What is the secret of healthy ageing?

A study by researchers at the Babraham Institute using Yeast suggests that diet in early life could play an important role.

For decades, scientists have pointed to animal studies that show the heath benefits of calorific restriction – intentionally reducing the number of calories consumed, without becoming malnourished. It has been shown to improve health in later life and potentially even extend lifespan.

But studies in mice suggest calorific restriction has to be maintained throughout life to have an impact – and if a normal diet is resumed, the health benefits disappear.

It is also impractical.

“The problem is, the number of calories that you have to actually consume to achieve this effect is borderline starvation, so even if we can spend our lives consuming the right amount of calories to achieve this effect, it’s incredibly unpleasant, so no-one really does it,” said Dr Jon Houseley, group leader in the institute’s epigenetics research programme.

“What we asked in this research is whether we could achieve similar effects by just changing diet.”

The team’s study in PLOS Biology suggesting an alternative method of improving health through the lifecycle – by optimising diet in early life, without calorific restriction.

“What we did was to take budding yeast, which are a classic model organism for ageing, and raised them on a different diet,” explained Dr Houseley. “As we changed the diet away from rich glucose, which is what they are normally raised on, we found that although the cells didn’t really live any longer, they didn’t show the same markers of ageing pathology and loss of fitness that we see on their normal diet.”

Instead of growing yeast on their usual glucose-rich diet, the researchers swapped the diet to galactose. They found many molecular changes that normally accompany ageing did not occur.

The cells grown on galactose – a simple sugar found in milk – remained as fit as young cells even later in life. Their period of ill health towards the end of their life was dramatically reduced.

Dr Dorottya Horkai, lead researcher on the study, said: “We show that diet in early life can switch yeast onto a healthier trajectory. By giving yeast a different diet without restricting calories we were able to suppress senescence, when cells no longer divide, and loss of fitness in aged cells.”

And while the results in yeast cannot directly be translated to human life, they do suggest the value of diet at an early stage in life

Dr Houseley said: “Crucially, the dietary change only works when cells are young, and actually diet makes little difference in old yeast. It is hard to translate what youth means between yeast and humans, but all these studies point to the same trend – to live a long and healthy life, a healthy diet from an early age makes a difference.”

Further research, it is hoped, could eventually lead to the identification of pharmaceutical targets that can improve healthspan on normal diets.

Yeast are used as useful model organisms for studying ageing as they share many of the same cellular machinery as animals and humans.

And Dr Houseley’s group has also discovered one of the mediators of ageing in yeast that could give insights into the process in all animals.

Their findings overturn the current theory of what causes yeast to age, suggesting that it is damaged chromosomes that impair normal yeast cell division.

The team hope to understand if there are common roots of ageing for cells in all eukaryotes – multiple-celled organisms, including humans.

For more than 20 years, researchers have believed yeast cell lifespan is limited by the accumulation of huge amounts of seemingly useless circular DNA, which was thought to slowly overwhelm cellular systems, leading to a senescent state where they lose fitness and show many signs of pathology..

But circular DNA does not accumulate with age in other organisms.

The Houseley lab investigated the presence of different types of DNA in yeas to identify new culprits.

“We were surprised to find that senescence, when cells no longer divide, occurs even in yeast mutants which lack circular DNA. This indicates that circular DNAs do not cause senescence, so we then turned our eye to other genome changes that accompany ageing in yeast,” said Dr Houseley.

Examining aged mutant cells that do not accumulate circular DNA during ageing, they identified a chromosomal fragment formed by the breakage of yeast chromosome XII. This was always present when cells underwent ageing pathology, but was absent in healthy ageing cells. It is much less abundant than circular DNA, but this chromosomal fragment appears to be much more toxic.

“DNA circles as the cause of ageing in yeast was a nice theory, but the mechanism isn’t shared across species. By contrast, the aberrant DNA fragments we have identified might cause pathology in ways which are more similar between yeast and mammals.” said Dr Andre Zylstra, lead author on the paper.

There is lots of evidence for the gain or loss of whole or partial chromosomes, called aneuploidy, as we age.

While the importance of aneuploidy is not yet understood, the findings in yeast suggest it could yet turn out to be a major contributor to the ageing process in humans.