by Nick Lane
Inflammation again! We may be sure that NFB, the inflammatory transcription factor, will be involved, and indeed it is. NFB is a source of anguish among researchers. The chemistry of life is so appallingly complex that researchers are quick to regress into a childlike sense of good and evil, pitting the ‘good guys’ against the ‘bad guys’. This naive view of molecules is willingly embraced by the pharmaceutical industry, which strives to target the ‘bad guys’ — a molecule that is good and bad by turns is a dreadfully shifting target for a drug. This is unfortunate. As we saw in Chapter 9, even icons of goodness such as vitamin C can exert an unpredictable mixture of ‘good’ and ‘bad’ effects. Applying a simplistic moral order — are you with us or against us — invariably results in a ‘paradox’, a massively overused word in academic journals. A quick search for the word ‘paradox’ on Medline (the main database of medical abstracts) yields nearly 4000 articles in which it is a key term: ‘Another Calcium Paradox’;
‘The Paradox of Antioxidants and Cancer’ or ‘Beta-Carotene: Friend or Foe?’ One might think that biochemists were fond of solving paradoxes, but few are solved in these articles. Instead, the weight of evidence for and against is stacked into heaps and left for posterity to judge. For all the detailed scientific analysis of data, confusion radiates from many articles.
My own favourite is the title ‘Does Growth Hormone Prevent or Accelerate Ageing?’ It is hard to avoid the impression that, for all the astonishing advances in medicine, some fundamental questions remain unanswered even in outline.
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The trouble stems from the traditional approach of medical research, which takes a snapshot in time — sometimes a fraction of a second, before quenching a biochemical reaction — and then tries to piece together the frozen relationship between molecules. This approach is analogous to forensics, which scrutinizes clues scientifically to solve a murder mystery, but omits to consider motive. For all the science in the world, a proper understanding will only come from motive. Motive is often rooted in historical accident, such as a humiliating experience years before. The same is true of the way in which our bodies are built, right down to the molecular level. Our bodies are historical accidents of evolution and ultimately can only be understood from an evolutionary perspective: how things got to be the way they are. From this point of view, a good guys–bad guys philosophy is a woefully inadequate way of thinking about molecules as complex as NFB. Even so, this is the norm. NFB is usually portrayed as Janus-faced, capable of abrupt swings from the good to the bad and the ugly. Sometimes it destroys neurons, sometimes it protects them. It is important, but profoundly unreliable as a drug target.
Seen in the light of infections, though, the behaviour of NFB is consistency itself. Activation of NFB in Alzheimer’s disease, as in an infection, has two complementary effects: it fans the fires of inflammation, and at the same time shields our healthy cells from the same flames. In infections, the rationale is obvious: the immune system attacks the invader with free radicals that might just as easily harm our own cells. To prevent damage to our own cells, their genetic resistance to oxidative stress is tuned up. A shock that might normally kill our body’s cells, or make them commit suicide (apoptosis) is now weathered out until the storm is over. Some cells are stimulated to divide, to repopulate tissues that were less prepared for the storm, and which suffered accordingly.
The difference in Alzheimer’s disease is that the storm is never-ending, albeit less violent. The inflammatory glial cells in the brain are incited by chemical messengers to attack the plaques and tangles, but healthy neurons are threatened with collateral damage. They respond by stepping up their own resistance to the onslaught. Powerful protectors, such as haem oxygenase and SOD, are produced like so many sandbags (see Chapter 10) to bulwark the neurons. Yet even such powerful protectors cannot help indefinitely. They impose a curfew on the cell and, like real curfews during a continuous bombardment, there is a limit to how long cells can bear the strain. This is not a paradox: it is a clockwork response to oxidative stress, which is strained by its own duration.
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If NFB is ‘switched off’, healthy neurons are more vulnerable to damage — of course, they no longer have their sandbags to protect them —
but then the inflammation may at least come to an end, so there is less need of protection. The balance is delicate and unpredictable. A practical solution is to block the activation of NFB only in inflammatory cells. To some extent this can be achieved using aspirin or non-steroidal anti-inflammatory drugs (NSAIDs).11 Several studies have shown that people prescribed aspirin or NSAIDs over a number of years to control rheumatic pain have less than half the risk of dementia, compared with their contemporaries. Conversely, people who have other sources of brain inflammation, such as a stroke, traumatic brain injury and viral infections, have several times the risk of dementia. I imagine that such vulnerable groups would benefit most from aspirin or antioxidants, though I am not aware of any systematic studies to prove the point.
Before drawing this chapter to a close with some parallels in other age-related diseases, what have we learnt from Alzheimer’s disease? First, the known genetic mutations affect a small fraction of people with Alzheimer’s disease and their effects are delayed until middle age. This delay implies that, as in mice and monkeys, oxidative stress must cross a threshold before neurons die en masse and dementia can be diagnosed clinically. Second, all other known risk factors for Alzheimer’s disease, including Down syndrome, ApoE4 and herpes simplex infection, are associated with a rise in oxidative stress. Third, oxidative stress alone is sufficient to cause dementia in old age in people with no known risk factors (about half the people who succumb to dementia in old age).
Fourth, factors that lower oxidative stress, such as aspirin and vitamin E, can postpone the onset of dementia by a few years, if not indefinitely.
11High or continuous doses of aspirin and NSAIDs can cause gastrointestinal bleeding and ulcers, and thousands of people are hospitalized for side-effects each year (although about 97 per cent of people can tolerate moderate doses of aspirin without problems, the other 3
per cent totals many thousands). New, more specific versions of aspirin, known as COX-2
inhibitors, are now on the market and hold the prospect of similar potency with fewer side-effects. At low doses, however, COX-2 inhibitors and aspirin inhibit the enzyme cyclo-oxygenase, and so have only a limited effect on other proteins whose production is controlled by NFB, such as tumour necrosis factor or nitric oxide synthase. At high doses, aspirin (but not the COX-2 inhibitors) inhibits NFB, which might account for some of its previously unexplained effects — a startling finding published in Science in 1994 by Elizabeth Kopp and Sankar Ghosh at Yale University. Glucocorticoids suppress the activity of NFB even more strongly, accounting for their potent immunosuppressant effects. When taken in medicinal doses, however, glucocorticoids have many unpleasant side-effects, including weight gain, chronic infections, bone loss and glandular atrophy.
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In conclusion, Alzheimer’s disease is linked with age because age is a function of oxidative stress. Factors that exacerbate oxidative stress early in life accelerate the onset of dementia, while factors that alleviate oxidative stress postpone dementia. However, unless we abolish oxidative stress we can never get rid of Alzheimer’s disease. The difficulty is that we cannot abolish oxidative stress, because it is necessary to coordinate our resistance to infections and other physical stresses; but we can probably modulate it with a little more subtlety. At the beginning of this section on Alzheimer’s disease, I posed a question: why do people without known risk factors still get dementia? I believe we have answered the question.
They still get oxidative stress. Another permutation of the same question may throw a more practical light on the prevention of dementia. Why do some people
with known genetic risk factors (such as ApoE4) not get Alzheimer’s disease? What do they have that is protecting them? These are questions we will touch on in the final chapter.
I have argued that ageing and age-related diseases are degenerative conditions brought about by the combination of mitochondrial leakage, oxidative stress and chronic inflammation. Some genes, infections and environmental factors exacerbate oxidative stress at an earlier age, and this speeds up the ageing process, in some organs at least. We have seen that amyloid deposition, apolipoprotein E4, Down syndrome and reactivation of latent viral infections all exacerbate oxidative stress. So too do smoking, high blood glucose and various environmental toxins.
Nicotine is blamed for many things but, although addictive, it is not responsible for the deadly diseases caused by smoking. This is why nicotine gums and patches offer a safe way of quitting smoking. Cigarette smoke is dangerous because it is the most dastardly free-radical generator known (I enjoy smoking, though I intend to quit when I finish this book).
Many chemicals in cigarette smoke, including semiquinones, polyphe-nols and carbonyl sulphide, react with oxygen to form superoxide radicals, hydroxyl radicals and hydrogen peroxide, as well as nitric oxide and peroxynitrite. A single puff of cigarette smoke is said to contain 1015 (a million billion) free radicals. The mind boggles. If this were not enough, cigarette smoke activates inflammatory cells, which add their own toxins to the brew. The result is oxidative stress, especially in the lungs and the walls of blood vessels. Cellular glutathione levels are suppressed (quitting
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smoking raises blood glutathione levels by 20 per cent in three weeks) and this activates transcription factors like NFB. Smokers ‘turn over’ antioxidants such as vitamin C much faster, and so should take more dietary antioxidants to counter the threat. Most do not. Smoking thus provokes inflammation, and this is the chief reason for the high risk of both heart disease and cancer.
Too much glucose is another modern killer, for surprisingly similar reasons. Poor control of blood glucose levels is the hallmark of diabetes (see Chapter 12), and in diabetics glucose may reach very high levels after meals. Glucose reacts in a complex manner with proteins to form brownish caramels that accumulate with age, known as advanced glycation end-products, or AGEs (this is also why meat browns when it is cooked). Such caramels account for the clouding of the lens of the eye in a cataract.
Caramelization of proteins is accelerated by oxygen, and most AGEs are really oxidation products. Not surprisingly, caramelization blocks the function of proteins, but worse follows. AGEs, like amyloid, are free-radical amplifiers: they are mostly formed by free radicals and then exert their toxic effects by producing more free radicals, causing oxidative stress and so inflammation. Because glucose is delivered to cells via the blood stream, the vessel walls are worst affected. In diabetes, small blood vessels in the eyes, kidneys and limbs become damaged and blocked, causing blindness and kidney failure, and all too often necessitating amputations.
This whole process is speeded up in diabetes, but it happens at a slower speed in everyone, as AGEs accumulate with age as a result of mitochondrial leakage in all tissues. For this reason, diabetes is often referred to as a form of accelerated ageing; it is really an accelerated form of oxidative stress.
Inflammation of blood vessel walls induces cellular proliferation, oxidation and deposition of cholesterol, and the development of atherosclerosis. These are ideal culture conditions for some tough bacteria, such as Chlamydia pneumoniae, which infect damaged arterial walls, and from their safe haven antagonize immune cells. Up to 80 per cent of people with cardiovascular disease are infected with Chlamydia, but whether this is a cause or an effect of heart disease is still disputed. It is simplest to say it could be both: the cause of atherosclerosis is oxidative stress, and the process can be started, or perpetuated, by smoking, AGEs, oxidized cholesterol, ApoE4, infections, or just old age. Any one of these factors makes the others more likely. All are united by oxidative stress, and converted into the common currency of inflammation by NFB and its kin.
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Because many of these factors are ‘external’ (not produced within our own cells by mitochondrial leakage) they are more responsive to antioxidant therapies than is mitochondrial ageing, which cannot be easily reversed. This is why a healthy diet, or possibly antioxidant supplements, can postpone the onset or progression of heart disease, but do not ultimately prevent ageing.
Cancer is also provoked by oxidative stress and inflammation. We have seen that the effects of radiation are mediated by the production of oxygen free radicals from water (see Chapter 6), which then attack DNA, proteins and lipids. Because oxygen itself produces the same radicals, it is in fact a carcinogen (or more technically, a pro-carcinogen). The more air we breathe, the more likely we are to get cancer, hence the strong association between cancer and age. Many carcinogens, including benzene, quinones, imines and metals, also act by generating free radicals. The importance of oxygen radicals in this process is borne out by tell-tale chemical signatures of hydroxyl radical attack on DNA, such as 8-hydroxydeoxyguanosine (8-OHdG; see Chapter 6, page 124), which are excreted in the urine. Smoking can increase the excretion of 8-OHdG by 35–50 per cent. For the most part, the oxidized fragments are excised from the DNA and replaced with new, correct, letters; but mismatches do occur (for example, guanine (G) is replaced with thymine (T)). When cells divide, the mistakes are passed on in the genetic code as mutations. Both oxidative damage and mutations accumulate with age. By the time a rat is old (two years) it has about a million lesions in DNA per cell, twice as many as a young rat.
The frequent mutations in cancer cells are usually considered to be the cause of cancer, but in fact it is not known whether such mutations occur first, and then stimulate cancer cells to proliferate, or whether the mutations accumulate in cancer cells that are already proliferating. Certainly, tumours ‘evolve’ and accumulate more mutations over time. There is good evidence to suggest that oxidative stress and inflammation create an environment conducive to cell division in the first place. Apart from the oxidative stress associated with irradiation, smoking, carcinogens and ageing, a third of cancers worldwide (notably in the developing world) are caused by chronic infections, such as hepatitis B and C and schisto-somiasis. Not surprisingly, given the ubiquity of oxidative stress, NFB is involved. High levels of activated NFB are found in most cancers and may be necessary for the transformation of a normal cell into a cancer cell. Why should this be? Again, the normal response to infection pro-
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vides the clue. First, NFB strengthens the cell’s resistance to oxidative stress: it makes cancer cells tough. Second, NFB stimulates cell proliferation. In an infection, the rationale is to replace damaged tissue with new cells, but in cancer, activation of NFB simply makes proliferation more likely. Thus, perpetual activation of NFB toughens cancer cells and stimulates their proliferation. Apart from anything else, this makes tumours more resistant to treatments such as chemotherapy and radiotherapy.
Switching off NFB, if possible, makes tumours more sensitive to treatment, and is a promising line of cancer drug development.12
There are hundreds of diseases in which oxidative stress is known to play a role. I hope these few examples are enough to establish my general point, the ‘double-agent’ theory of ageing: oxidative stress rises with age and activates the genes responsible for fighting off infections by way of transcription factors such as NFB. These genes were never intended to be switched on for months or years at a time: their purpose is to improve our chance of surviving infection in youth, so that we may recover, go forth and multiply. In terms of selective pressure, or pleiotropic trade-offs, the importance of this task outweighs the personal misfortune of ageing and age-related disease. Even so, the message of this chapter is positive. We are no
t the victims of a thousand random genetic muggers, intent on ‘doing us in’. Quite the contrary. The behaviour of our genes depends on oxygen and oxidative stress. When we learn how to modulate oxidative stress with more finesse, then, and only then, can we go beyond our genes and destiny.
12In cancer, the gene for NFB is often mutated to be continuously active. One possible problem with blocking the activity of NFB is that this causes immune suppression. Immunosuppression makes the progression of cancer more likely, as the immune system normally targets and eliminates cancer cells. Such involuted links are painfully difficult if not intractable.
C H A P T E R F I F T E E N
Life, Death and Oxygen
Lessons From Evolution on the Future of Ageing
hich came first, the chicken or the egg? This question
symbolizes our fascination with cause-and-effect problems. It Wmight be rephrased, did the egg ‘cause’ the chicken, or did the chicken ‘cause’ the egg? Given that the one follows the other in an apparently endless succession, the question seems impossible to answer: it is the kind of infinite regression that philosophers love. Some people see such regressions as evidence of a prime mover, who created both the chicken and egg simultaneously. Then there are the pedants, who insist on answering the question. The tiresome truth of it is that the pedants are right: there is an answer. We will look into this answer briefly, because it throws light on the more important problems of life, death and oxygen.
The answer is not logical but historical: we confuse an infinite regression with an incomprehensibly long time and the contingencies of history. There were not always chickens and eggs: they evolved. More than this, they evolved in a particular way, by sex and natural selection. In a sexual species, the tiny changes in genes, which accumulate generation after generation, are only passed on through the sex cells. The genes in the sex cells are largely unchanged by the experience of the organism: we can mutate them by smoking or irradiation, but if we develop large muscles through working out in the gym, we cannot pass them on to our children (though we may pass on our frame or propensity for working