Switching on “youth genes” in older mice limited brain damage after a stroke

In older mice, switching on four genes that can turn adult cells back into embryo-like cells, in short bursts for a month, left their brains noticeably less damaged two days after a stroke, a team in Madrid reports. The study is small, in genetically modified mice, and looked only at the first 48 hours, so it says nothing yet about recovery or about people.

In 2006, researchers found that four genes, now called the Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc, or OSKM), can turn an adult cell back into a stem cell that can become any cell type. Doing that inside a living animal is dangerous: when the genes are left on, mice develop tumours and die early. But switching them on only briefly and repeatedly, called partial reprogramming, seems to make cells behave more like young cells without losing their identity. In mice it has improved muscle, liver, skin and other tissues.

Age is the biggest risk factor for an ischemic stroke, where a blocked artery cuts off blood to part of the brain, and older patients tend to recover worse. The team asked whether partial reprogramming could make the aging brain more resilient.

What they did

• They used 30 mice aged 12 to 18 months (middle-aged to old for a mouse). Some carried the four Yamanaka genes, which switch on only when the mice drink the antibiotic doxycycline; the others were normal littermates. All mice got doxycycline.
• For four weeks, the mice drank doxycycline for three days, then four days without, each week.
• Then the team permanently blocked a major artery feeding one side of the brain (a model of stroke) in 14 mice, and performed sham surgery without blocking it in 16.
• They tested movement and coordination at 6, 24 and 48 hours, then examined the brains under the microscope. The researchers didn't know which mouse was which during the tests.

What they found

• Smaller damaged area. In normal mice, the damaged region covered about 31.5% of that side of the brain; in the reprogrammed mice, about 24.9%.
• More nerve cells survived. After the stroke, normal mice had clearly fewer nerve cells in the affected cortex; the reprogrammed mice kept about as many as mice without a stroke.
• Myelin was kept. Myelin, the fatty insulation around nerve fibres, was lost in normal mice after the stroke but stayed at normal levels in reprogrammed mice. They also had more oligodendrocytes, the cells that make myelin, and more of their precursor cells in the damaged area.
• Less scarring response. Astrocytes, support cells that multiply after brain injury, roughly doubled in normal mice but not in reprogrammed ones. Microglia, the brain's immune cells, didn't differ.
• Movement: mixed. On a rope test of front-paw grip, the reprogrammed mice did better after the stroke; on a beam-walking test there was no difference.
• More active without a stroke. After sham surgery, reprogrammed mice walked almost twice as far in an open box as normal mice (about 22 metres versus 12 in ten minutes) and rested less.

What to keep in mind

• Mice, not people. These mice were genetically built so the genes could be switched on in every cell. No such treatment exists for humans, and the Yamanaka factors carry a known cancer risk if not tightly controlled.
• Very small groups. Brain measurements came from 3 to 5 mice per group, behaviour tests from 6 to 10. The study wasn't large enough to look at males and females separately, the authors note.
• Only 48 hours. The team stresses it looked only at the acute phase; whether the mice recovered better in the long run wasn't tested.
• Given before, not after. The genes were switched on for four weeks before the stroke. That says something about resilience, not about treating a stroke once it has happened.
• Doxycycline. The antibiotic itself can affect the brain, gut bacteria and mitochondria. All mice received it, but the authors acknowledge its effects could differ between the two strains.
• A confusing score. On a neurological scale that the paper describes as scoring deficits (higher is worse), the reprogrammed mice scored higher than normal mice at 24 and 48 hours, yet the authors describe this as an improvement. That result is hard to interpret from the text.
• Mechanism unknown. The team suggests the reprogrammed brain cells might rely less on oxygen, but says this wasn't tested.

Why it matters

Partial reprogramming is one of the most talked-about ideas in aging research, because it seems to reset some features of old cells rather than patching single problems. Most tests so far have looked at muscle, skin or the liver. This study extends the idea to the aging brain under acute stress: four weeks of on-off reprogramming left older mice's brains better able to withstand a stroke, at least in the first two days. Longer studies, larger groups, and ways of delivering the effect that could ever be safe in people would all be needed before this becomes more than a promising lead.