Blood cells from donors ranging from newborn to 101 years old were transformed into neural stem cells in this study. Remarkably, cells from an 80-year-old donor showed a molecular age of less than 20 years after reprogramming, according to University of Bonn researchers. The study, published in the journal Aging Cell, describes experiments conducted in laboratory cell cultures.
How reprogramming works in the lab
Researchers created paired cell lines from the same donors, generating neural stem cells both directly and via an intermediate step through induced pluripotent stem cells, using samples from newborns to centenarians. Cell age was determined using DNA methylation patterns analyzed with an epigenetic clock method based on earlier work by Horvath.
Rejuvenation over weeks, not overnight
For cells from older donors, the epigenetic clock showed pronounced rejuvenation. In early culture stages, about 13 percent of the original donor age remained; after longer cultivation, about 5 percent remained. The process stretched over several weeks and continued even when researchers slowed cell division with glycerol or thymidine. The acquisition of neural stem cell characteristics extended well beyond the point where dividing PAX6-positive cells appeared. Over time, differences in gene expression patterns between young and old donor cells disappeared; established cell lines eventually showed no age-related characteristics, similar to cells derived from pluripotent stem cells. According to lead researcher Oliver Brüstle, the rejuvenation occurred gradually and could be tracked over more than 100 days, with cells actually behaving like young cells.
Direct approach versus intermediate pathway
When researchers used a two-stage process instead, epigenetic clocks reset much more rapidly, quickly reaching an embryonic state. Cells from donors over 80 years old, however, took considerably longer on the direct pathway but ultimately closely resembled the embryonic-like comparison cells.
Limitations of the findings
The researchers themselves note that calculated age based on DNA methylation is only an approximation for biological age because it does not directly measure age-related cell functions. The temporal progression was studied in only a few donor cell lines, and all experiments occurred exclusively in cell cultures. Whether this approach could ever treat diseases or rejuvenate tissue in a living organism remains unknown. Researchers also identified possible mathematical distortions in their rejuvenation models, the absence of naturally aged neural stem cells for comparison, and possible differences between cell culture and a living organism as limitations.
In earlier studies, the Bonn researchers demonstrated that nerve cells generated this way form connections with existing neurons after transplantation into mouse brains. Brüstle identified aging as the most important risk factor for neurodegenerative diseases like Alzheimer's and sees the gradual rejuvenation process as a model to investigate factors and drugs that might accelerate or slow it.