New Kiwi study could lead to new treatments, ageing insights

Kiwi research into the "epigenetic clocks" of sheep could lead to new insights into the ageing process, and the development of new medical treatments. Photo / Andrew Warner

It’s called an “androgen clock” - and the Kiwi scientists trying to build it say it could help us create new medical treatments and better understand the ageing process.

A team led by Otago University’s Associate Professor Tim Hore has received a Marsden Fund grant worth nearly $1 million for their major new study, which builds upon research on better-known “epigenetic” clocks.

These clocks – which we could think of biochemical tests used to measure age – were turned to sheep in a study published last year by Hore’s colleague, Victoria Sugrue, along with the US scientist credited with inventing them, Professor Steve Horvath.

For the first time, their clock allowed them to predict the chronological age of sheep using only DNA, and proved surprisingly accurate - within roughly five months of actual age.

Epigenetic clocks that Horvarth developed for humans have been proven accurate to within a few years of age.

More recently, he’s worked with a large number of groups internationally to produce epigenetic clocks in a range of species, from naked mole rats to horses and Tasmanian devils.

“In short-lived species like mice, age can be predicted to within just a few weeks using DNA alone - it is staggering,” Hore said.

“For other species like whales, which are really long-lived, this could be only way to get an accurate measure on age.”

But the sheep study was particularly unique, Hore said, because it tested a large number of castrated males known as wethers - Shrek being our most famous example.

“These are quite common on high country farms of the South Island high country, where they are left to age in a fairly natural way in return for a fleece of wool,” Hore said.

“When we compared wethers to intact males, we found that not only did the DNA of the wethers age slower, but the intact male DNA changed throughout life in a regular ‘clock-like’ manner.”

At the same biochemical sites, the DNA of female and castrated sheep were found not to have changed at all.

“Because intact males and castrates are genetically the same, we figured these effects must be because of a lack of male hormones – or androgens - produced in the gonad, rather than some other masculine trait.”

That led them to question whether they could find a new way to predict age – but also the years of androgen exposure.

“We’ve tested our idea out in both mice and sheep so far, and it appears to hold up very well,” Hore said.

“But to prove the relevance and generality of the androgen clock, we need more samples and more species - something support from Marsden will really help with.”

One of the biggest questions the team wanted to answer was how exactly androgens affected DNA.

“We think that a protein known as the androgen receptor is key because it can bind to androgens as well as DNA,” he said.

To test if this true, they planned to create mice where androgen receptors had been genetically removed in specific tissues, but not other tissues.

“This will mean we can effectively ‘stop’ the androgen clock in some tissues and not others,” he said.

“We’re also proposing to use synthetic androgens, like those used by sports cheats, to speed up the androgen clock.

“In this way, we should be able to make the androgen clock ‘tick’ in a female.”

If the team succeeded in developing an accurate way to measure androgen exposure, there could be plenty of potential applications in medicine.

One target could be polycystic ovarian syndrome (PCOS), a reproductive disorder thought to be caused by excess androgens during development.

“Unfortunately, PCOS is difficult to diagnose - an androgen clock could help with this.”

On a more fundamental level, the androgen clock to tell much more about epigenetic predictors in general, he said.

“While epigenetic clocks are fantastic biomarkers helping us understand the process of ageing, we still don’t know if the molecular changes they are built upon are that significant for the ageing process,” he said.

“Our androgen clock is unique because we will be able to turn it on and off easily and see how this alters DNA and cellular processes.”