Researchers rejuvenate aging mice with stem cell genes

Activating stem cell genes made aging mice more like these youngsters.

Stem cells can spawn other types of body cells, but they have another striking capability—they remain young. Researchers have now harnessed this ability to boost the life spans of mice and refurbish some of their tissues. Although the approach won’t work in humans, it could lead to ways to keep our bodies vigorous even as we get older.

“It’s a beautiful piece of work,” says genome scientist Howard Chang of Stanford University School of Medicine in Palo Alto, California, who wasn’t connected to the research. The study, he adds, reinforces the idea that “aging is not just a passive process. We can intervene to change the outcome.”

Like our hair and skin, our chromosomes show our age. Chromosomes carry molecular attachments, known as epigenetic marks, that help control how tightly DNA coils and how active genes are. As we get older, the arrays of these marks change, potentially fouling up the precisely coordinated patterns of gene activity that keep our cells working.

Epigenetic modifications aren’t permanent, however. By turning on a few genes normally active only in embryos, researchers can “reprogram” adult body cells into stem cells. This process returns epigenetic marks to their youthful settings and seems to rejuvenate even elderly cells. In one 2011 study, scientists reprogrammed cells from people as old as 101 in the lab, resetting their epigenetic marks and tuning up their metabolism. But could this chromosomal reboot provide similar benefits outside the lab dish?

To find out, developmental biologist Juan Carlos Izpisúa Belmonte of the Salk Institute for Biological Studies in San Diego, California, and colleagues genetically modified mice to respond to the antibiotic doxycycline by switching on four key genes that—in the lab—can turn adult cells into stem cells. The researchers tried their approach in mutant mice with symptoms of Hutchinson-Guilford progeria syndrome (HGPS), a rare genetic disease that resembles premature aging. Children with HGPS develop health problems typical of senior citizens, such as weak bones and atherosclerosis, and they usually die of heart attacks or strokes in their teens.

Dosing the animals with doxycycline reduced several signs of old age, including thinning of the skin. It also delayed the deterioration of the animals’ kidneys and spleens and kept their hearts beating at a sprightly pace. In addition, switching on the stem cell genes boosted the mutant mice’s life spans by more than one-third, the researchers report online today in Cell.

As we get older, our ability to replace dead or injured cells declines. To determine whether activating stem cell genes restores this capacity, the researchers tested healthy, middle-aged mice whose insulinmaking β cells they had removed. Turning on the stem cell genes increased the rodents’ ability to replace their lost β cells. Izpisúa Belmonte and colleagues also tested how well a different group of middle-aged mice could repair muscle damage. If the stem cell genes were active, the animals were better at mending muscle injuries caused by an injection of cobra venom. “We believe that cellular reprogramming has the capacity to convert an old epigenetic program into a young program, slowing down the aging process,” Izpisúa Belmonte says.

But tampering with epigenetic marks could have a price. Previous studies have found that turning on the stem cell genes in adult mice can lead to cancer or teratomas, abnormal growths that sometimes sprout teeth or hair. The researchers found, however, that they could prevent tumors and teratomas by giving the mice fewer doses of doxycycline.

“I think it’s a proof of concept that partial reprogramming can rejuvenate some tissues,” says regeneration biologist Clive Svendsen of Cedars-Sinai Medical Center in Los Angeles, California, who was not involved with the work. But he says he wants to see evidence that resetting the epigenetic marks increases longevity in healthy animals and that it works in parts of the body, such as the central nervous system, where cell replacement is limited. “Who wants to have a young heart and an old brain?”