Immortality on hold

In its fight to prolong human life, modern gerontology increasingly relies on evidence from nature and wildlife, as E&T discovers.

Engineering immortality has been put on temporary hold. At a time when rising average life expectancy is creating enough problems of its own, the main immediate research focus will be on remedies for the problems of the elderly while they are still alive, mostly relating to either cognitive or physical disability. Indeed, the predicted rise in dementia from 400,000 to 800,000 sufferers in the UK over the next two decades led recently to top researchers calling for a dramatic increase in research funding to avoid the NHS being overwhelmed. 

Researchers themselves are focusing more on quality of life, according to Lynne Cox, who specializes in ageing research at Oxford University. "What we'd rather do is try to improve health in later life than push the boundaries of lifespan."

Cox is pursuing an interesting line - seeking the mechanism of a gene that causes a premature ageing disease called Werner Syndrome (WS) in humans - by studying a similar gene in fruit flies. The point is, there are no known genes in either humans or fruit flies whose function is directly related to the ageing process. 

However, a mutation in the WS gene does cause a dramatic acceleration in ageing, with sufferers often having the same level of hair greyness, voice and skin thickness, deterioration in sight, and incidences of osteoporosis and arteriosclerosis, as most people in their 60s.

The interest in WS for Cox is that a variant in a single gene accelerates many aspects of ageing simultaneously, seemingly reprogramming other genes. By studying the changing expression and regulation of genes in the fruit fly in response to the WS gene variant, she hopes it will be possible to identify some of the pathways associated with normal ageing. "We now have a model system to work out what the gene does at the level of a complex multicellular organism where we can do genetic manipulation and look throughout the life course, from eggs through development through to adulthood," says Cox.

Werner Syndrome

WS is a rare example of apparent programmed ageing in humans, although use and understanding of this term is still hotly debated within the gerontology research community. The point to note is that evolution does not normally bear directly on ageing, which can be seen as partly wear and tear, coupled with the consequences of processes necessary for earlier reproductive success eventually going wrong and becoming counter-productive. 

There are a host of mechanisms involved in ageing, including damage to proteins within cells by the processes of metabolism leading to production of free radicals, and loss of telomeres that protect the ends of chromo-somes from destruction during meiosis (cell division).

Evolution has naturally had to counter these processes via various repair mechanisms just to prolong healthy life through the reproductive phase. One such mechanism is autophagy, which is the degradation of waste components within the cell. In the event of starvation, autophagy is stepped up as the cell has no choice but to feed on its own detritus. 

It is possible that calorie restriction operates at one level by making autophagy more effective at mopping up damaged components that otherwise would gum up the works.

The big question is whether it is feasible to extend these remediation processes almost indefinitely through therapeutic intervention. Evidence from nature suggests that this is possible, in principle. Consider first the germline of all mammals, including humans. This is effectively immortal, for a species that passed on defects accumulated during the individual's lifetime would rapidly become extinct. 

This suggests that when there is selective pressure for immortality it can be achieved, at least at the level of individual cells.

As for vertebrates, there are plenty of more primitive species, such as the salamander, that are capable of regenerating entire limbs and organs. Some non-vertebrates, and all plants, can regenerate the entire organism from almost any component given the right conditions. In the hydra - a small freshwater invertebrate typically 5-10mm long - biological immortality has been achieved in effect by blending reproduction with tissue regeneration. 

The hydra normally reproduces asexually by forming buds that break off, but some of these buds are incorporated within the body, perhaps replacing damaged tissue. At any rate, hydra do not exhibit the usual symptoms of sene--scence, and tend to die only through misadventure.

The case of salmon

Then there is the strange case of the salmon, or some varieties, whose breeding regime where they come out of the sea and up river to spawn has led to an unusual adaptation.

At about three years old salmon undergo an orgy of reproduction, followed by accelerated ageing and death. The evolutionary explanation is that since food is relatively restricted while up river, survival prospects for the young returning to sea are enhanced if their parents conveniently get out of the way. In this way, evolution has pulled on the levers of programmed ageing. 

However, the intriguing point is that the anti-ageing mechanisms are still present, as has been proved by the existence of a small pearl mussel that infects salmon quite regularly. In this event, the salmon abandon their accelerated ageing and live up to four times longer, in some cases reproducing again. 

The mussel, which itself is one of the longest lived organisms, does not want its host to die young and so has evolved a way of intervening in its accelerated death programme.

The mechanism involved has yet to be fully elucidated, but it is known that the pearl mussel releases a protein that is very effective at mopping up damaging free radicals; in effect, acting as a sacrificial decoy. The protein takes the hit and is then degraded gracefully into its constituent amino acids which can then be used for assembling more proteins.

New dynamics

All the evidence then is that there is plenty of scope for intervention, but in humans the challenge is to develop a coherent strategy for dealing with the success already achieved in prolonging life.

At least the urgency has been acknowledged by major funding agencies, resulting in the New Dynamics of Ageing (NDA) Programme, currently a UK initiative but aiming to become a worldwide platform for ageing related research. Started in 2006, the programme is supported by five UK research councils, with the focus on boosting quality of life for the elderly.

"It is the largest and most ambitious research programme on ageing ever mounted in the UK (and Europe)," says Alan Walker, programme director and professor of Social Policy and Social Gerontology at the University of Sheffield. "It must generate new knowledge about the changing dynamics of ageing and create the basis for new policies, practices and/or products to promote the quality of later life."

As Walker emphasises, ageing research must be very broad based and consider approaches at many different levels, including simple practical remedies and socially-based initiatives, as well as research into the genes and mechanism that effect quality of lifespan just as much as absolute longevity.

Inevitably, such programmes cannot ignore ethical issues, such as euthanasia as well as the more subtle question of the role for, say, cognitive enhancing drugs for elderly people who are essentially healthy, as opposed to sufferers from Alzheimer's or other dementias.

Advocates for such cognitive therapy for the healthy, perhaps even staring earlier in life, include the Oxford Future of Humanity Institute.

"We tend to focus more attention on enhancing medicine, such as cognitive enhancing drugs that work for healthy people," sats Nick Bostrom, the Institute's director. "We think such drugs should be developed, and that people should be given access to them." Bostrom argues it is vital to counter the bioconservatives who oppose the idea of tampering with 'human nature'.

But perhaps Bostron should not worry, for the genie is already out of the bottle, and the line between treating specific disease and the ageing process itself is going to be impossible to rule for much longer.

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