Long life in the balance

C&I Issue 8, 2012

It was always too good to be true, but hopes of living longer on red wine and chocolate have been dealt a blow by recent studies in mice. While the key ingredient resveratrol extends the lives of laboratory fruit flies, yeast and worms, researchers have discovered that its effectiveness is often limited and only works in obese mice that are on a high fat diet.

Disappointingly, a more promising strategy for lifespan expansion in people is caloric restriction – a drastic cutting of food intake found to increase the longevity of mice by around 30-40%.

But dreams of a ‘quick fix’ to hold back the years have not gone away, with the recent discovery of a novel dietary route to increase longevity that researchers believe may one day lead to a coveted anti-ageing pill, which could also ward off many of the diseases of ageing.

In 2009, a team of researchers in the US reported that feeding the immunosuppressant drug rapamycin to ageing mice increased lifespan by roughly 15% and 10% for females and males, respectively (Nature, doi:10.1038/nature08221). While rapamycin itself is an unlikely candidate for a life-extension pill, ‘chemical analogues and drugs that block the target of rapamycin and their effectors may eventually turn out to be useful in humans to slow ageing,’ says Richard Miller at the University of Michigan, US, one of the researchers involved in the work.

Researchers reported progress towards that end in March 2012, by separating the useful life extension effects of rapamycin – resulting from inhibition of the enzyme complex mTORC1 – from its diabetes-like side effects – due to disruption of the related complex mTORC2 (Science, doi:10.1126/science.1221365).

Even more tantalising, however, is the possibility of influencing the same mammalian (m) TOR signalling pathway by changing the balance of amino acids that we ingest in proteins in the diet. At the Institute of Healthy Ageing at University College, London, UK, for example, Matthew Piper and colleagues have been investigating the effects of making precise manipulations to the balance of amino acids in the diet of fruitflies called Drosophila melanogaster.

Strikingly, in 2009 the group reported that the lifespan of fruitflies increased by about 10% when levels of the dietary amino acid methionine were reduced (Nature, 2009, doi:10.1038/nature08619) – similar to the level achieved by dietary restriction.

‘The traditional explanation for why reduced methionine might increase lifespan is that it acts as a trade-off between fecundity and lifespan,’ Piper explains. ‘Methionine limits fecundity and as a consequence the organism recognises food resources are falling and preserves what scarce nutrition it has to survive. The side effect of this is that the organism lives longer.’

The group’s research, however, has shown that this trade-off can be uncoupled, allowing both traits to be simultaneously optimised: adding methionine alone back to the diet did not decrease lifespan, though it did increase fertility, which is seen to decrease on cutting food intake.

It also suggests that rebalancing the diet rather than cutting calories per se may be the key to healthier ageing, Piper elaborates, adding that the team is now trying to determine exactly what balance of amino acids works best and how this may be tailored to suit particular lifestyle changes or circumstances. ‘For instance, some insects will preferentially intake a higher protein diet when facing an immune challenge, due to an increased physiological demand. It may be possible to prescribe dietary balance alterations for humans in response to stress.’

One theory of ageing concerns our ability to regulate proteins, according to Nathaniel Szewczyk, associate professor in the school of graduate entry medicine and health at the UK’s University of Nottingham. ‘Generally we think of proteins as the molecular machines that let our cells and bodies live. If we don’t replace or repair our proteins this can lead to failure of our cells and bodies to work properly.’

Szewczyk’s work involves studying the muscles that control muscle degradation in the human body – particularly the loss of bone and muscle mass experienced by astronauts during extended spaceflight. In a paper in July 2012, the group reported the discovery that spaceflight suppresses the accumulation of toxic proteins that normally accumulate within ageing muscle in the worm C. elegans – a good model for studying long-term changes in human physiology (see Spaceflight may extend life).

A major function of the TOR protein, meanwhile, is to alter protein production; high levels of amino acids lead to the activation of TOR, which increases protein synthesis. When amino acids are scarce, however, or rapamycin blocks TOR, there is a drop in protein synthesis, Piper explains. ‘This may be beneficial because it spares nutrients from growth for other purposes or that protein synthesis drops as a whole, but becomes more specialised. There is evidence that while the synthesis of many proteins drops, that of protective proteins is enhanced. Thus physiological protection is actually increased.’

Understanding the detailed molecular responses to these various amino acid manipulations could open up opportunities for new drug or anti-ageing pill targets. For now though, it appears that we can eat and drink as much red wine and chocolate as we like, but the main predictor of human lifespan is predetermined in the genes.

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