in monkeys.' Source: BBC

Synopsis

From Start: Taster of this hour long Michael Mosley Horizon programme first broadcast on 6th August 2012.

Fauja Singh

@ 2 minutes: London Marathon - Fauja Singh is 101 years and the oldest marathon runner. Unknowingly he has been testing the reduced calorie diet by eating child size (ie half) portion meals for most of his life.

9m: in 1930s at Cornell University [Clive McCay] showed that mice live longer on a restricted diet

Luigi Fontana

10m: Prof. Luigi Fontana (profile & research papers eg  http://www.ncbi.nlm.nih.gov/pubmed/17482403 & http://ajpendo.physiology.org/content/293/1/E197.long, also http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673798/ & CR Society Research (cited in The Longevity Diet by Brian Delaney and Lisa Walford) of BJC Institute of Health at Washington Uni & Salerno school of medicine studies people on severe calorie restricting diets ('these people look like a new species!') aka CRONies Calorie Restriction with Optimal Nutrition (CRON-Diet Wikipedia). Joe Cordell (twitter) has 11.5% body fat typical of a super athlete, has a 1 in a million chance of CVD (nb. myocardial infarction, stroke or heart failure are responsible for 40% deaths in UK/USA) and eats lots of fruit and veg. He only eats apple skins which have 95% of apple nutrition, the rest of an apple is sugar! Living a healthy lifestyle is fun, claims Joe!

Joe has eaten 1900 calories a day, weighs 134 pounds (cf Mike Mosley 190 pounds, 27% body fat, abdominal fat 30% - not good for his age - higher risk of CVD, stroke, cancer). If Mosley went on Joes Calorie Restriction lifestyle he would be 'cured within a year'.

[There are 100,000 CRONies worldwide (who eat food rich in nutrients but low in calories) I presume members of the CR Society International. CRONies say that body fat content should be 6-9% for men, 10-15% for females (The Anti-Aging Plan: Strategies and Recipes for extending your Healthy years by Lisa and Roy Walford, page 19)].

Valter Longo

Professor Longo has investigated growth hormone deficiency in humans
19m: Prof. Valter Longo, Uni Southern California, LA (profile & example). Experiments with a tiny mouse give 40% increased lifespan (equiv. to 120-year-old human) with genetically engineered low levels of Insulin-like Growth Factor 1 (IGF-1).


'Growth Hormone: The world record for extending life expectancy in a mammal is held by a new type of mouse which can expect to live an extra 40%, equivalent to a human living to 120 or even longer. It has been genetically engineered so its body produces very low levels of a growth hormone called IGF-1, high levels of which seem to lead to accelerated ageing and age-related diseases, while low levels are protective.' source: BBC

A 32-year-old community leader and artist who has the rare dwarfism condition (Laron Syndrome), with his bride, 17.
Source:  http://www.nytimes.com/2011/02/17/science/17longevity.html?_r=2&hpw
21m 45s: Equador - Laron Syndrome (wikipedia) & (research paper) dont get diabetes or cancer (Longo research, Sci Transl Med. 2011 Feb 16;3(70):70ra13) with images in paper.

Michael Mosley says 'Professor Longo has investigated growth hormone deficiency in humans - a similar, but natural, genetic mutation has been found in humans with Laron syndrome, a rare condition that affects fewer than 350 people worldwide. The very low levels of IGF-1 their bodies produce means they are short, but this also seems to protect them against cancer and diabetes, two common age-related diseases.

The IGF-1 hormone (insulin-like growth factor) is one of the drivers which keep our bodies in go-go mode, with cells driven to reproduce. This is fine when you are growing, but not so good later in life. There is now evidence suggesting that IGF-1 levels can be lowered by what you eat. 

Studies on calorie restrictors suggest that eating less helps, but it is not enough. As well as cutting calories you have to cut your protein intake. Not entirely - that would be a very bad idea. It's about sticking to recommended guidelines, something most of us fail to do. The reason seems to be that when our bodies no longer have access to food they switch from "growth mode" to "repair mode". 

As levels of the IGF-1 hormone drop, a number of repair genes appear to get switched on according to ongoing research by Professor Valter Longo of the University of Southern California.' source: BBC

NY Times article: 'physiology of Laron patients links up with the longevity studies that researchers have been pursuing with laboratory animals. IGF-1 is part of an ancient signaling pathway that exists in the laboratory roundworm as well as in people. The gene that makes the receptor for IGF-1 in the roundworm is called DAF-2. And worms in which this gene is knocked out live twice as long as normal.'

The single point mutation produces individuals that have very low levels of the growth hormone IGF-1. (Is IGF-1 hormone reduction good for you?) . Our cells are constantly made to divide by IGF-1 (24m) but with low levels of IGF-1 our body stops making new cells and repairs instead existing cells, DNA damage is more likely to get fixed which is why the mice and the villagers are protected from age-related diseases. High levels of protein make high levels of IGF-1 (the body is in go-go mode) (25m) and body is growing too fast for cancer and diabetes to be repaired. Eating less is not enough (26m) - you also have to cut your protein intake. You don't have to be a CRONe to lower IGF-1. Instead, fasting (plenty of water, black tea & 50 calories Cuppa-soup) for 3.5 days lowers IGF-1 and glucose levels. Michael Morley's IGF level was 210ng/ml before the fast (could increase prostate cancer risk) (33m) (normal range for humans 80-230ng/ml). After 3.5 days fast MM IGF-1 level was 110 ng/ml. MM blood glucose levels 110mg/dl (pre-fast) dropped to 80mg/dl after 4 day fast (34m). But effects will not last unless switch to a lower protein plant based diet and fast once a month to maintain benefits.

IGF-1 levels are tested by LabTestsOnline.

Krista A. Varady

Krista A. Vardy with Michael Mosley
38m: Assistant Prof. Dr Krista A. Varady (profile) the University of Illinois at Chicago. Has done research on Alternate Day Fasting (ADF) which involves 500-600 calories for men (400-500 calories for women) (25% of normal intake) on a fast day. On feed days you could eat 'whatever you want'. This ADF can result in decreased LDL, triglycerides and blood pressure levels. On the feed days, no difference in levels was found among people who had low or high-fat diets (41m). Actual consumption on feed days was only 110% of normal calorie intake (not 175% or a gorge as might be expected!) so, surprisingly, you can really tell people to eat 'whatever you want' [and however much you want] on feed days.

http://www.ajcn.org/content/86/1/7.full - Krista Vardy Review of Intermittent Fasting IF (accessed 13th August 2012) via http://www.huffingtonpost.com/andrew-weil-md/fasting-health_b_1557043.html (accessed 13th August 2012).

Vardy concluded inter alia:-

"both human and animal experiments indicate that Alternate Day Fasting ADF may effectively decrease the risk of CVD, whereas results from animal studies suggest a protective effect on cancer risk. In terms of diabetes prevention, animal data suggest a beneficial effect, but human data have been equivocal. However, it is important to note that the human studies examined in this review are limited; they all lacked control groups and used short trial lengths. Future studies with longer trials and including control groups are needed to answer these important questions.

Moreover, human ADF trials in modestly overweight persons, who are at greater risk of chronic disease, are warranted. In this context, it is important to note that the control animals in both the CR and ADF studies are likely to have been obese because they were fed ad libitum.


ADF regimens also may be as efficacious as daily Calorie Restriction CR in improving certain indexes of the risk of type 2 diabetes and CVD. Further analysis of the mechanisms responsible for beneficial effects of ADF is clearly warranted. Finally, it seems intuitively likely that persons will find it easier to fast or reduce intake on alternate days than to reduce their intake every day. For this reason, ADF regimens may allow better compliance than would CR regimens and may represent an attractive area for investigation.


It will also be important to understand whether the mechanisms by which ADF protects against chronic disease risk are similar to those of CR. Indirect evidence suggests that the 2 regimens may share mechanisms. For instance, the study of Descamps et al (26) reported increases in spleen mitochondrial Superoxide Dismutase (SOD) activity accompanied by decreases in the mitochondrial generation of Reactive Oxygen Species (ROS) as a result of ADF. Such findings suggest that ADF may act by increasing resistance to oxidative insult, which is a key feature of the stress resistance hypothesis.


In summary, this still nascent literature suggests that ADF may effectively modulate metabolic and functional risk factors, thereby preventing or delaying the future occurrence of common chronic diseases, at least in animal models. The effect of ADF on chronic disease risk in normal-weight human subjects remains unclear, however, as do the mechanisms of action. Much work remains to be done to understand this dietary strategy fully."


'Intermittent fasting (IF) (wikipedia)
Michael Mosley says 'One area of current research into diet is Alternate Day fasting (ADF), involving eating what you want one day, then a very restricted diet (fewer than 600 calories) the next, and most surprisingly, it does not seem to matter that much what you eat on non-fast days. Dr. Krista Varady of the University of Illinois at Chicago carried out an eight-week trial comparing two groups of overweight patients on ADF. "If you were sticking to your fast days, then in terms of cardiovascular disease risk, it didn't seem to matter if you were eating a high-fat or low-fat diet on your feed (non-fast) days," she said.' source: BBC

Mark P. Mattson

43m: National Institute of Ageing, Baltimore Mark P. Mattson (profile & papers) - effects of ageing on the brain. Fasting may slow onset of diseases (Alzheimers, dementia and memory loss). Mice on Intermittent Energy Restriction (IER) (Feast / fast) have equivalent to 30 years (in human terms) slower onset of Alzheimer's.

new brain neurons develop when IF regime is followed
Fasting mice have newly born brain neuron cells (46m) which are an evolutionary survival advantage if you are hungry and you can remember where the location of the food source is. Fasting exercises your brain like exercise stretches your muscles. Hunger makes you sharper. Alternate day fasting has a better outcome on the brain than daily Calorie Restriction (at least in mice, but human trials are needed to prove its true in us). Mark P. Mattson recommended MM try a 5:2 diet (48m) (5 days normal & 2 days 600 calories/day fast. Eat anytime (ie breakfast /lunch or breakfast/dinner or lunch/dinner) during the fast day (50m) for 5 weeks to see if get results (49m).
'Science is not belief, but the will to find out' (50m 34s)

5:2 feed:fast trial

In the period of filming (~5+ weeks) Mosley lost over a stone (~190 pounds to 174 pounds), total body fat reduced (27% to 19%) (53m). Luigi Fontana gave 5-week results (54m): IGF-1 reduced by 50% - enough to reduce the risk of prostate and colon cancer, blood sugar was borderline diabetic (110mg/dl) reduced to 90mg/dl (normal), total cholesterol reduced and higher HDL cholesterol. Same results as the 3.5 days fast. 
Drs Michael & Clare Mosley
Michaels wife Clare (a GP) was also delighted with his results (56m)! But more trials are needed to see whether Intermittent Energy Restriction is safe and effective. With diabetes and obesity timebomb set to explode we need as a nation a means to reverse the effects. Fasting could be the means.


Michael Mosley says 'I decided I couldn't manage ADF, it was just too impractical. Instead, I did an easier version, the so-called 5:2 diet [suggested by Mark Mattson]. As the name implies you eat normally 5 days a week, then two days a week you eat 500 calories if you are a woman, or 600 calories, if you are a man. There are no firm rules because so far there have been few proper human trials. I found that I could get through my fast days best if I had a light breakfast (scrambled eggs, thin slice of ham, lots of black tea, adding up to about 300 calories), lots of water and herbal tea during the day, then a light dinner (grilled fish with lots of vegetables) at night.  On my feed days, I ate what I normally do and felt no need to gorge. 

I stuck to this diet for 5 weeks, during which time I lost nearly a stone and my blood markers, like IGF-1, glucose, and cholesterol, improved. If I can sustain that, it will greatly reduce my risk of contracting age-related diseases like cancer and diabetes. 

Current medical opinion is that the benefits of fasting are unproven and until there are more human studies it's better to eat at least 2000 calories a day. If you really want to fast then you should do it in a proper clinic or under medical supervision, because there are many people, such as pregnant women or diabetics on medication, for whom it could be dangerous. I was closely monitored throughout and found the 5:2 surprisingly easy. I will almost certainly continue doing it, albeit less often. Fasting, like eating, is best done in moderation.' source: BBC

Info

  1. http://en.wikipedia.org/wiki/Calorie_restriction (Accessed 12th August 2012)
  2. http://www.theiflife.com/intermittent-fasting-101-how-to-start-part-i/  (Accessed 13th August 2012)
  3. Letter to BBC from Paul McGlothin at CR Society - Mosley did not take account of his 'happiness biochemistry'!