Human anti-ageing interventions ‘could appear in next decade’ says University of Cambridge researcher

A University of Cambridge scientist has predicted that human anti-ageing interventions could appear within the next decade, writes editor Paul Brackley.

As efforts to increase our understanding of the biological causes of ageing are stepped up, it is hoped that we can increase our healthspan – that is, the number of years we live in good health.

What has already increased is our lifespan – in 1841, the life expectancy at birth in the UK was about 40 years. It is now around 81. But from the age of 60, at least half of us will begin to develop an age-related condition.

Scientists do not, however, fully understand what causes ageing.

Dr Alex Cagan, from the University of Cambridge’s Department of Genetics, says: “Our bodies undergo lots of biological changes as we age, but it’s not really clear which of those are consequences of ageing, and which of those are actually causing it.”

A key change in our cells’ DNA is the gradual accumulation of mutations in our cells’ DNA, which can ultimately lead to disease and features of ageing. DNA damage occurs all the time in our cells – with mistakes made when DNA is repaired or copied as cells replicate.

We know that DNA damage is also caused by external factors, including smoking, UV rays from the sun and pollutants.

Dr Cagan is comparing mutational processes in long and short-lived species.

“All the species we’ve looked at get to the end of their lives with a similar number of DNA mutations – from mice that live about three years, to humans that live about 80 years,” he said. “This suggests there’s an evolutionary constraint to how many mutations an organism can accumulate.”

He intends to explore whether animals with very long life-spans, such as whales, elephants, and ‘immortal jellyfish’, have evolved a better ability to repair their DNA damage than we do.

Understanding this could enable the process to be transferred into humans.

Prof Ewan St John Smith, in the Department of Pharmacology, keeps five colonies of naked mole-rats in Cambridge. This bizarre and intriguing species are roughly the size of mice, which might suggest they would live for three to five years, but they actually live for more than 30. They age healthily and are particularly resistant to cancer.

“Naked mole-rats live a long time, and as mammals they’re more closely related to humans than other long-lived species we know about, like certain species of bird,” notes Prof St John Smith.

He adds: “Ageing is a major risk factor for most forms of cancer. Our cells accumulate mutations over time, so the longer we live, the more likely we are to develop cancer.

“We’re trying to understand what enables the naked mole-rats to be cancer resistant, in the hope it will provide insights to help us prevent cancer – or treat it more effectively – in humans.”

While it might seem logical that larger species, with more cells, would get cancer more often than smaller species, this does not prove to be the case. Some large whale species, which have quadrillions of cells, would not even reach their first birthday without developing it if they had the same cancer risk per cell as humans but in fact they live long lives.

Dr Cagan says: “This suggests whales must have better mechanisms of cancer resistance than humans. It’s possible that whatever they’re doing to resist ageing – some can live to 200 years old – is also what’s making them less likely to get cancer.

“If mutations to DNA cause both ageing and cancer, then reducing the mutation rate by having more accurate DNA damage responses would potentially solve both problems at once.”

DNA mutations are also believed to be involved in some forms of neurodegeneration, such as Alzheimer’s and Parkinson’s diseases.

Dr Janet Kumita, in the university’s Department of Pharmacology, is investigating how proteins misfold and form clumps called aggregates in the brain in many forms of dementia.

“I’m trying to discover how the youthful body deals with protein aggregates, to see if we can put those mechanisms to work again in older age to keep the body healthy,” says Dr Kumita.

“Protein aggregation is a very time-dependent process. In terms of a human lifespan, it takes a while for a single protein to bump into its neighbours and form the first clumps, but once that happens it’s easier for the clumps to get bigger and bigger. That’s why most neurodegenerative diseases are linked to ageing.”

Our mechanisms to identify and get rid of misfolded proteins decline with age, leading more aggregates to form and cause debilitating effects on the brain.

“In theory, if you can target the misfolded proteins, you could get rid of them before they cause problems,” says Dr Kumita. “When patients are showing symptoms and being diagnosed with Parkinson's or Alzheimer’s, these pathological aggregates are often already forming. If we could diagnose patients very early on, we’d have a better chance of preventing aggregation and the progression of dementia.”

Scientists have identified some of the specific protein aggregates that form in the brain and Dr Kumita is testing ways to target and destroy them. She wants to progress from experiments in test tubes to see how the process works in the body’s cells, amid all their other activities.

The brains of naked mole-rats also seem to stay healthy in their lives.

“There’s very little evidence that naked mole-rats develop protein aggregates or get neurodegenerative diseases,” says Dr Kumita. “By looking at what’s happening in their cells to prevent these diseases, we hope to find clues to what’s going wrong in human cells – and maybe we can recreate in humans whatever the naked mole-rats are doing.”

Another approach is being taken by Dr Delphine Larrieu, in the Department of Pharmacology, who is investigating the premature ageing condition, progeria syndrome, a very rare disease that affects about 400 children worldwide at any one time.

They begin to develop the signs of ageing at just a few years old and by 14, their bodies are like that of an 80-year-old, with wrinkled skin, stiff joints and cardiovascular disease, which usually causes their very early death. It is caused by a mutation affecting the structure of the nuclear envelope in cells which protects DNA from damage, among other functions.

“What’s interesting is that nuclear envelope dysfunction also occurs to some extent during normal ageing. So some of the cells of people who are 80-90 years old look similar to the cells of progeria patients,” says Dr Larrieu.

“In my lab we’re trying to understand whether the mechanisms behind this are the same – both to find new treatments for progeria patients and also to learn more about what’s happening during normal ageing.”

There is genuine excitement that Dr Larrieu has identified the genes that cause – when ‘knocked out’ – the structure and function of the nuclear envelope to be improved, a form of cellular rejuvenation.

“To modify the functional state of an old cell back to a young cell we need to act on the cell biology of ageing itself,” says Dr Larrieu. “The idea is that rather than tackling age-related conditions one by one, rejuvenating cells back to a younger functional state could delay the appearance of all of these conditions at once.

“Until around 15 years ago we always thought that a cell could only go one way, to get older. But a landmark discovery from Nobel Prize winner Shinya Yamanaka showed that it can also go in the reverse direction in a process of cellular reprogramming. This is fascinating.”

Old mice have already been made more youthful and energetic through cellular reprogramming and studies from the Salk Institute showed it works in progeria mice too.

But it is not understood what is happening at the molecular level and the technique is far from being ready for human testing.

“A full cellular reprogramming in humans could lead to the formation of a lot of cancers, so we need a more subtle approach. We need to make the cells younger, but not take them back so far that they lose their identity,” says Dr Larrieu. “Obviously until we really understand what’s going on we won’t try it in humans.”

The aim of all these lines of research is not to find a way to enable humans to live forever, but to improve the proportion of our lives we live healthily. We know our chronological age is not the same as our biological age, and that the right lifestyle choices – such as avoiding smoking, drinking too much alcohol, maintaining a good diet and exercising regularly – can even reduce our biological age. With medical interventions, even stronger anti-ageing effects may be possible.

Dr Larrieu concludes: “It’s a really exciting time for ageing research. I think we’re going to start seeing human anti-ageing interventions appearing within the next decade.”