Friday, 18 February 2011

What causes the aging process?

For a long time the most popular theory of aging has been the free radical theory, based on the observation that older cells accumulate oxidative damage over time. Unfortunately antioxidants have only had a slight impact on overall lifespan and in some cases have even reduced life expectancy. For example studies have shown that taking Beta carotene increased death rates by 7 per cent, vitamin A by 16 per cent and vitamin E by 4 per cent, while the popular antioxidant Vitamin C gave contradictory results. Although, plant compounds like Resveratrol have antioxident activity, they have mainly been shown to increase life span through activation of specific like SIRT1 or AMPK which effect metabolism and food intake. So if the antioxidants like Vitamin E, don't seem to help then what is wrong with the free radical theory of aging?

One answer seems to come from a few researchers who inhibited a transcription factor for inflammatory processes called NF-kappaB within the epidermal tissue of old mice, this they say “caused the skin to revert to the state of very young tissue, both in observable characteristics and in genetic expression profile”. Now it just so happens that in order for NF-kappaB to trigger Inflammation, free radicals must first initiate changes to unbind NF-kappaB from the cytoplasm of the cell, so it can translocate to the cell's nucleus and bind with the DNA to turn “on” the genes to initiate pro-inflammatory processes responsible for the visible signs of ageing. So in other words free radicals do seem to trigger the symptoms of ageing through Inflammation. Although other processes can cause Inflammation, such as viral or bacterial infections, Cytokines released by the immune system or damage to the cellular membranes, these pathways appear to be caused more by external factors than from those originating from within the cell.

So what triggers the formation of the free radicals inside the cell? The culprit turns out to be the mitochondria, which are small organelles that burn most of the calories we eat. The theory used to be that the fewer calories you consumed the less oxidative damage would occur, but studies now shown that those cells which are able to sustain the most mitochondria have the least oxidative damage, which was unexpected and seems to suggest that healthy mitochondria can moping up free radicals. The situation is only reversed when oxygen levels run low in a state called hypoxia where the mitochondria are not able to maintain the integrity of their electron transport chain which starts to leak electrons. These electrons then bind with oxygen atoms to form a very destructive free radical called Superoxide, which triggers inflammatory processes that produce all the visible signs of aging. So given that a number of antioxidant compounds react with dissolved oxygen required for healthy mitochondria are they really such a good option to prevent these free radicals? This is not to say all Antioxidants are bad, there is lots of evidence that Antioxidants like Glutathione or mitochondrial SOD ( MnSOD) located within the mitochondria help prevent mitochondria damage. Also the plant compound Resveratrol has been shown to increase MnSOD expression via FOXO3a activation, which could explain some of Resveratrols benefits. So although nature has evolved Antioxidants in just the right locations to prevent cellular damage, taking similar compounds without getting them transported to the mitochondria could instead lead to more cellular damage as they restrict the supply of oxigen for the mitochondria.

While a number of studies have shown the oxygen requirement of older cells to be greater than that of younger cells, it is not fully understood why? One possibility is that since older cells are more acidic, this causes them to become oxygen depleted more quickly. Acidity or the pH scale is a measure of the hydrogen ions dissolved within a solution, so because individual hydrogen ions or Protons don’t normally exist freely in solution but hydrate to form hydrogen ions ( H3O+), they use-up any dissolved oxygen. You can observe the effects of this processes in places where Acid rain depletes the lakes and streams of oxygen and kills the fish. Within our own body this means as older cells accumulate acidic waste products of metabolism, the supply of oxygen for the mitochondria is restricted, thus triggering the production of Superoxide, inflammation and the signs of aging.

If the cells within our own body react to free radicals like Superoxide by turning on genes to trigger inflammation, then maybe this is an evolved strategy to increase the supply of oxygen for the mitochondria? The evidence for this includes inflammatory prostaglandins which dilate the blood vessels and promote angiogenesis which is the growth of new blood vessels which increases the supply of oxygen. Inflammation also triggers local Cortisol production which turns off protien synthesis; this has the effect of reducing acidity within the cells. Cortisol also increases the break down of proteins like muscle fibers into a very alkaline compound called urea, which helps to neutralize acid. Other effects of inflammation include Insulin resistance through the down regulation of the glucose transport enzymes within the cell. This makes some sense because if the mitochondria do not have enough oxygen to burn all the available glucose then it will only accumulate outside the mitochondria and get converted into lactic acid, restricting the oxygen supply. Another effect of inflammation is the up-regulation of Lipogenesis which helps prevent the production of lactic acid by converting simple sugars into fatty acids. The production of these fats can contribute to obesity, or when they are removed from organs like the Liver cause an increase in blood lipids assosiated with heart disease. Other effects of inflammation include increased cell proliferation, which would appear to help dilute the acidity of the cells.

What happens if after all this, inflammation fails to reduce the acidity of the hypoxic cells and increase the supply of oxygen? Then it's possible for mitochondria to become dormant and stop functioning, the evidence for this comes from Cancer. For example in 1931, Otto Warburg won a Nobel Prize for the discovery that the cellular environment of cancer cells is very low in oxygen, he also wrote about oxygen’s relationship to the pH of cancer cells and discovered that cancer maintains a low pH of around 6 as opposed to 7.4 for a normal cell. Cancer cells are able to survive such a low Oxygen environment and the loss of their mitochondria by relying on an ancient form of energy production called the lactic acid cycle, which as you can guess keeps the cancer at a low Ph. It was once thought that the mitochondria in cancer cells were damaged, but a cheap drug called Dichloroacetate (DCA) already used for years to treat a rare metabolic disorder was then found to block the lactic acid cycle cancer cells used for energy and this reactivated the mitochondria required to trigger apoptosis or programmed cell death, which then caused the cancer cells to die. But if the mitochondria in Cancer cells are not damaged, then why are they not functioning? Might the low Ph and lack of Oxygen simply stop them from functioning? Also what about Inflammation, if this is an evolved condition to prevent cancer then is it such a good idea to take anti-inflammatory drugs like paracetamol?

Diet is probably the best way to reduce the body’s acidity, early experiments on mice showed that dietary restriction increased life span, but later research found the effect was mostly due to the restriction of protein. Researchers analyzed the different amino acids and identified the sulfur-containing one amino acid called L- Methionine as the culprit, this has a very high acidity where a 1% solution produces a Ph of about 5.6. Restricting the intake of L- Methionine was found to increase the average life span of mice by around 40%. Methionine is mostly found in animal proteins such as meat, eggs and cheese, while vegetable protein may contains as little as 10 times less than meat when measured relative to the other amino acids. Unfortunately Methionine is required for protein synthesis to build muscle and for the production of neurotransmitters, but then you can get around this problem by taking Vitamin B12 required to recycle Methionine from its metabolite form Homocysteine back to Methionine. This also means Vitamin B12 can help reduce Homocysteine levels, which is important since studies have shown a better correlation between blood levels of Homocysteine and atherosclerosis than other markers of heart disease like cholesterol.

In the book "The China Study" researchers studied rats administered the carcinogen aflatoxin along with either a diet of 5% - 20% Animal protein or 20% Soya protein, results showed every Single animal that consumed a diet of 20% Animal protein along with the aflatoxin developed cancer, while none of the animals which had either 5% Animals or 20% Soya protein did. So why did a high Animal protein intake predispose these animals to cancer? I think the evidence suggests, that a diet containing high levels of Methionine may have could cause the cells to become acidic and switch off the mitochondria, then in the presence of a carcinogen like aflatoxin, the mitochondria might not have been able to trigger apopsis (programmed cell death) required to prevent cancer if the carcinogen mutated the DNA. Although Soya has been given some bad press, most of the problems can be avoided by using Organically roasted Soya flour, because roasting the bean inactivates the anti-nutrient compounds and flavonoids like genistein.

Although Methionine has a low pH, it’s not the reason why meat is acidic, the reason for that is what happens when live flesh with an Alkaline pH of 7.4 stops living, the ATP, which is the energy currency of the cell is then broken down into ADP and releases hydrogen ions which cause the pH of meat to drop down to a Ph of about 5. All the energy produced by Mitochondria is released into cells as ATP and metabolic processes then convert this into ADP to release energy in a process which makes the cells more acidic. So there needs to be a balance, between the Mitochondria which recycle and produce ATP keeping the pH high and the metabolic processes that cause the cell to become acidic. Creatine can also help recycle ADP back to ATP helping to maintain the cells pH, in this way Creatine works as an effective pH buffer and is known to increase the lifespan of mice by 20%.

The alkaline minerals Calcium and Magnesium have both been shown to increase lifespan, for example one study shows that those who consume the most calcium in their diets, about 2,000 milligrams a day, had a 25 percent lower risk of dying overall and a 23 percent lower risk of dying from heart disease. Researchers also cultured human cells in different concentrations of Magnesium and found that a 50% reduction in Magnesium caused a 10% decline in the life span of those cells. Another interesting connection between Magnesium and lifespan is found in an aria of New South Wales Australia, where sheep and cattle have access to the spring water at the base of a volcano. Here the horses are said to live up to over 40 years and sheep 20, which is about 30% longer than normal. The apparent reason for this has been put down to high levels of magnesium bicarbonate found in those spring waters. One of the locations said to have the highest concentration of centenarians in the world is the island of Okinawa which is composed of coral rocks and limestone. Analyses of the drinking water of Naga city (Okinawa prefecture) was said to indicate one of the highest concentrations of Magnesium ions studied so far. Here in the west the concern is that over 70% of people are believed to be deficient in Magnesium, because the foods which contain the most like Whole grains or the chlorophyll part of Green vegetables or nuts and seeds are not regularly consumed.

The pH Buffering capacity of animals tends to be higher in marine mammals, possibly because of the low oxygen environment. The ph buffering capacity of various animals is based on the concentration of Histidine-related compounds which include carnosine, anserine and balenine. Whales and dolphins have similar levels to warm blooded fish like tuna reaching 400mmol/kg in contrast animals which hunt by running have levels at around 90mmol/kg while human levels are at about 25mmol/kg. Though it maybe possible to increase the levels of Histidine in people by taking extra Histidine, this Amino-Acid isn't normally in short supply, what is in short supply is another Amino-acid called Beta-Alanine which is also found within the dipeptides of carnosine, anserine and balenine. Research has showed a 20% increase in the life span of mice given carnosine. Though what is most interesting about carnosine is its ability to increase the life span of cultured cells. Most of our cells have a limited capacity to divide called the Hayflick Limit, for example human fibroblasts (connective tissue cells) divide no more than about 55 times in laboratory cultures but when transferred to medium containing carnosine this was extended to 70 PDs (population doublings) and their lifespan was extended from 126 days to 413.

Another amino acid found predominantly in fish at higher concentrations is Taurine, with crustaceans, molluscs and octopus containing the most. Taurine is also the second most abundant amino acid within brain tissue especially within the retina, due to the high oxygen demands of the nervous system. But what is it about Taurine which helps cells maximise their use of oxygen? The mitochondria is a bit like a fuel cell and stores Hydrogen ions pumped in from the electron transport chain within the mitochondrial outer membrane, which relies on the pH gradient between the mitochondrial matrix, being higher than the outer membrane. This means something must be working as an effective pH buffer inside the Mitochondria? Turns out that of all the compounds within the matrix, Taurine has the largest pK 8,6. The value of pK represents the pH value at which a molecule has the best buffering capacity. Which suggests Taurine can best accept hydrogen ions within a solution as alkaline as pH 8.6. In other words Taurine helps maintain the pH gradient required for the Mitochondria to store energy, which explains how Taurine enables cells to make the best use of oxygen. But then what happens if there is a Taurine deficiency? Then the pH gradient would be effected and the mitochondrial electron transport chain would be interrupted and start producing free radicals. The effects of a Taurine deficiency include retinal degeneration as the retinal cells in the eyes require a lot of oxygen, while other effects are associated with the aging process like heart disease and obesity. Scientists have also looked at the effects of Taurine on lifespan and found the addition of 100 mM to the drinking water of Fruit flies increased their median lifespan by 14% and maximum lifespan by 27%.

Vegetables are generally considered one the most alkaline foods because of the high level of potassium and magnesium which form alkaline ions, another reason potassium is very beneficial is because cells can exchange the hydrogen ions for potassium ions in the blood. Vegetables and fruit are generally more alkaline when eaten raw, since cooking breaks down the hydrogen bonds in water and cooking oils, which then react with your food causing it to become more acidic. It may be surprising that some of the most metabolically alkaline foods includes fruits like lemons, but it turns out the citric acids in fruit and even Vinegar are metabolized in the liver during the "citric acid cycle" into bicarbonate which is very alkaline. A drink like Coca-Cola on the other hand, which has a pH of 2.5 is 31,622 times more acidic than a glass of water, this much acid would reduce the pH of the blood from 7.4 down to about 4.6, and since Oxygen levels in the blood stream are directly correlated with the pH scale which is based on powers of ten, this means a single drink of Cola could reduce your supply of oxygen to 0.1% normal levels if the body didn’t neutralize the acid.

One of the simplest ways to buffer the body’s pH is to replace salt with sodium bicarbonate which neutralizes the hydrogen ions. Just half a gram of sodium carbonate dissolved in a pint of water produces a solution with a pH of 11.3. This is 20,000 times more alkaline than water so just enough to neutralize one Coca-Cola. In one study, they gave athletes a sodium bicarbonate solution prior to performing high-intensity interval training three times a week for eight weeks, while a placebo group drank a salt solution. The results from this study showed a 41% improvement in the time to fatigue for athletes taking the sodium bicarbonate. Another study looked at the effects of sodium bicarbonate on cell cultures as compared to salt and found an increase in the number of mitochondria within the cells of approximately 50%. In other words, simply reducing the acidity with a little bicarbonate caused a massive 50% increase in the supply of energy.

One of the potential consequences of an acidic diet is Acidosis, in which the bicarbonate system of the arteries fails to keep the blood alkaline, as this system fails it is then up to the kidneys to remove hydrogen ions from the blood. Unfortunately this affects the kidneys ability to reabsorb some important minerals like calcium back into the blood. The thyroid detects this loss of calcium and releases the Parathyroid hormone which triggers the release of calcium ions from the bones leading to osteoporosis. Calcium ions are different from calcium absorbed by the intestines, since the lining of the intestines binds calcium to a transport enzyme so it can travel safely through the blood, unfortunately this dose not happen with calcium ions who's positive charge is attracted to the walls of the veins causing Atherosclerosis ( calcification of the arteries) or high blood pressure. One of the best treatments for Acidosis is Potassium Bicarbonate and since the average American diet only contains about 50% of the RDA, most people could probably benefit by taking more. In the studies done for Acidosis, the Potassium Bicarbonate was found to significantly reduce the loss of calcium from the kidneys, which should in theory help to prevent problems like osteoporosis and hart disease. In relation to cancer, one of the treatments reported to have had success is Sodium bicarbonate, which can be used on the skin to improve the pH of melanomas. But I wonder if Potassium Bicarbonate maybe even better, after all our calls are designed to store Potassium while maintaining a balance of sodium outside the cell.

If you trace the sequence of cell division within the body all the way back through time to the start where they originate from an egg, you will notice that this egg can also be traced back to the previous egg. So at each step back there has always been a living, breathing cell all the way back through the billions of years of evolution. Now the question has to be asked, how has this sequence of living cells managed to survive through billions of years? The only explanation I can think of, is that they must have an amazing ability to fix, repair and rejuvenate when given the chance. The common assumption has been that old age is caused by the slow unavoidable break down of our bodies, but the evidence now suggests, that what we observe as aging is actually initiated by the body to prevent the mitochondria from being starved of oxygen. Whether this is inflammation to increase the direct supply of oxygen or osteoporosis in which calcium from the bones is used to neutralize acids in the blood, or obesity to prevent accumulation of sugars which cause a build up of lactic acid. In other words, all these diseases of old age are not caused by degeneration but to prevent degeneration of the cells! If the mitochondria don’t get enough oxygen, they simply cannot produce enough of the ATP required for the DNA to be repaired or for the Liposome’s to recycle worn-out organelles. Our own bodies even store stem cells to travel through the body and repair damaged organs like the liver, but they cannot do any of this without oxygen.

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