Hormesis - a small amount of 'toxin' eg exercise or Intermittent Fasting can help

reposted from: http://www.grc.nia.nih.gov/branches/lns/BestinSmallDoses.pdf - copy of New Scientist 2008 article

crabsallover highlights, key points, comments / links.

Hormesis (wikipedia) involves a biphasic response in which a small amount of a toxin has a beneficial effect whilst increasing quantities are toxic.

An example of a hormetic product is selenium which is a micronutrient and improves health at low doses but is toxic at high doses. Plants and vegetables (5 a day) and Exercise have a hormetic effect too.

A very low dose of a chemical agent may trigger from an organism the opposite response to a very high dose.

Tentative evidence re: Alzheimers prevention - Michael Mosley IF diet

reposted from: http://vimeo.com/50224011, from 4 minutes

crabsallover highlights, key points, comments / links.

In mice on Intermittent Fasting (IF), Mark P. Mattson found that 'sporadic bouts of hunger trigger new neurons to grow'. 'Why should a brain cell generate new cells when you stop feeding it?' asked Michael Mosley of Mark Mattson (5.30s) :- In evolutionary terms, if when you are hungry, it is good to increase your cognitive ability as this could give a survival advantage eg food, predator and hazard locations. In mice, Mattson found that new brain cells [in the hippocampus] grow more than on restricted calorie diet.

But this is just one researcher with trials on mice. Was this research published in a peer reviewed journal? Has his research been repeated in other labs? We do not know whether this growth of brain cells will happen in humans.

Mark P Mattson said (4.10s) that the evidence was 'very good' to 'excellent' that 'Intermittent Fasting IF could reduce the risk of brain diseases in people like Michael Mosley.'

Brain-derived neurotrophic factor

In human terms, putting genetically modified, Alzheimers susceptible mice, on IF means that they develop Alzheimers at 80 rather than at 50 years. Mice on IF diet have increased production of Brain Derived Neurotrophic Factor (BDNF - wikipedia) which stimulates stem cells to turn into new nerve cells in the hippocampus, a part of the brain essential for learning and memory. Research on humans on IF diets, may show, using MRI, that hippocampi size changes. When people exercise (eg walking) the hippocampus size can increase (1). Regular walkers have brains that in MRI scans look, on average, two years younger than the brains of those who are sedentary. (Ref: Michael Mosley & Mimi Spencer, 'The fast diet, The simple secret of Intermittent Fasting: Lose weight, stay healthy, live longer', pub. January 2013 by Short books, pages 44-48)

(1) Erickson, KI; Voss, MW et al, Salk Institute, CA, USA. 'Exercise training increases size of hippocampus and improves memory'. Proceedings of the National Academy of Science USA, January 2011

5-2 Fasting - Excerpts from Michael Mosley's Horizon 'Eat, Fast and Live Longer' from Jon Brewerton on Vimeo.

Michael Mosley (pg 49 in above book) took the cognitive test http://cognitivefun.net/test/2 - the Stroop Test before and after starting the IF and found, purely anecdotally, that his memory had improved.

NHS Choices Review of IF

What is the evidence intermittent fasting prevents cognitive decline?

It seems that all of the studies on the supposed protective effects of IF against conditions that can cause a decline in cognitive function (such as dementia or Alzheimer’s disease) involve animals.

For example, a 2006 study (PDF, 843.1Kb) involved mice that had been genetically engineered to develop changes in brain tissue similar to those seen in people with Alzheimer’s disease.

Mice on an IF diet appeared to experience a slower rate of cognitive decline than mice on a normal diet (cognitive function was assessed using a water maze test).

While the results of these animals tests are certainly intriguing, animal studies have inherent limitations. We can never be sure that the results will be applicable in humans.

Links to the science

Halagappa VKM, Guo Z, Pearson M, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease (PDF, 843.1Kb). Neurobiology of Disease. Published online January 13 2007

Mark Mattson - Ageing Research

reposted from: 

crabsallover highlights, key points, comments / links.

Mark Mattson Background and Research Summary: http://www.grc.nia.nih.gov/branches/irp/mmattson.htm and http://www.grc.nia.nih.gov/branches/lns/mcnu.htm
New Scientist Article 2008: http://www.grc.nia.nih.gov/branches/lns/BestinSmallDoses.pdf
Hormesis Project: http://www.grc.nia.nih.gov/branches/lns/linka.htm

Mark Butcher emails Michael Mosleys Horizon scientists - One meal on fast days

reposted from: http://feedfastfeast.wordpress.com/2012/08/25/grabbing-the-bullshit-by-the-horns/

crabsallover highlights, key points, comments / links.

I was not clear from the Michael Mosley Horizon film whether on the fast days you could split the 600 calories into 1 meal or up to 3 meals ie 3 x 200 cals. Mark Butcher has found that the 600 calories should be used in 1 meal. Mark Butcher emailed Longo, Mattson and Vardy from the film.

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 between 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.

It would be much better if you could just get through a fast day without eating at all. Obviously, very few people are able to do that, so if you are going to eat a (600 for a man, 500 for a woman) calorie reduced meal, you are much better to consume that as one meal than to spread those calories throughout the day. This is because the stress that going for 24 hours without food places on your brain actually has produced identifiable positive brain responses such as the growth of new brain cells. It’s like a workout for the brain. How to add that into an intermittent fasting or alternate day plan?

Easy. Either, take a note of what time you last ate on the feed day prior to your fast and then do not consume your 600 calorie fast day allowance until 24 hours has past. So, if you ate at 6pm on a feed day, do not eat your 600 calories until 6pm on the fast day. That way, you’ve gone 24 hours without food AND you get to eat (albeit a restricted) dinner! If that doesn’t grab you, eat breakfast on a fast day and then don’t eat again until your breakfast the next day.

Contact Mark Butcher: 

Twitter: @FeedFastFeast; FeedFastFeast Facebook Group: http://www.facebook.com/groups/feedfastfeast

Mark P. Mattson talks about Intermittent Energy Fasting

reposted from: http://mpegmedia.abc.net.au/rn/podcast/2012/05/hrt_20120507_1740.mp3 via https://twitter.com/DrMichaelMosley# 17th August 2012

crabsallover highlights, key points, comments / links.

Prof. Mark P. Mattson (ChNat. Inst. Ageing in Baltimore): CR in animals reduces cancer, kidney disease, diabetes - all animals live longer. Animals in wild are geered to feast or famine so the human 3 meals a day is abnormal from evolutionary standpoint. Intermittent energy restriction (IER) (eg 2 days a week have low calorie intake) imitates evolution. IER v daily CR (calorie restricted every day): IER has more powerful effects for nerve cells to resist stress and disease.

With IER before animals become symptomatic can protect brain: reduces Amyloid accumulation (gunk ceases up the brain) of Alzheimers disease and preserves dopamine producing neurons which reduces Parkinsons disease. On alternate Day Fasting, before symptoms become symtomatic, mice live 30% longer on IER.

IER reduced Oxidative stress (reduces rusting of brain ie reduced free radicals), reduced local inflammation (reduced cytokines eg tumour necrosis factor TNF - immune system less active so brain ages less).

Fasting increases production of protein neurotrophic factors (causes nerve cells to grow), increases stem cell Brain Derived Neurotrophic Factor (BDNF wiki) which increases production of nerve cells (neurogenesis). With increased exercise AND IEF, BDNF:-

1. Strengthens neuron synapses - maintains cognitive function
2. Increases antioxidant enzymes (counteract free radicals), suppresses free radicals and inflammation

Muscle Analogy

This increase in stress in your brain is analogous to exciting muscle cells which make them stronger and contract. Nerve cells when exited send signal to next neuron, become more active when they are hungry.  With mild stress - nerve cells become more active and this is evolutionary important.

Downside of IER 

Reduced wound healing, increased risk of infection for cave men ancestors.

Human Trials

In breast tumour patients (with Michelle Harvie, Wythenshawe Hospital, Uni Manchester reported by Daily Mail), Press Release, full article Int. Journal of Obesity. 100 subjects split into 3 groups. 1) control diet ate normally, 2) 15% reduction in calories (CER) 3) 5:2 day fast diet (IER) - had less insulin resistance than other groups.

IER and CER are equally effective for weight loss, comparable reductions in: leptin, C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure, increased IGFBP-1 and IGFBP-2, negligible changes in total and free IGF-1.

on IER:-

1. sugar reaching breast cells decreased 
1. breast cells divide less frequently, reducing chances of cancer
2. had fewer cancer-causing hormones in their blood six months later 
1. Leptin fell by 40 per cent 
2. Insulin fell by 25 per cent
3. C-Reactive Protein fell by 15 per cent

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

http://www.bbc.co.uk/news/health-19112549 - BBC

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'!