The world’s oldest known land animal – Jonathan the giant tortoise – has had his genome probed for the first time. This has revealed that parts of his genome to do with mitochondrial function are as efficient as those of a 5-year-old member of his species. Efficient mitochondria may give his DNA repair systems more energy to fight off the effects of ageing, enabling him to live to an estimated age of 194.

What’s more, some of his genetic changes seem similar to those of supercentenarians. “This study adds to the body of evidence that the mechanisms of ageing may be conserved across species,” says at the Kallel Foundation, a non-profit organisation focused on interventions to extend human healthspan, in Nashville, Tennessee.

Jonathan, an Aldabra giant tortoise (Aldabrachelys gigantea), and Napoleon Bonaparte are the two most famous residents of St Helena island in the South Atlantic. Napoleon arrived at the remote British territory after he was exiled in 1815, while Jonathan is thought to have been shipped there, possibly from Aldabra Atoll, in 1882. Jonathan arrived as a fully grown adult that was thought to already have half a century under his belt, putting him at around 194 years old today.

The researchers calculated that Aldabra tortoises have an average lifespan of around 80 years, but they can live much longer. To understand the mechanisms behind Jonathan’s extraordinary longevity, Clark and his colleagues have studied his genome.

“I firmly believe we can learn about the global mechanisms of ageing by looking at the exceptions,” says at the Josep Carreras Leukaemia Research Institute in Barcelona, Spain, who led a study into a 117-year-old woman, once officially the world’s oldest person.

Free newsletter

Sign up to 91ɫ��Ƭ Check

Sign up to newsletter

Esteller and his team found that the woman had exceptionally efficient mitochondrial function, which led Clark and his colleagues to suspect Jonathan similarly had “very efficient and very young” mitochondria, says Clark.

They had to study his genome via saliva samples and cheek swabs. This was because St Helena authorities refused their requests to draw Jonathan’s blood, given his fame and the risk of infection.

This was a major limitation, because it meant the researchers were unable to isolate large pieces of DNA, which are more stable in blood. Instead, they had to assemble fragments from Jonathan’s saliva, where DNA is more prone to bacterial contamination, and fill in the gaps using DNA from another Aldabra tortoise.

Once they had made the best possible composite of his genome, they compared it to the DNA of four other Aldabra tortoises. “We found 287 genes that had changes in them that were unique to him,” says Clark.

Is stem cell therapy about to transform medicine and reverse ageing?

A clinical trial to reverse age-related vision conditions using stem cell treatment could finally deliver on the promise of a major discovery in ageing and regeneration made 20 years ago, says columnist Graham Lawton

Of these genes, 41 are though to be functionally significant, meaning they actively contribute to an organism’s biology, survival and regulation. A dozen of them were also found in ageing databases of the genes of other long-lived animal species.

Parts of Jonathan’s genome to do with mitochondrial function were as young as a 5-year-old Aldabra, says Clark. “This, in turn, has helped him manage the effects of ageing by giving the DNA repair systems more energy from the mitochondria to fight off the effects of ageing.”

at the University of Osaka, Japan, says the work is “fascinating”, but notes that Jonathan’s genome was compared against that of only a few other tortoises, which may have unique genetic changes themselves.

Protein-rich products – from cereal to crisps to coffee – are all over supermarket shelves, but mounting evidence in non-human animals suggests that restricting our intake could slow ageing and extend lifespan. So, does that mean eating too much protein is harmful?

“We have this impression that dietary protein is sort of a universally good thing,” says at the University of Wisconsin-Madison. But according to the latest review of the evidence, “increasing dietary protein, beyond what’s needed, for sedentary individuals or animals leads to metabolic problems and can lead to shorter lifespan as well”, he says.

But others point out that nutritional studies in animals like mice and rats don’t readily translate to people, and a high protein intake has been linked to benefits in humans.

Lamming and his colleagues sifted through more than 300 studies, mostly in sedentary rodents, that explored how restricting protein intake to the minimum required to prevent deficiency affects ageing and lifespan.

In these studies, rodents generally either ate the equivalent of the minimum protein requirement recommended by US guidelines – 0.8 grams of protein per kilogram of body weight – or about double that. The latter is similar to the intake recently recommended by US dietary guidelines for optimal health, 1.2 to 1.6 grams of protein per kilogram of body weight.

In one study, rats that ate around the minimum protein intake lived nearly 120 days, or more than 50 per cent, longer than those that ate about double that.

This may be because protein restriction increases levels of the hormone FGF21, says Lamming. In rodents, this acts on the brain, fat tissue and the liver to improve blood sugar levels and reduce the number of senescent cells. These cells, which accumulate with age, have stopped dividing and cause chronic inflammation.

Free newsletter

Sign up to 91ɫ��Ƭ Check

Sign up to newsletter

Restricting protein intake has also been shown to dampen the activity of a protein called mTORC1 in mice. mTORC1 ordinarily stimulates cell growth, but reducing its activity boosts cellular repair. “It essentially switches cells from a proliferative state, where they’re growing and engaging a lot of metabolism, to one where they’re dividing more slowly, if at all, and focusing on repair,” says Lamming. Studies suggest this in mice, he says.

All this suggests that the recent trend to up our protein intake is probably fine among people who exercise regularly, because they may need more protein to repair muscle damage, but eating more than is needed could cause harm in sedentary individuals, says Lamming.

But at the University of Illinois Urbana-Champaign points out that rodents vary hugely from people when it comes to protein metabolism. For instance, mTORC1 is activated by feeding, and while people tend to a have a few big meals a day, rodents graze more regularly. Protein restriction may therefore affect mTORC1 pathways differently between the different species, he says. We are also more exposed to factors that accelerate ageing, like infections and extreme heat, than lab animals, says Layman.

What’s more, the review does not include most of the studies in people that suggest that upping our protein intake beyond the minimum , he says.

Lamming says no studies were intentionally omitted. “We were focused on protein restriction, not the many studies looking at higher levels of protein intake,” he says. Beyond building muscle and preventing frailty, there is mixed evidence on whether a higher protein intake helps with ageing, says Lamming.

The 3 things you need to know about protein, according to an expert

Why have so many people become fixated on protein? Donald Layman is one of the people behind the research showing the benefits of getting more protein in your diet, but he thinks things have gone too far and wants to set the record straight

For instance, one study linked this to a reduced risk of age-related muscle loss, or sarcopenia, among . But the rates of sarcopenia were so low that the link is unreliable, says at the University of Sheffield in the UK.

Still, some studies showed that restricting intake of certain amino acids – such as isoleucine and valine, which are highest in meat, fish and dairy – in mice has a similar effect to limiting overall protein intake, says at the University of Nottingham, UK.

Atherton says he is planning a study to investigate whether drugs that deplete specific amino acids in people improve outcomes like blood sugar control, with results expected in the next few years.  

As we age, our body loses its ability to clear out zombie-like cells that have stopped dividing, instead dripping out poison and turning other cells rogue. Restoring the ability to remove these “senescent” cells prevented signs of cognitive decline and frailty in older mice, with hints that the same outcomes could occur in people.

“What’s attractive about this study is that it is not trying to kill [senescent] cells directly,” says at University College London, who wasn’t involved in the research. “It is repairing the body’s own waste-disposal system that should have removed them in the first place.”

To better understand why this system goes awry, at Stanford University, California, and her colleagues compared mice aged 6 to 8 months (roughly equivalent to people in their 20s) with mice aged 23 to 25 months (equivalent to people in their late 60s or 70s). They found that the older mice had more of these senescent cells in their organs, including the liver and spleen, as well as in their bone marrow.

Specifically, the senescent cells were neutrophils, immune cells that are normally the body’s first line of defence against infection. These would normally be cleared away by macrophages residing in tissue, which remove damaged cells and debris, but this ability .

Andreasson and her colleagues traced this decline to prostaglandin E2, a signalling molecule that increases with age. They found that higher prostaglandin E2 activity overstimulates a receptor called EP2 on tissue-resident macrophages, which leaves them less able to remove senescent cells.

Free newsletter

Sign up to 91ɫ��Ƭ Check

Sign up to newsletter

Next, the team tested whether blocking this overstimulation could improve signs of ageing by genetically modifying the EP2 gene from tissue-resident macrophages in older mice. These animals went on to clear more senescent neutrophils and showed signs of healthier ageing, including lower levels of inflammation, reduced muscle loss, less visceral fat and better mobility, compared with unmodified mice of the same age. They also performed almost as well as young mice in memory tests.

“We were very surprised at the magnitude of the effect,” says Andreasson. “The paradox is that we had only reduced the level of [the receptor protein] EP2 by 50 per cent.”

The researchers also tested an experimental drug that blocks the EP2 receptor protein. When given orally to older mice for two months, this caused similar age-related improvements to those experienced by the genetically modified mice.

A negative attitude towards ageing is making you age faster

We know that a person’s outlook can have a huge effect on their health, and it’s no different when it comes to ageing. Columnist Graham Lawton looks at new evidence of just how powerful our attitude is – and how to use it to age better

“This is a very promising study, but we need to be careful,” says Gilroy. “[The EP2 receptor] is part of a normal signalling system, and blocking it throughout the body could have unwanted effects.” The mice experienced no known side effects, but Gilroy says it may be safer to target the EP2 receptor in ageing macrophages specifically.

Finally, the team found similar patterns in human tissue, with liver samples from older people showing higher EP2 receptor activity and more senescent neutrophils. “The human data are supportive, but still correlative,” says Gilroy. “We haven’t yet shown that blocking [the EP2 receptor] can restore neutrophil clearance in aged human tissue.” 

The researchers are now planning to study whether this process affects the onset of conditions such as Alzheimer’s disease.