Why can't we live forever?

The only certainties in life, said Benjamin Franklin, are death and taxes. Don't expect either to disappear anytime soon.

The prospects for a longer life currently seem rosy, at least if you are a laboratory mouse. This year has seen headlines about mice, engineered to produce lots of antioxidants, who can live 20 per cent longer than usual, and equally impressive gains for animal altered to produce high levels of a peptide hormone known as Klotho (after the minor Greek deity). Ultra-low-calorie diets, big doses of vitamin E, and even transferring ovaries from a younger mouse into elderly females also seem to extend lifespan. Shepherds may say that sheep are just looking for new ways to die, but mice seem to be susceptible to almost anything that can make them live a bit longer.

So what are the prospects for a rather larger mammal that normally lives 70-80 years, rather than the mouse's two, and very occasionally makes it to 120 before keeling over? Will what works in mice work in humans?

There are well-publicised optimists who think it will. The most often quoted is Aubrey de Grey of Cambridge, proponent of a big expansion of research on what he has called Strategies for Engineered Negligible Senescence. He is also one of the leading lights of the Methuselah Mouse Prize, which is offered to the scientific team that develops the longest-lived mouse.

But for all his energy and revolutionary zeal, Professor de Grey is not actually doing the research - his day job is as a computer expert in a genetics lab. And many researchers in biogerontology are sceptical about his predictions. That scepticism came through recently when Tom Kirkwood of the University of Newcastle's Institute for Ageing and Health asked in 'Nature': "Why must advocates of life extension make preposterous claims about imminent longevity gains if they are to gain public notice?"

Professor Kirkwood is the author of the influential 'disposable soma' theory of ageing, that the body decays because there is little genetic interest in keeping it going beyond reproductive age. This means that he sees no programmed limit to lifespan, in mice or people. Ageing is a biological sin of omission, not commission. So perhaps we could block whatever is doing the damage. But, he stresses, "this does not imply that major increases in lifespan are imminent. As we grow older the accumulated burden of molecular and cellular damage increases and the going gets harder."

Others in the field tend to agree. One reason is simply that ageing is very complex and we do not know enough to make sensible predictions. Caleb Finch of the University of Southern California says: "I have a simple view: we don't know what we don't know about ageing processes. So, what can be said on future longevity?"

Linda Partridge of University College London's Centre for Research on Ageing, well known for work on fruit flies, backs Professor Kirkwood. In any case, she adds, "I think that we should be working to promote health during ageing rather than increases in lifespan per se." Either way, she believes that "progress will be gradual and based on existing promising areas of work, rather than saltatory and based on unproven approaches".

Her colleague David Gems, who works on nematode worms, is optimistic that the basic biology of ageing will be understood in the next decade or two. But he stresses that how easily this translates into treating or preventing ageing-related diseases depends on what ageing really turns out to be: "There's a huge margin of uncertainty." He suggests that cancer treatments are a better historical guide than, say, antibiotics - and most cancers remain incurable.

Martin Brand of the Medical Research Council's Dunn Human Nutrition Unit in Cambridge also urges caution. "There have been spectacular increases in lifespan caused by simple treatments and mutations in model organisms," he concedes. But he is mindful that flies and mice in the laboratory tend to live shorter lives than wild strains. "I worry that these results can be explained as putting right bad husbandry of the model organisms rather than affecting ageing itself."

An investment too far?

However, the most basic argument against major extension of lifespan for humans is a general one: that the eventual triumph of entropy can only be delayed, not denied. Doug Wallace of the University of California, Irvine, is an expert on how damage accumulates in the energy-generating organelles, the mitochondria, through the action of mitochondrially generated reactive oxygen species, one of the main classes of free radical.

They damage not only the enzymes that generate energy but also the mitochondrial DNA (mtDNA) that preserves the information needed to repair the organelle. "Once the mtDNA becomes sufficiently compromised, the mitochondrial power plants go off-line and the cellular, tissue and organ systems fail," he says.

But while Professor Wallace believes mitochondrial degradation is crucial, he does not believe that preventing it would open the path to immortality. Instead, he reads the mitochondrial story as an example of a broader principle.

He argues that lifespan is determined by the balance between the processes that degrade our bodies' systems, and the investments our cells can make in maintenance and repair. Those investments cover both the DNA coding for the machinery needed to monitor and correct cellular damage, plus the allocation of resources, particularly energy, to actually make the repairs (including repairs to DNA itself). "It follows that the longer the individuals wish to extend life the greater the resources that will be needed to achieve the end," he says. So in the end the cost will exceed the benefit.

In other words, fix the damage to the mitochondria, and something else will bring the system to a halt instead: "As each life-limiting process is countered, some other process will become limiting."

So while all these researchers believe the current results are valuable for advancing understanding of ageing, and age-related diseases, they do not think they hold the key to a society where death comes only through accident or ennui.

Professor Kirkwood draws an athletic analogy: "No one thinks the current world record for the mile represents the limit to how fast this distance can be run. The record can always be broken. But no one seriously expects the mile to be run in two minutes any time soon."

How to live longer

Eat less: Research on animals has shown that the only surefire way to extend life is through dietary or calorific restriction - eat just enough to stay alive. You won't have energy to do much, though.

Refrain from sex: In many species, having sex seems to shorten lifespan. Resist temptation and you might be blessed with more time in which to regret not enjoying yourself more.

Be popular: Good social networks, happy marriage and close family contacts promote longer life.

Choose your parents: There appears to be a genetic contribution to longevity - long-lived parents tend to give rise to long-lived offspring. As George Sheehan put it to would-be athletes: "choose your parents carefully".

Why can't we live forever?

An investment too far?

How to live longer

Further reading