Mini methuselahs

Three score years and ten, the often quoted average lifespan of humans, is becoming an underestimate in many parts of the world. Typical UK male lifespans have risen from 48 in 1901 to 75 in 2000 and female lifespans from 49 to 80. This trend shows no sign of abating: female life expectancy in Japan is estimated to reach 100 in 2060, with the UK following in 2085.

While ageing populations will place increasing demands on healthcare, people are, in general, healthier than they ever were for any given age. Yet little is known about the underlying principles of ageing, only that, as we get older, a bewildering array of changes occurs in the body, with proteins, DNA and lipids accumulating multiple forms of damage. Such damage can lead to disease in almost all tissues, and different types of disease in any one tissue. "For a long time people thought that ageing wasn’t a process, it was lots of processes and had many different causes," says Professor Linda Partridge, who is leading a new collaborative project that aims to understand the processes of ageing. "So it was thought that we wouldn’t be able to find experimental interventions that could slow things down, and therefore we couldn’t find medical treatments that could slow things down either."

Remarkably, two different ways of slowing down ageing have emerged over the last few years, and these will be the focus of the six researchers in the collaboration, backed by £4.8 million funding from the Wellcome Trust Functional Genomics Development Initiative. Both methods of slowing ageing work in distantly related organisms. "That’s what we’re after: interventions that are evolutionarily conserved," says Professor Partridge. "We can then use the fantastic power of genetics and genome sequences in the fruit fly [Drosophila] and the nematode worm [Caenorhabditis elegans], both of which have short lifespans and age quickly, to discover things and test their role in mammals."

Eat less, live long

The first of the two interventions is the simple matter of eating less. This phenomenon was originally found in rats and mice put on a diet of about half of their normal food intake. Not only was their lifespan extended greatly, but there was also a decline in the rate at which death rate increases with age - a hallmark of altering the ageing process itself.

"Those rodents are quite amazing," says Professor Partridge; "almost all age-related pathologies are greatly slowed down, damage to macromolecules is reduced, and tissue strength and immune function is maintained at youthful values."

Eating less extends the lifespan across the evolutionary range. Creatures ranging from yeast to mammals show the characteristic slowing of mortality. Such an advantage comes at a price, however: in every organism it is accompanied by often dramatic decreases in fertility.

"Drosophila do a beautiful caloric restriction response," says Professor Partridge. "Average lifespan almost doubles, and the changes in patterns of gene expression seen during normal ageing are slowed down. But caloric restriction is not really understood - so in our programme we are discovering some of the genes and mechanisms at work in worms and flies. If a gene or mechanism is present in both, it is likely to be conserved across very large evolutionary distances, and it is then worth looking in mice to see whether it also plays a role in ageing in mammals."

Energy control

The second intervention that affects lifespan was also discovered serendipitously. Researchers studying a hibernating larval form of the nematode worm, which the worm goes into if it hits hard times through lack of food or overcrowding, found certain mutations that direct worms into this larval state even during good times. And it turns out that mutations in the same genes also caused the adult worm to be long lived.

The worm genes involved are components of a pathway that controls metabolism, growth and fecundity: the insulin/insulin-like growth factor (IGF) pathway. Certain mutations in genes in the same pathway in Drosophila make the flies long lived, indicating that this role of the pathway may be conserved in evolution. Interestingly, the mutations that make the fly long lived - such as chico (Spanish for small boy) - also cause dwarfism, a characteristic that these flies share with long-lived mutant strains of mice, such as the Snell, Ames and Laron dwarves. Mutations in this pathway in fly and mouse can also cause sterility.

"So longevity and reproduction keep coming up as a recurrent theme," points out Professor Partridge. "Both these two interventions - caloric restriction and mutations in the insulin/IGF pathway - seem to affect mechanisms that match reproductive rate to nutrient supply. These are the two interventions that we’re focusing on, trying to find a lot more about how they work in the fly, the worm and the mouse."

If eating less or genetic mutations increase lifespan, how do they do so? The likelihood is that they are influencing the amount of ageing-related damage that accumulates in cells and tissues. "The leading candidate is the oxidative damage theory - that free radicals cause damage to all sorts of different molecules," says Professor Partridge. Free radicals are highly reactive versions of oxygen, produced by the energy-producing powerplants of the cells, the mitochondria. "We know that the impact of oxidative damage increases with age," she says, "but actually getting an experiment to show that these are the critical mechanisms of damage associated with ageing, and are affected by these interventions, that’s much tougher."

The approach the team is using is to look at oxidative damage in the mouse, using uncoupling proteins - a family of proteins found in mammalian mitochondria - to vary the amount of free radicals produced. These proteins were first discovered in studies of non-shivering thermogenesis: if you cool down a mouse - or indeed a newly born human - it can warm itself up again without shivering. Using uncoupling proteins, mitochondria in brown fat tissue short circuit, producing heat instead of ATP energy. "We can manipulate the levels of uncoupling proteins in mice," says Professor Partridge. "In theory, high levels of these proteins should reduce the production of oxygen free radicals, so it will be very interesting to see whether oxidative damage is also reduced. And it if is, then we can find out if lowering the impact of oxidative damage also slows ageing."

In time, Professor Partridge hopes to discover enough about how eating less and the insulin/IGF pathway influence the body to be able to say whether or not the beneficial effects can be separated from the bad effects: "What are they doing to make flies live longer? Can we disentangle the mechanisms? Can we slow ageing and reduce age-related pathologies without reducing fertility?"

"The attractiveness of this line of research is that you don’t just have to do research on a particular disease. These interventions capture so many things at once, and they could be a really powerful method of improving many aspects of health. A side-effect may be that it increases the length of time that people live, but that is not an aim in itself."

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