Found in cheddar cheese and mushrooms, this could be the key to fertility in older age

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The first person conceived through IVF (in vitro fertilisation) – Louise Joy Brown, of Manchester, England – is only 45 years old. As a ’90s test tube baby who sometimes takes the technology for granted, that fact always reminds me that IVF is a relatively young science.

IVF’s advancement has hurtled along since Brown’s birth. Recent Australian research found one in three mothers undergoing IVF now give birth after their first cycle.

Patrick Steptoe (left), Jean Purdy and Dr Robert Edwards with the world’s first IVF baby Louise Brown in 1978.Credit: PA

But a stubborn roadblock remains: age. IVF success rates fall from 38.9 per cent for women aged 18-34 down to 5.6 per cent for those older than 43, according to IVF Australia. And about 87 per cent of women can’t fall pregnant naturally after 45.

That’s because the health and abundance of oocytes – the cells that develop into mature eggs – decline as the years go on.

Enter a substance dubbed “the longevity elixir”.

New research published in Nature Ageing found that spermidine, which is widely sold in tablet form as an “anti-ageing” supplement, restored fertility in middle-aged mice. The results have stoked excitement that we could be on the precipice of therapies that boost the success of pregnancy later in life.

Spermidine is already being hailed in the media as the “holy grail” of fertility and experts have called the study “groundbreaking in its scope and complexity”.

So what is spermidine, and is it really a holy grail?

What is spermidine?

Spermidine was first isolated from sperm (hence the name), and is found naturally in animals and plants. Wheatgerm, soybeans, cheddar cheese, mangoes and mushrooms all have high concentrations of the stuff.

The compound has been found to increase the lifespan of mice, fungi and nematode worms, and boost the memory of ageing fruit flies.

Two prospective studies in 2018 analysed the diets of 2540 people, and found that higher intake of spermidine was linked with lower mortality from cardiovascular disease and cancer.

Spermidine has also been found to stabilise DNA and RNA, facilitate cell growth, soothe inflammation and act as an antioxidant.

It also boosts autophagy, which is basically cellular housekeeping. This critical process dismantles ageing or damaged cellular structures, keeping organisms fighting fit, which could help fend off the effects of ageing.

Spermidine has boosted the memory and lifespan of fruit flies, a commonly studied insect.

Pinkies in petri dishes

A reproductive biologist named Bo Xiong from Nanjing Agricultural University in China, along with his colleagues, noticed spermidine levels were far lower in the ovaries of middle-aged mice compared to younger ones.

They administered spermidine to older mice through injection and by spiking their drinking water, finding both methods increased the quality of oocytes and how quickly they matured into full egg cells. The middle-aged mice treated with spermidine also had larger litters.

The exact results are complicated, but a series of three photos included in the research paper – showing three different litters of mouse pups or “pinkies” in petri dishes – neatly illustrate the study’s basic findings.

A litter produced by a young mouse fills an entire dish, like a plate crammed with 15 cocktail frankfurts (which somehow sprouted legs and tails). A litter produced by an older mouse had only three. But an old mouse supplemented with spermidine doubled her luck; her petri dish wriggled with six pink pups.

How does it work?

“In summary, spermidine supplementation partially reversed the effects of ageing on the mice’s ovaries,” explains Associate Professor Alex Polyakov, a fertility specialist at Melbourne IVF.

“Similar results were obtained in experiments with pigs, suggesting that spermidine’s mechanism of action is conserved across species and may be relevant to humans.”

Bella Templeman with Cooper, five months, who was conceived after one round of IVF.Credit: Dion Georgopoulos

Polyakov says spermidine’s autophagy-boosting superpower probably improved the function of mitochondria, the organelles that produce the energy our cells use for the biochemical processes.

The deterioration of mitochondria is a key driver of ageing.

An improvement to the cell’s clean-up crew – stripping out broken mitochondria and allowing newer, stronger organelles to take over – may be behind the fertility boost.

A holy grail (for mice, at least)

Polyakov says that “the holy grail of reproductive medicine would be a technique or treatment that could reverse the effect of age on the ovaries”.

“[The researchers] appear to have discovered such a holy grail.” But he, and other experts, also urge caution.

Other studies of similar off-the-shelf supplements, including a Sydney-led study into a coenzyme called NAD+, have produced fertility boosts in mice but are yet to prove effective in humans, explains Associate Professor Cecilia Sjoblom from the University of Sydney’s Reproductive and Perinatal Centre.

“Applied in mouse models, [the supplements] do magical things. But it’s very different applying that to a human situation. A lady in her 40s taking those tablets will not have any guaranteed improved chance [of pregnancy],” says Sjoblom. “It’s hopeful to draw parallels, but it has to be done with caution because the human ovary ages in very different ways to the mouse ovary.”

Boosting mouse fertility also required an enormous dose of spermidine, she says. “If you look at the dose used in these mice, it’s equivalent to 300 tablets that are available on the market today.

“You would have to inject the equivalent of 300 tablets, something I wouldn’t recommend, and something the TGA would not approve.”

Still, the promise of a drug that could improve fertility later in life is a tantalising prospect, and future studies into dose and delivery could one day deliver a useful therapy, if proved through a large, expensive randomised control study, using the proportion of live births as a measure of success.

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