Aging is the price paid for the ability to experience existence, one might philosophize. Natural cellular aging begins with differentiation. Once a stem cell becomes a specific type of cell, it is locked in forever: fat cells can never become muscle cells, no matter how much you want them to or poke and prod at them in front of the mirror. Or that’s what happens in nature, but scientists can definitely transform cells, as if biologically compensating for all the failed alchemical attempts of the past. Now, scientists have transformed old blood cells into young brain stem cells, which continued to rejuvenate as they aged. The researchers, from the University Hospital Bonn and the University of Bonn in Germany, described their methods in the journal Aging Cell. Cellular transformations can be carried out in two main ways. The first, more circuitous route, converts a specific cell back into a pluripotent stem cell, or an embryonic “blank slate,” and then into a different type of cell. The second method involves a “direct conversion,” which skips the intermediate stage and directly transforms a cell into a different type. “With this method we have directly converted red blood cell precursors into neural stem cells,” summarizes Oliver Brüstle, director of the Institute for Reconstructive Neurobiology at the University Hospital of Bonn. Neurons generated through the differentiation of neural stem cells, initially derived from blood. (Brüstle Research Group/University of Bonn) The researchers used donor cells from 15 people across the age spectrum, from newborn to 101 years old. Specifically they took erythroid progenitor cells (EPCs), which are similar to red blood cells that have not yet graduated from college, and converted them into induced neural stem cells (iNSCs), which are the pre-graduate cells of the brain. They achieved the genetic shortcut of direct conversion through an unlikely agent that usually destroys cells. The researchers used a virus to deliver two transcription factors, or proteins that bind to DNA to regulate gene activity, to make cells change type. They then used two genome sleuthing methods (DNA methylation measurements and RNA sequencing) to track the resulting anti-aging effects and genetic behavior. On day 12 after viral “infection,” the cells began to show their new identity, abandoning their blood proteins and replacing them with the expression of neuronal proteins. Initially, the epigenetic age (changes in DNA accumulated over time) of EPCs was highly correlated with the chronological age of their donors. Evidently, the blank slate cells revert to an embryonic state and become rejuvenated, regardless of the age of the person who donated the blood sample. So the researchers wanted to see if the direct conversion method they used also rejuvenated the converted cells. Curiously, they did, although it took more than twice as long. But this was just the appetizer, because neural stem cells continued to rejuvenate as they aged (sorry for the paradox). Over the next 50 to 100 days, they continued to age, eventually reaching about 5 percent of the donor’s age, and most age-related epigenetic traits were restored around 50 days into the conversion process. In other words, counterintuitively, they got younger as they got older. Indeed, the converted cells became 60 years younger in 50 days, the researchers note in their official statement, proving that you really can “melt away the years” as hotel and spa brochures and late-night infomercials promise (if you’re a cell, at least). The induced neural stem cells, which can differentiate into some types of brain cells, such as neurons, were derived from the blood of a 101-year-old donor. (Brüstle Research Group / University of Bonn) But were these cells really younger or did they just look that way? In other words, anyone can wear a Thrasher hoodie, but that doesn’t give them skate-worthy balance. “We also know that this epigenetic rejuvenation ensures that the cells actually behave like young cells,” says Brüstle. The researchers analyzed this through numerous measures, including protein expression and the recycling capacity of the rejuvenated cells. The cells also showed less DNA damage and mitochondrial toxicity, demonstrating that direct conversion cells enjoyed benefits comparable to blank slate cells. Interestingly, they continued to rejuvenate biologically even under conditions that inhibited their proliferation or ability to divide and multiply, suggesting that their rejuvenation is not dependent on their ability to divide. The researchers mention some limitations of the study. These include possible mathematical biases in aging models, the absence of naturally aged neural stem cells to use as comparisons, and possible behavioral differences in cells in vitro versus in vivo. But promisingly, the engineered cells appear to be viable. In previous research by Bonn scientists on the Franken mouse, the cells formed connections with existing neuronal cells after being transplanted into the brains of mice. These Pinky and the Brain-style transgenic mice demonstrate future therapeutic value, suggesting the possibility of engineering brain cells for individuals affected by neurodegeneration. Finally, the prolonged nature of the cells converted in this work allows for easier study: “Rejuvenation that lasts over such a long period of time is ideal as an experimental model,” emphasizes Brüstle. “Since epigenetic clocks reset slowly over several weeks, we can investigate with this model which factors and active substances accelerate or slow down the rejuvenation process.” The research has been published in Aging Cell. This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. While we take pride in our process, we are human. If you spot an error, please let us know.
