Power, Sex, Suicide: Mitochondria and the Meaning of Life (55 page)

Without this subtle self-correcting mechanism, the performance of the mitochondria, and the cell as a whole, would be seriously undermined. Mutations in mitochondrial DNA would escalate, and cellular function spiral out of control in an ‘error catastrophe’. In contrast, the signalling role of free radicals maintains near optimal respiratory function in long-lived cells for many decades. Damaged mitochondria are removed, and undamaged mitochondria replicate to take their place. In the end, though, at least in long-lived cells, the supply of undamaged mitochondria runs out, and then a new level of signalling must take over.

If too many mitochondria become deficient in respiration simultaneously, then the general load of free radicals in the cell rises, and this signals the general respiratory failure to the nucleus. Such oxidizing conditions shift the kaleidoscope of active nuclear genes to compensate—a shift known as the retrograde response, for the mitochondria control the activity of genes in the nucleus. The cell enters a stress-resistant state and may survive like this for many years. It is limited in its powers of energy generation, but can get by so long as it is not
placed under too much strain. However, any stressful episodes are likely to undermine such cells, and lead to some degree of organ failure. This in turn probably contributes to the chronic inflammation that underpins many diseases of old age.

In ageing organs, the more damaged cells are removed by means of free-radical signalling, coupled to the decline in respiratory function. When cellular ATP levels fall below a critical threshold, the cell commits apoptosis, removing itself from the firmament. The removal of damaged cells in this way contributes to the shrinkage of organs with age, but at the same time removes malfunctioning cells, so that the remainder are selected for optimal function. There is no sudden meltdown, no exponential error catastrophe, as there would inevitably be if free radicals merely played a destructive role. Likewise, the quiet elimination of cells by apoptosis, rather than the gory end of necrosis, curbs inflammation across the tissue as a whole, and so prolongs life.

So if a cell can’t meet metabolic demands, it commits apoptosis. The likelihood of cell loss therefore depends in part on the metabolic requirements of the organ. Metabolically active organs, like the brain, heart, and skeletal muscle, are most likely to lose cells by apoptosis. The exact timing of cell death depends on the general stress levels. These are calibrated by the mitochondria, as we saw in
Part 5
; and one important factor involved in this calibration is the accumulated exposure to free radicals. As a result, long-lived animals suffer from age-related diseases late in life, while short-lived animals capitulate more quickly. The general stress levels of a cell can also be raised by particular inherited or acquired genetic mutations, or physiologically traumatic events, such as falls, heart attacks or diseases, or exposure to cigarette smoke and suchlike. The conclusion we can draw from this is hugely important: if all genetic and environmental contributions to the diseases of old age are calibrated by the mitochondria, we ought to be able to cure, or postpone, all the diseases of old age at once. Conversely, attempting to tackle them piecemeal, as we do today, is doomed to failure. All we need to do is to lower free-radical leakage over a lifetime.

Therein lies the problem. At each stage in the life of cells, the physiology of mitochondrial and cellular function
depends
on free-radical signalling. Simply attempting to quash free-radical generation with massive doses of antioxidants is likely to exacerbate the situation, if it could be made to work at all. In
Oxygen
, I put forward the idea (dubbed the ‘double-agent’ theory) that the body is refractory to high doses of antioxidants—we eliminate superfluous antioxidants from the body because they have the potential to play havoc with sensitive free-radical signals. I have probably down-played the possible utility of antioxidants to a degree, if only as a corrective to the usual hyperbole; it may be that they can benefit us in various ways, but frankly, I’m sceptical that they can
do much more than correct dietary deficiencies. And I think that the problem with signalling means that if we wish to prolong our healthy lifespan, then we need to tear ourselves away from the lure of antioxidants, and think afresh.

So what else could we do? Relative to mammals, birds slow down the rate of free-radical leakage. By studying the differences between birds and mammals, we might gain insight into how best to cure ageing, and its attendant diseases, in everyone. So could we make ourselves more like the birds? That depends on how they do it.

According to the pioneering work of Gustavo Barja in Madrid, most free-radical leakage comes from complex I of the respiratory chains. In a series of simple but ingenious experiments using respiratory-chain inhibitors, Barja and colleagues pinpointed the site of leakage to one of more than forty subunits in complex I; and their work has been confirmed by others using different techniques. The spatial disposition of the complex means free radicals leak straight into the inner matrix, in the immediate vicinity of mitochondrial DNA. Clearly, any attempt to block leakage needs to be targeted to this complex with extraordinary precision—no wonder antioxidant therapies fail! Apart from the fact that they can potentially play havoc with signalling, it’s virtually impossible to target antioxidants at a high enough concentration in such a small space. There are, after all, tens of thousands of complexes in a single mitochondrion, and typically hundreds of mitochondria in cells. And of course perhaps 50 trillion cells in the human body. Luckily, we’ve learnt from birds that this is not the way; they have quite low antioxidant levels. So how do they reduce free-radical leakage?

The answer is not known with any certainty, and there are a number of possibilities. It may be that birds combine bits of them all. One possibility is that the differences are written into the sequence of a handful of mitochondrial genes. The best evidence to support this possibility, ironically, derives from studies of human mitochondrial DNA, most inspiringly from Masashi Tanaka’s group in Japan. In 1998 Tanaka’s group reported in
The Lancet
that nearly two-thirds of Japanese centenarians shared the same variation within a mitochondrial gene—a single letter change in the code for a subunit of complex I—compared with about 45 per cent of the population as a whole. In other words, if you have the letter-change, you are 50 per cent more likely to live to a hundred. The benefits don’t stop there. You are also
half
as likely to end up in hospital for any reason at all in the second half of your life: you’re less likely to suffer from
any
age-related disease. Tanaka and colleagues showed that the letter change probably resulted in a tiny reduction in the rate of free-radical leakage—a tiny benefit at any one moment, but one which mounted up imperceptibly over a whole lifetime, to finally make a substantial difference. This is exactly the sort of evidence needed to confirm the theory that all age-related diseases can be
targeted by a single simple mechanism. On the other hand, there are drawbacks too. The Japanese letter-change is hardly ever found outside Japan, and although its prevalence there may help explain the exceptional longevity of the Japanese, that doesn’t help the rest of us a great deal. Not surprisingly, the news inspired a worldwide gene hunt, and it seems there are other mitochondrial letter changes that have a similar effect. The same problem applies to all of them, however, which is that we can only alter gene sequence by genetically modifying ourselves. Given the great rewards, this might be worth doing, but it is dangerously close to the ethically indefensible waters of choosing human traits in embryo. So at present, unless society has a major about-turn in its attitudes to genetic modification (GM) of humans, the best that can be said is that all of this is scientifically extremely interesting.

But GM is not the only possibility. Another way that birds might lower their rate of free-radical leakage is by uncoupling their respiratory chains. The term uncoupling refers to the dissociation of electron flow from ATP production, so that respiration dissipates energy as heat. In the same way, uncoupling a chain on a bike dissociates peddling from forward movement, which dissipates energy in a sweaty brow. The immense benefit of uncoupling the respiratory chain is that electrons can keep flowing, just as a cyclist’s legs keep peddling, and this in turn reduces free-radical leakage. (I suppose that an uncoupled bike has the advantage of allowing us to burn off excess energy as heat in the same way; we now call it an exercise bike.) Because fast free-radical leakage is associated with both ageing and disease, and uncoupling reduces free-radical leakage, then uncoupling surely has the potential to extend lifespan. Like a bike chain, it is possible to partially uncouple respiration (it’s called changing gear on a bike) so that some ATP synthesis can continue, but a proportion of energy is frittered as heat (just as we could still peddle while whizzing down hill, but can’t engage the chain). The long and short of it is this: by enabling a constant flow of electrons down the respiratory chain, uncoupling restricts the leakage of free radicals.

We noted in
Part 4
(
page 183
) that uncoupled mice have faster metabolic rates and do indeed live longer than their well-coupled brethren. Likewise, in
Part 6
, we noted that differences in the vulnerability to disease of Africans and Inuit might be related to differences in uncoupling. In a similar vein, it is quite feasible that birds are more uncoupled than the equivalent mammals, and that this might explain why they live longer. Uncoupling generates heat, as we just noted, so if birds really are more uncoupled, they should also generate more heat than equivalent mammals. In support of this idea, birds do indeed maintain a higher body temperature, of about 39°C rather than 37°C, which might be the result of greater heat production from uncoupling. In fact, however, direct measurements imply that this isn’t the case: the respiratory chains of birds and mammals seem to be similarly coupled, so presumably the temperature
difference can be ascribed to differences in heat loss and insulation. Feathers are better than fur.

That’s not to say that uncoupling couldn’t help us though. Not only could it, in principle, lower free-radical leakage, and so prolong our lives, but it would also enable us to burn more calories and lose weight. We could cure obesity and all the diseases of old age in one go! Sadly, the experience so far with anti-obesity drugs is rather sorry. Dinitrophenol, for example, is a respiratory-chain uncoupler that has been tested as an anti-obesity drug. It proved toxic, at least at the high doses used. Another uncoupler is the popular recreational drug, ecstasy, which illustrates the potential dangers well: uncoupling generates heat, inducing some revellers to dance with a water supply strapped to their backs; even so, a few have died of heatstroke. Certainly more finesse is needed. Curiously, aspirin is also a mild respiratory uncoupler; I do wonder how many of its more mysterious benefits may relate to this property.

Barja’s own work suggests that birds decrease free-radical leakage from complex I by lowering its reduction state. Remember that a molecule is ‘reduced’ when it has received electrons, and oxidized when it has lost them. Accordingly, a low reduction state means that birds tend to have relatively few electrons passing through complex I at any moment. We have noted (
page 77
) that there are tens of thousands of respiratory chains in each mitochondrion, and each one has its own leaky complex I. If they are in a low reduction state, then only a small proportion of them are in possession of a respiratory electron; the rest are as bare as Mother Hubbard’s cupboard. If there are relatively few electrons milling around, they are less likely to escape to form free radicals. Barja argues that a similar mechanism also underpins calorie restriction, the only method so far proved to extend lifespan in mammals; there, too, the most consistent change is a fall in the reduction state, despite little change in oxygen consumption. Furthermore, this line of thinking explains the exercise paradox that I mentioned earlier—the fact that athletes consume more oxygen than the rest of us but don’t age more quickly. Exercise speeds up the rate of electron flow, which in turn lowers the reduction state of complex I—the electrons are quicker to leave it again, and this makes the complex less reactive. That explains why regular activity doesn’t necessarily increase the speed of free-radical leakage and might actually lower it in trained athletes.

In all these cases, the common denominator is a low reduction state. We could think of this as a half-empty cupboard, or, perhaps more helpfully, as spare capacity. But importantly, the spare capacity in birds differs from that in exercise and uncoupling (dissipating energy). In both of the latter cases, free-radical leakage is restricted because electrons are flowing down the chain, and their departure from one complex frees that complex to receive another electron: it therefore frees up some capacity. As a result, electrons are less likely to
leak out as free radicals. In birds, however, spare capacity is maintained at rest, compared with mammals that have an equivalent metabolic rate and degree of uncoupling. In other words, when all else is equal, birds have more spare capacity than mammals, and for this reason they leak fewer free radicals. And because they leak fewer free radicals, they live longer lives.

If Barja is correct (and some researchers disagree with his interpretation) then the key to longer life is spare capacity. So how, indeed why, do birds retain spare capacity? To understand the answer, think of the workforce in a factory that needs to cope with fluctuating workloads. Imagine that the management have two possible strategies (no doubt they have many more, but let’s focus on two): either they can retain a small workforce, and oblige them to work harder whenever extra work arrives; or they can employ a large workforce, which can cope easily with the heaviest demands, but idle away much of the year. Now consider the morale of the workforce. Let’s say the small workforce becomes downright rebellious whenever they’re forced to work long hours, and when in rebellious spirits, they wilfully damage equipment. On the other hand, they have short memories, and their resentment soon fades after a few beers; then they work well. Management calculates that it’s worth losing a little equipment to save on labour costs. So what about the morale of the large workforce? Now, even when the extra work arrives, the large team has no difficulty accomplishing the task, and their morale remains high. But, of course, for much of the year they have too little to do, so they get bored. Their resentment is not strong (better to have a job and put up with a little boredom) but nonetheless there is a risk that the workforce may look for a less boring job, and drift away just when they’re needed.