Yamanaka factor proteins are used to transform adult cells into induced pluripotent stem cells which can become nearly any type of cell in the body regardless of the cell from which they originated, and these iPS cells have become important in drug discovery and regenerative medicine.
In the study published in Nature Communications inducing old human cells in a lab dish to briefly express Yamanaka factor proteins was found to rewind many of the molecular hallmarks of aging, and to render the treated cells nearly indistinguishable from younger counterparts in the study according to the researchers.
“When iPS cells are made from adult cells, they become both youthful and pluripotent,” said Vittorio Sebastiano, PhD, assistant professor of obstetrics and gynecology and the Woods Family Faculty Scholar in Pediatric Translational Medicine. “We’ve wondered for some time if it might be possible to simply rewind the aging clock without inducing pluripotency. Now we’ve found that, by tightly controlling the duration of the exposure to these protein factors, we can promote rejuvenation in multiple human cell types.”
“We are very excited about these findings,” said study co-author Thomas Rando, MD, PhD, professor of neurology and neurological sciences and the director of Stanford’s Glenn Center for the Biology of Aging. “My colleagues and I have been pursuing the rejuvenation of tissues since our studies in the early 2000s revealed that systemic factors can make old tissues younger. In 2012, Howard Chang and I proposed the concept of using reprogramming factors to rejuvenate cells and tissues, and it is gratifying to see evidence of success with this approach.” Chang, MD, PhD, is a professor of dermatology and of genetics at Stanford.
The researchers devised a way to use messenger RNA to temporarily express 6 reprogrammed factors: the four Yamanaka factors plus two additional proteins in human skin and blood vessel cells. Gene expression patterns were compared to treated cells and control cells obtained from elderly adults with those from younger people.
Cells from the elderly were found to exhibit signs of aging reversal after four days of exposure and more closely resemble younger cells in their gene expression patterns while untreated cells expressed higher levels of genes associated with known aging pathways. When examining patterns of methyl group chemical tags, treated cells appeared to be 1.5-3.5 years younger on average than the untreated elderly cells, with peaks of 3.5 years in skin cells and 7.5 years in blood vessels.
“We saw a dramatic rejuvenation across all hallmarks but one in all the cell types tested,” Sebastiano said. “But our last and most important experiment was done on muscle stem cells. Although they are naturally endowed with the ability to self-renew, this capacity wanes with age. We wondered, can we also rejuvenate stem cells and have a long-term effect?”
When old mouse stem cells that were treated were transplanted back into elderly mice, the animals were found to regain the muscle strength of younger mice.
When isolating cells from cartilage of humans with/without osteoarthritis the temporary exposure of osteoarthritic cells to reprogrammed factors was found to reduce the secretion of inflammatory molecules and to improve cell ability to divide and function.
The team is working to optimize the panel of reprogrammed proteins to rejuvenate human cells and are exploring treating cells/tissues without removing them from the body; they have also formed Turn Biotechnologies to work on developing therapies for osteoarthritis and other diseases with the goal to Turn Back Time.
“Although much more work needs to be done, we are hopeful that we may one day have the opportunity to reboot entire tissues,” Sebastiano said. “But first we want to make sure that this is rigorously tested in the lab and found to be safe.”
