Power, Sex, Suicide: Mitochondria and the Meaning of Life (54 page)

The fate of the tissue, and the function of whole organs, depends on the types of cell from which they’re composed. If the cells are replaceable, by way of the division of stem cells that preserve an unsullied mitochondrial population, the loss of cells by apoptosis doesn’t necessarily perturb the status quo, so long as a dynamic balance is maintained in the cell population. But if the cells forced to die are more or less irreplaceable, like neurones or heart-muscle cells, then the tissue becomes depleted of functional cells, and the survivors are placed under greater strain, pushing them closer to their limits—their own particular metabolic threshold. Any other factors that force cells closer to their limits could precipitate a specific disease. In other words, as cells draw closer to their limits, with advancing age, various random factors are more likely to push them over the abyss to apoptosis. Such factors may include environmental assaults such as smoking and infections, and physiological traumas such as heart attacks, but also any genes associated with disease.

This link between metabolic threshold and disease is critical. It explains how mitochondria can be responsible for a whole gamut of diseases, even if they appear to be completely irrelevant. This simple insight explains why rats succumb to the diseases of old age within a few years, whereas it takes decades for humans. What’s more, it helps explain why birds don’t age in a particularly ‘pathological’ way, and how we can cure many of our own diseases at a single stroke. It explains in short how we can be more like elves.

I’ve been enumerating the failings of the original mitochondrial theory of ageing. Here’s another: it’s very difficult to link the underlying process of ageing with the occurrence of age-related diseases. To be sure, there was a hypothetical relationship between free-radical production and the onset of disease, but if this is taken at face value then the theory is forced to predict that all the diseases of old age are caused by free radicals. Obviously, this is not true. Medical research has shown that most diseases of old age are an appallingly complex amalgam of genetic and environmental factors—and most of them have little to do with free radicals and mitochondria, at least not directly. Proponents of the mitochondrial theory have spent years trying to identify specific links between genes and free-radical production, but to little avail. Mutations in some genes
are
associated with free-radical production, but this is not the rule. Of more than a hundred different genetic defects known to cause degeneration of the retina, for example, only a few affect free-radical production at all.

The solution was put forward in a beautiful paper by Alan Wright and his colleagues in Edinburgh, and published in
Nature Genetics
in 2004. I personally think this paper is one of the most important to emerge for a long time, for it gives a new, unifying framework for considering the diseases of old age, which ought to replace the current paradigm—both fallacious and counterproductive, in my view.

The paradigm underlying most medical research today is gene-centric. The approach is first to pinpoint the gene, then to find out what it does and how it works, then dream up some pharmacological way of correcting the problem, and finally to apply the pharmacological solution. I think this paradigm is fallacious, as it is based on a view of ageing that now seems incorrect—the idea that ageing is little more than a dustbin of late-acting genetic mutations, which have broadly independent effects and so must be targeted individually. This is the hypothesis, you might recall, of Haldane and Medawar, which I criticized earlier on the grounds that recent genetic research shows that ageing is far more flexible. Extend the lifespan, and
all
diseases of old age are postponed by a commensurate period, if not indefinitely. More than forty different mutations extend lifespan in nematodes, fruit flies, and mice, and all of them postpone the onset of degenerative diseases in general. In other words, the diseases of old
age are tied to the primary process of ageing, which is somewhat flexible. The best way of targeting the diseases of old age is therefore to tackle the underlying process of ageing itself.

Wright and colleagues considered specific mutations in genes known to increase the risk of particular neurodegenerative diseases. Rather than asking what these genes do, they wondered what happens when the
same mutation
is found in different animals with differing lifespans. Of course, the same mutations
are
often found, and not only by chance. Animal models are essential for medical research, and genetic models of diseases figure at the centre of research today. So all that Wright and colleagues needed to do was to track down data on animal models in which the same genetic mutations cause equivalent neurodegenerative diseases. Nothing else was different. They came up with ten mutations that they could flesh out with data from five species with a wide range of lifespans—mouse, rat, dog, pig, and human. The ten mutations caused different diseases, but the same mutations produced the same disease in each species. The main difference was the timing. In the case of mice, the mutations produced disease within a year or two; for people, it might take a hundred times as long to cause exactly the same disease.

It’s important to appreciate that the ten mutations are all inherited genetic mutations of
nuclear
DNA. None of them have anything to do with mitochondria or free-radical production directly. Wright and colleagues considered mutations in the
HD
gene in Huntington’s disease, the
SNCA
gene in familial Parkinson’s disease, and the
APP
gene in familial Alzheimer’s disease, plus a number of genes causing degenerative diseases of the retina, leading to blindness. In each case, the pharma industry is ploughing billions of dollars into research, as any effective treatment would recoup billions of dollars every year. More human ingenuity goes into this research than into rocket science these days. In no case has a really serious clinical breakthrough been made—the kind of breakthrough that leads to a genuine cure, or a delay in the onset of symptoms beyond months, or at best a few years. As Wright and colleagues put it, with nice understatement: ‘There are few situations in which neurodegeneration rates can be altered as substantially as the differences between species shown here.’ In other words, we can’t begin to slow down the progression of diseases, through medical interventions, by anything like as much as happens naturally in different species.

Wright and colleagues plotted out the time of onset and the progression of disease from mild symptoms through to severe illness in the different animals. What they found was a very tight correlation between disease progression and the underlying rate of production of free radicals from mitochondria. In other words, in the species that produced free radicals quickly, the disease set in early and was quick to progress, despite no direct link with free-radical production.
Conversely, in animals that leak free radicals slowly, the onset of diseases was delayed many-fold, and they progressed more slowly. This relationship could hardly be chance, for the correlation was too tight; clearly the onset of disease is tied, in some way, to the physiological factors that regulate longevity. Nor could the relationship be ascribed to differences in the genes themselves, for in each case the defects were exactly equivalent, and the biochemical pathways were conserved. It could not be ascribed to free radicals in general, as most of the genes didn’t change free-radical production directly. And it couldn’t be linked to other aspects of metabolic rate, as the metabolic rate doesn’t correlate with lifespan in many cases, including birds and bats—and, critically in this case, humans.

The most likely reason for the correlation, said Wright, is that in all these degenerative diseases, the cells are lost by apoptosis—and free-radical production influences the threshold for apoptosis. Each of the genetic defects creates cellular stress, culminating in the loss of cells by apoptosis. The probability of apoptosis depends on the overall degree of stress, and the ability of the cell to keep meeting its metabolic demands. If it fails to meet its demands, it commits apoptosis. And the likelihood that it will fail depends on the overall metabolic status of the cell, which is calibrated by mitochondrial free-radical leakage as we have seen. The speed at which cells activate the retrograde response and amplify defective populations of mitochondria, leading to an ATP deficit, depends on the underlying rate of free-radical leakage. Species that leak free radicals rapidly are closer to the threshold, and so more likely to lose cells by apoptosis.

Of course, all this is correlative, and it is hard to prove that a relationship is causal. But one study published in
Nature
in 2004 suggests that there is indeed a causal relationship. The study won several of its senior authors, among them Howard Jacobs and Nils-Göran Larsson, of the Karolinska Institute in Stockholm, the prestigious EU Descartes Prize for research in the life sciences. The team introduced a mutant form of a gene into mice, termed
knockin
mice, as they have a gene knocked in (which is to say that a functional gene is added to the genome, rather than knocked out, the more common approach). The knockin gene in this case encoded an enzyme known as a proof-reading enzyme. Like an editor, a proof-reading enzyme corrects any errors introduced during DNA replication. In their study, however, the researchers introduced a gene that encoded a faulty version of this enzyme, which, ironically, was prone to errors. Like a bad editor, an error-prone version of the proof-reading enzyme leaves behind more errors than usual. The gene introduced in this study encoded a proof-reading enzyme specialized to work in the mitochondria, so that the errors it left behind were in mitochondrial, rather than nuclear, DNA. Having succeeded in setting the slapdash editor to work, the investigators were
duly rewarded with a several-fold rise in the usual levels of mitochondrial errors, or mutations. There were two intriguing findings. The finding that captured the headlines was that the affected mice had foreshortened lives, coupled with an early onset of several age-related conditions, including weight-loss, hair loss, osteoporosis and kyphosis (curvature of the spine), reduced fertility, and heart failure. But perhaps the most intriguing aspect of the study was that the number of mutations
did not rise
with the age of the mice. As the mice got older, the number of mitochondrial mutations in body tissues remained relatively constant, as happens in humans—there was no big increase in mutational load during ageing.

Although the reason was not ascertained, I imagine that any cells that acquired an unworkable load of mutations were simply eliminated by apoptosis, giving an impression that mitochondrial mutations did not accumulate with age. Overall, the study confirms the importance of mitochondrial mutations in ageing, but does not conform to the expectations of the original mitochondrial theory of ageing, which predicts a large accumulation of mitochondrial mutations leading into an ‘error catastrophe’. But the findings do support the more subtle version of the mitochondrial theory, in which free-radical signals and apoptosis continually relive the burden of mutation.

Some critically important conclusions emerge from this thinking. First, it seems that mitochondrial mutations genuinely do contribute to the progression of ageing and disease, even if they can’t always be seen—they are eliminated, along with their host cells, by apoptosis. Second, other genes associated with particular diseases add to the overall levels of cellular stress, making it more likely that the cell will die by apoptosis. From Alan Wright’s work, we have seen that it makes little difference what the gene codes for, or what the particular mutation may be—the timing and mode of cell death is virtually independent of the gene itself, if we consider the differences between species; it depends on how close a cell is to the threshold for apoptosis. This means that it is pointless trying to target individual genes or mutations in clinical research—and that means that the whole caravan of medical research is bound in the wrong direction. Third, research strategies that aim to block apoptosis are also likely to fail, for apoptosis is merely a useful way of disposing of broken cells without leaving behind a bloody signature. Blocking apoptosis doesn’t solve the underlying problem that the cell can no longer fulfil its task; it would be doomed to die instead by necrosis, leaving blood and gore on the pavement, and this could only make matters worse. Finally, hugely importantly, the degenerative diseases of old age,
all of them
, could be slowed down by orders of magnitude, perhaps even eliminated altogether, just by slowing down the rate of free-radical leakage from mitochondria. If some of the billions of dollars devoted to medical research were directed to the target of free-radical leakage,
we could potentially cure all the diseases of old age at a stroke. Even a conservative view would put that as the greatest revolution in medicine since antibiotics. So can it be done?

Ageing and age-related diseases can be ascribed to mitochondrial free-radical leakage. Unfortunately, or perhaps fortunately, the way in which the body deals with free-radical leakage from the mitochondria is far more complex than the rather naïve early formulation of the mitochondrial theory would have us believe. Rather than simply causing damage and destruction, free radicals play a vital role in keeping respiration fine-tuned to needs, and in signalling respiratory deficiencies to the nucleus. This is possible because the proportion of free radicals leaking from the mitochondria fluctuates. High levels of free radicals signal respiratory deficiency, which can be corrected by compensatory changes in the activity of mitochondrial genes. If the deficiency is irreversible, and the mitochondrial genes are unable to re-establish control over respiration, then the overload of free radicals oxidizes the membrane lipids, which collapses the membrane potential. Mitochondria that lose their membrane potential are effectively ‘dead’ and are swiftly broken down and destroyed, so free-radical overload hastens the removal of damaged mitochondria from the cell. Other, less damaged, mitochondria replicate to take their place.