A genetic alteration that extends the life of mice can be transferred to other mice via blood stem cells, and this could soon be tested in humans as a cancer treatment.
A genetic modification has been discovered that protects mice against cancer and allows them to live up to 20 per cent longer. The discovery is especially promising as the benefits can be transferred to ordinary mice by a single transplant of blood stem cells.
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| Genetically modified blood stem cells are being studied as possible treatments for cancer and ageing STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY |
“It was a big surprise,” says Che-Kun James Shen at Taipei Medical University in Taiwan. “So far, we have not found any negative side effects.”
Shen says his team is already collaborating with biotech companies interested in using the findings to improve cancer treatments in humans. Blood stem cell transplants are already part of the treatment for certain blood cancers, and the hope is that making this genetic alteration to the transplanted cells will reduce the risk of cancers returning.
If this proves successful, enough people might receive blood stem cells with the modification to show whether it extends human lifespan too.
Shen’s team made the discovery while studying a protein called KLF1. This is a kind of master switch produced in some blood cells – including some immune cells – that helps control the activity of many different genes.
Cells can alter the activity of KLF1 by attaching a chemical to a specific site on the protein. To study this, Shen’s team created mice with a mutation in both copies of the KLF1 gene that alters this part of the protein.
Team member Yu-Chiau Shyu at Chang Gung Memorial Hospital in Taiwan noticed that these mice were unusually active in middle age and that their hair stayed black and shiny for longer. This led the team to discover that the genetically engineered mice live between 10 and 20 per cent longer, says Shen.
What’s more, they remain healthy for longer, with their physical and mental performance starting to decline later than unmodified mice, and with less scarring in their internal organs.
Researchers have identified many other genetic variants that extend the lifespan of mice. However, many extend the lives of females only and there is also no obvious way to confer their benefits to individuals born without these variants.
In this case, however, because the findings indicated that blood cells were involved, the team tried taking certain types of blood cell from the modified mice and injecting them into unmodified mice. For instance, repeated injections of T-cells every two weeks reduced the spread of cancers, the team reported last year.
Now the team has gone on to show that 2-month-old mice given a single transplant of modified blood stem cells typically live five months longer than those given unmodified blood stem cells, an increase of around 20 per cent. Two-month-old mice are very roughly equivalent to 18-year-old people.
The findings suggest that people’s lifespans could be extended by removing some of their blood stem cells, modifying them to have this mutation and putting them back in the body. However, this procedure, which is much the same as a bone marrow transplant, has serious risks – not least because the unmodified blood stem cells have to be killed off with chemotherapy and radiotherapy.
It is far too early to think of trying this in people just to extend lifespan, says Shen. But for people already getting blood stem cell transplants to treat cancers, the risk-benefit balance is very different.
“I am convinced of the life-extending properties of this mutation,” says João Pedro de Magalhães at the University of Birmingham, UK. Many mutations that increase lifespan in mice do so purely by preventing cancer, says de Magalhães, but this mutation appears to have wider benefits.
More generally, de Magalhães thinks that gene editing blood stem cells has “great potential as a therapy for ageing”.
Because mice with the mutation have better motor skills than non-modified mice as they age, Shen and his colleagues also tried transplanting the modified cells into mice that develop a condition resembling amyotrophic lateral sclerosis. ALS, also known as motor neurone disease, is characterised by loss of motor control, and there are currently no treatments. The transplants significantly slowed the progression of the condition, says Shen.
Shen’s team has looked in genetic databases to see if any people already have this mutation, but none were found.
The researchers have also identified one of the reasons why this mutation has anticancer effects. It lowers levels of PD-1, a protein that many cancers exploit to evade immune attack. Several anticancer drugs work by inhibiting PD-1, and in some cell therapies for cancer, the PD-1 gene is deleted.
Previous studies have shown that replacing the blood of an old mouse with blood from a young mouse can have rejuvenating effects. However, it remains unclear why young blood has this effect or how to turn it into a practical treatment.
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