Researchers in Germany have succeeded in reversing more than 60 years of molecular aging, while simultaneously transforming blood progenitor cells into neural stem cells capable of producing neurons.
This discovery, made by scientists at the University Hospital Bonn and the University of Bonn, could provide new insights into one of biology’s greatest mysteries: how aging can be reversed at the cellular level.
Unlike previous methods that reset a cell’s molecular age relatively quickly, this approach operates gradually, allowing researchers to monitor the rejuvenation process over a period of more than 100 days.
The study titled “Protracted Fate Acquisition and Epigenetic De-Aging During Induced Neural Stem Cell Conversion of Human Blood Cells“, published in the journal Aging Cell, offers scientists a rare opportunity to investigate what triggers cellular rejuvenation, what slows it down, and whether the underlying mechanisms could one day help in addressing age-related diseases, such as Alzheimer’s disease.
Changing Cell Identity and Age
Most cells in the body carry essentially the same genetic instructions; however, they develop into specialized cell types with distinct functions. Their identity depends largely on which genetic instructions they utilize. Under normal physiological conditions, a blood cell cannot simply transform into a neuron.
Researchers can redirect a cell’s identity through reprogramming, using combinations of proteins known as transcription factors, which alter gene activity and guide the cell’s development. This approach has already enabled scientists to generate neural tissue from skin cells—a development that could, in the future, contribute to the creation of therapies for neurodegenerative diseases.
The Bonn-based team employed reprogramming to convert red blood cell precursors into neural stem cells. In previous experiments, neurons generated via this method formed connections with existing neurons following their transplantation into the brains of mice. In this study, scientists focused on a different phenomenon: specifically, the observation that cells undergo significant rejuvenation during the reprogramming process.
What do molecular clocks measure?
To track this rejuvenation, the researchers examined chemical modifications to DNA that change with age. These modifications influence how genetic information is utilized, without altering the DNA sequence itself. This field of study is known as epigenetics.
Epigenetic clocks use patterns of these markers to estimate a cell’s molecular age. Following reprogramming, cells from an 80-year-old individual showed a molecular age of less than 20 years—a reduction of over 60 years in just 50 days.
The researchers also knew that this epigenetic rejuvenation ensures that the cells truly behave like young cells.
Scientists had previously observed rejuvenation during a two-stage reprogramming process. Initially, a specialized cell reverts to a pluripotent stem cell state, gaining the ability to develop into almost any type of cell. Subsequently, researchers guide it to transform into a neural stem cell, which has a much more limited potential for differentiation.
A slower path toward understanding rejuvenation
In contrast to the conventional two-stage approach, which brings about rapid rejuvenation, the Bonn-based team converted blood progenitor cells directly into neural stem cells, bypassing the pluripotent stem cell stage.
The cells’ molecular clocks were reset gradually, allowing researchers to monitor the process for over 100 days. This extended timeframe enables scientists to examine the process as it unfolds and to investigate which factors accelerate or slow it down.
“A rejuvenation process that spans such a long period serves as an ideal experimental model. Since the epigenetic clocks are reset slowly—over the course of several weeks—we can use this model to explore which factors and active substances accelerate or slow down the rejuvenation process.”
For Brüstle, understanding these regulatory mechanisms is of particular importance for brain research. “After all, age is the most significant risk factor for neurodegenerative diseases such as Alzheimer’s disease!”
