Tuesday, September 13, 2011

Intrinsic and Probably Constitutive Arterial Cleansing

Cardiovascular Disease remains a big killer in modern societies. While various drug interventions have enabled millions to go on living when they would otherwise be dead, the spikes in obesity and type 2 diabetes in the last 30 years are harbingers of a cardiovascular disease epidemic in the making. This has already been hinted at with a piece of recent research. As stated in the news release:
A large study has revealed that the rate of strokeamong children, adolescents and young adults in the USA has been increasing at an alarming rate. The rate at which ischemic stroke patients are being hospitalized has also increased considerably, the authors reported in Annals of Neurology.
 If you go to the above link the authors have kindly provided a breakdown of the stats. The nutshell is that from 1995 to 2007 we have witnessed a 50% rise in ischemic stroke among males aged 35-44 years, a rise of 46% for males aged 15-34, for females the rates are considerably lower, 29% and 23% respectively.

Note: there are two types of stroke: ischemic, where a blood vessel becomes blocked, and hemorrhagic, where a blood vessel ruptures. The former arises from clogged arteries, the latter can arise from sustained high blood pressure which wears down the arterial walls. 

Citation: Christian Nordqvist (2011, September 3). Stroke Incidence Increasing Among Children And Young Adults, USA. Medical News Today. Retrieved September 12, 2011 from
  1. New imaging technologies are possibly increasing the rate of detection. However, given the v. large increase in hospitalizations for stroke(30-37%), one must assume that the increased rates of detection primarily reflect a real increase in stroke rate rather than being an artefact arising from improved detection methods. 
  2. Unfortunately the abstract does not mention the incidence rate of stroke. There is a huge difference between an increase of 50% from 2 in 100 to 4 in 100 compared to 20 in 100 to 40 in 100! My guess is that the absolute incidence rate is still on the low side but if the trend noted above continues obviously that is going to change. For rates of stroke this site provides a good breakdown of the data. To date least 80% of all strokes occurred in those over 65. We are probably going to witness a flattening of the age curve over the coming decade. 
It is troubling to think that a condition typically associated with old age is increasing in those who haven't even reached middle age.

The above findings remind me of how 30 years ago type 2 diabetes was almost unheard of. There is now data suggesting 1 in 10 USA citizens have type 2 diabetes, a rate guaranteed to overwhelm an already terminally ill health system. Around the world many countries are experienced unsustainable increases in health costs. The USA is simply the "poster boy" in this regard. At present at least the USA is a very sick puppy, one should consider putting it down but there is no need, it is killing itself.

Some weeks ago I read an interesting article that stated while we are now living longer we are also living longer with disability. This comes back to my second sentence in this cantankerous rant because while modern medicine has done a magnificent job in saving so many people one unfortunately result of this is that many people are now living much longer with permanent disability. Recent therapeutic advances in stroke treatment will accelerate that trend and even moreso because younger people have a much better chance of survival from stroke than those over 65. Much more worryingly, a person who has had a stroke is much more likely to have cardiovascular events in the future. So anticoagulants are often administered and these drugs, while life saving, create other problems. This constitutes a vicious cycle of medicalisation. So the goal for everyone must be to avoid any cardiovascular issues as long as possible. Indeed, in relation to longevity a key marker is "morbidity compression". That simply means that the chances of a long life are very contingent on avoiding any major illnesses for as long as possible.

We have to disavow ourselves of this notion that modern medicine will save us from our bad habits. In fact the findings of modern medicine suggest the exact opposite: that by maintaining a healthy lifestyle we are not only doing ourselves a favour but also doing society a favour. For that reason in Japan it is considered a moral obligation for citizens to take care of their health. This recent study on how the body may be cleansing the arteries opens one of many doors that enables us to realise how we can reduce the risk of cardiovascular events. The abstract can be read here. 

This study found that the autophagy pathway appears to play a vital role in preventing atherosclerosis(clogged arteries). It has long been known that when are arterial walls accumulate fatty deposits a class of immune cells, macrophages, migrates to the relevant site and then attempts to clean up the deposits. The macrophages literally absorb the deposits and through a process known as autophagy degrade the products and possibly allow their transport back to the liver. These macrophages are known as "macrophage foam cells" because they accumulate huge amounts of cholesterol and appear bloated. The finding opens up the possibility of a reversal of atherosclerosis. For a long time it was thought that atherosclerosis was irreversible but I never believed that because I knew people who had reversed atherosclerosis.

Autophagy is a fascinating set of processes and over the last few years has attracted a great deal of research interest. I first came across it in 2007 when I was studying retinal degeneration. Age related macular degeneration(AMD) is at least in part caused by a failure of autophagic processes(probably chaperone mediated autophagy) to dissolve the various waste products arising from visual processes. It is perhaps no co-incidence that atherosclerosis is a risk factor for age related macular degeneration, the commonality may lie in a physiological state that precludes adequate activation of autophagic pathways.

As noted in that prior blog post there is considerable evidence that in AMD persistent retinal inflammation plays a key role in driving the pathology. Over recent years the emerging view is that atherosclerosis has a significant inflammatory component, it may even be the case that the anti-inflammatory action of statin drugs as well as their cholesterol modulating functions are important factors in reducing deposit build up in the arteries. The issue of inflammation remains something of a mystery to me, it seems to be involved in so many pathologies that I often wonder if it is more guilt by association than causative. It will be both but that doesn't solve the mystery!

So the first thing we have to consider is our inflammatory state. There are many modulators of inflammation but in particular note the following:

The Omega 3 - Omega 6 balance. Modern diets contain far too much omega 6 and far too little omega 3. Omega 6 fatty acids are precursors for inflammatory prostaglandins while omega 3's are precursors for anti-inflammatory prostaglandins. It has long been known that diets high in fish, even if combined with very high total fat content, reduce the risk of atheroslerosis. The "Eskimo Story" basically.

Vitamin D status. Vitamin D is very important in maintaining an appropriate immunological balance. Too little can drive inflammation so it is not surprising that vitamin D insufficiency is now being implicated in everything from cancer to dementia. Forget that stuff about getting enough from sunlight. If you are over 30 there is no guarantee your body will generate sufficient vitamin D from sunlight. While I don't take vitamin D supplements all the time I do occasionally dose myself with 60,000 iu over the course of a month. It is fat soluble so the body can store it. Have your vitamin D status checked, if it is below 40 nmol/L, start taking a good quality supplement. Never rely on vitamin D in multivitamins, next to useless. Buy dedicated vitamin D supplements. Your target range for vitamin D should be 60-100 nmol/L, though 80 should be good enough.

Antioxidants There are many antioxidant rich foods available. Include these in your diet, especially nuts(eg. walnuts are rich in a powerful form of vitamin E), vitamin A or pro-vitamin A nutrient rich foods, and vitamin C rich foods. Also consider lowering your total iron intake and raising your magnesium and selenium intake.

Regular exercise. Whilst rigourous and sustained exercise can induce oxidative stress, and this being a major reason why I think "fitness nuts" are truly nuts, moderate regular exercise is one of the best strategies we can do to maintain a healthy cardiovascular system. Burn off the fat, enjoy the scenery, don't make your exercise a competition, and you will lower your body's inflammatory status.

Bad Habits. Smoking, persistent exposure to various toxins, being chronically psychologically stressed, all these factors can increase our systemic inflammation. Give up the bad habits, avoid toxin exposure, learn to relax(meditation is a treat!), and your health will slowly but surely improve.

All of the above will most certainly help in slowing the rate of atherosclerosis but the reality is that for most of us some degree of atherosclerosis is present and will probably increase with age. That isn't a problem, it only becomes a problem with the build up of deposits continues without any reduction occurring. As a general rule I rely on the assumption that inflammation must first be addressed and then consider specific strategies. So in relation to atherosclerosis we must first get the body in good condition. Then we can consider strategies to specifically enhance the reduction in atherosclerotic plaques. This is where autophagy becomes relevant.

As so often happens with modern biomedical research, a study which hits the news is not really news, it simply represents that result of a long line of investigation which prefigured the result or that the relevant laboratory\institute has a good public relations department. It didn't take me long to find other articles at least hinting at the importance of autophagy in modulating atherosclerosis. For example:

Protective role of autophagy in AGE-induced early injury of human vascular endothelial cells.
Mol Med Report. 2011 May-Jun;4(3):459-64.


[PubMed - indexed for MEDLINE]

Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease

Circulation Research February 19, 2010
Autophagy in Vascular Disease

Proc Am Thorac Soc Vol 7. pp 40–47, 2010

Autophagy came to the interest of researchers many years ago but was often ignored, possibly because it seemed irrelevant to pathology in general. However it now appears to be extremely relevant and raises very important questions about the the foods we eat and how often we should eat.

By now most people have heard about the extraordinary results in longevity obtained by caloric restriction(CR). Be it mice or yeast, persistent caloric restriction has been consistently demonstrated to prolong the life of organisms well beyond the "normal lifespan". CR induces autophagy and it is believed that this induction is one of the cardinal health benefits from CR. That's all well and good for the lab but in the real world we live in caloric restriction is neither viable nor desirable. It can create a number of problems including infertility, immunosuppression, energy loss, and generally feeling like shit all day. For modern humans who typically work long hours caloric restriction may even be harmful. I have never been in favour of CR for humans because I felt our physiology was so geared towards keeping the grey matter moving that any diet which restricted glucose and general nutrient availability to the grey matter was problematic.

However all is not lost, there are a number of studies which suggest the life prolonging benefits of CR are obtainable but without living in a perpetual state of semi-starvation. This is not the place to go into that and I'm no mood for archive mining so I'll save that for a latter day. By way of example, one study I read even claimed that simply limiting intake of the amino acid methionine could mimic the effects. Yeah sure, I'll take that with my SAMe thanks.

So why does CR induce autophagy? Quite simply because the major nutrient pathway for cells, often referred to as the mTOR\P13K pathway, inhibits autophagy. So when we are satiated, our bodies replete with nutrients to feed cells, autophagy is reduced but probably not stopped, I imagine it has a basal rate of function. As to why this nutrient - mTOR - autophagy relationship exists I cannot be sure, I can only suggest that a cell receiving nutrients should not then be degrading the very nutrients it is receiving. When nutrient reserves run low is when autophagy kicks into gear with a vengeance. Hence CR and autophagy and a long starved and miserable life.

So if we eat every time we are hungry, if we refuse to go hungry, we are denying our cells the opportunity to "clean up the mess after dinner". What happens in modern societies? Feeling hungry, I'll hit the snack bar, I'll grab a fructose laden drink, I'll stop my stomach complaining so I can keep working. Here's a hint - you'll look over hill and under dale to find a fat centenarian. Fat people eat fast and die young. Learn to stay hungry, it isn't that hard. You don't have to starve yourself all the time, in fact that is dangerous because while everyone knows that too much sugar is bad for our health, too little sugar is bad for our brains. Fortunately our bodies readily store sugar in the liver and muscles, but in spite of this many people will report that when starved they feel foggy. Their brains aren't receiving sufficient sugar to function properly.

So in addition to the general guide lines for living a healthy life, learn to stay hungry at those times when you are not working hard, be that work physical or mental. To fast a whole day though can be very difficult, I find I cannot sleep, possibly because the starvation has boosted my cortisol levels and cortisol is an arousal hormone. I don't believe a whole day fast is necessary, simply limiting eating a couple of days per week, avoiding snacks just because you're feeling peckish, and stay away from those damned fruit and other sweet drinks! I imagine, and only that, that as our nutrients levels drop autophagy is slowly increasing. This seems concordant with our evolutionary history. Many organisms experience starvation on a fairly frequent basis. We now live with abundant food, far too much food, far too often consumed. We are eating ourselves to death.

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