The liver is an essential organ that takes care of eliminating toxins from our body. Because he constantly deals with toxic substances, he is susceptible to regular injury. To overcome this, the liver has a unique ability among organs to regenerate after damage. Because much of the body’s ability to heal and regenerate itself declines with age, scientists wondered if the liver’s ability to renew itself also declines with age.
The nature of liver turnover in humans has also remained a mystery. Animal models have provided conflicting answers. “Some studies have pointed to the possibility that liver cells are long-lived while others have shown constant turnover. It was clear to us that if we want to know what’s going on in humans, we need to find a way to directly assess the age of human liver cells,” says Dr. Olaf Bergmann, research group leader at the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden.
The human liver remains a young organ
The interdisciplinary team of biologists, physicists, mathematicians and clinicians led by Dr. Bergmann analyzed the livers of several people who died between the ages of 20 and 84. Surprisingly, the team showed that the liver cells of all the subjects were more or less the same age.
“It doesn’t matter if you’re 20 or 84, your liver stays on average for just under three years,” says Dr. Bergmann. The results show that the adjustment of liver mass to the body’s needs is tightly regulated by the constant replacement of liver cells and that this process is maintained even in the elderly. This ongoing replacement of liver cells is important for various aspects of liver regeneration and cancer formation.
Liver cells with more DNA renew themselves less
However, not all cells in our liver are so young. A fraction of cells can live for up to 10 years before renewing themselves. This subpopulation of liver cells contains more DNA than typical cells. “Most of our cells have two sets of chromosomes, but some cells accumulate more DNA as they age. Ultimately, such cells can carry four, eight or even more sets of chromosomes,” says Dr. Bergmann.
“When we compared typical liver cells with the more DNA-rich cells, we found fundamental differences in their turnover. Typical cells renew themselves about once a year, while more DNA-rich cells can reside in the liver for up to a decade,” says Dr. Bergmann. “As this fraction gradually increases with age, this could be a protective mechanism that protects us from the accumulation of harmful mutations. We need to find out if there are similar mechanisms in chronic liver disease, which can in some cases turn into cancer.
Lessons from nuclear fallout
Determining the biological age of human cells is a huge technical challenge because methods commonly used in animal models cannot be applied to humans.
Dr. Bergmann’s group specializes in retrospective radiocarbon birth dating and uses this technique to assess the biological age of human tissue. Carbon is a ubiquitous chemical element that forms the backbone of life on Earth. Radiocarbon is one of many types of carbon. It appears naturally in the atmosphere. Plants incorporate it by photosynthesis, in the same way as conventional carbon, and pass it on to animals and humans. Radiocarbon is weakly radioactive and unstable. These characteristics are used in archeology to determine the age of ancient samples.
“Archaeologists have successfully used radiocarbon decay for many years to assess the age of specimens, one example being the dating of the Shroud of Turin,” says Dr Bergmann. “The radioactive decay of radiocarbon is very slow. It provides sufficient resolution for archaeologists, but it is not useful for determining the age of human cells. Nevertheless, we can still take advantage of radiocarbon in our research.
Aerial nuclear testing in the 1950s introduced massive amounts of radiocarbon into the atmosphere, plants and animals. As a result, cells formed during this period have higher amounts of radiocarbon in their DNA.
Following the official ban on surface nuclear testing in 1963, the amounts of atmospheric radiocarbon began to decline, as did the amounts of radiocarbon incorporated into animal DNA. Atmospheric and cellular radiocarbon values correspond very well.
“Even if these are negligible amounts that are not harmful, we can detect and measure them in tissue samples. By comparing the values to atmospheric radiocarbon levels, one can retrospectively establish the age of the cells,” says Dr. Bergmann.
Unrivaled information straight from the source
The Bergmann group is also exploring the mechanisms that drive the regeneration of other tissues considered static, such as the brain or the heart. The team has already used its expertise in retrospective radiocarbon birth dating to show that the formation of new brain and heart cells is not limited to the prenatal period but continues throughout life. Currently, the group is investigating whether new human heart muscle cells can still be generated in people with chronic heart disease.
“Our research shows that the direct study of cell turnover in humans is technically very challenging, but it can provide unprecedented insight into the underlying cellular and molecular mechanisms of human organ regeneration,” concludes Dr. Bergmann .
Paula Heinke, Fabian Rost, Julian Rode, Palina Trus, Irina Simonova, Enikő Lazar, Joshua Feddema, Thilo Welsch, Kanar Alkass, Mehran Salehpour, Andrea Zimmermann, Daniel Seehofer, Göran Possnert, Georg Damm, Henrik Druid, Lutz Brusch, Olaf Bergmann : Diploid hepatocytes drive physiological liver turnover in adult humans. Cellular systems (May 2022)
About the Center for Regenerative Therapies Dresden (CRTD)
The Center for Regenerative Therapies Dresden (CRTD) at TU Dresden is an academic home for scientists from over 30 countries. Their mission is to discover the principles of cell and tissue regeneration and leverage them for the recognition, treatment and reversal of disease. The CRTD connects the laboratory to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s disease. Alzheimer’s and Parkinson’s disease, hematological diseases such as leukemia, metabolic diseases such as diabetes, retinal and bone diseases.
The CRTD was founded in 2006 as a research center of the German Research Foundation (DFG) and funded until 2018 as a DFG research center, as well as a center of excellence. Since 2019, the CRTD has been funded by the TU Dresden and the Free State of Saxony.
The CRTD is one of the three institutes of the central science facility Center for Molecular and Cellular Bioengineering (CMCB) at TU Dresden.
The Web: www.tu-dresden.de/cmcb/crtd
The Web: http://www.tu-dresden.de/cmcb
Dr. Olaf Bergmann’s group website: https://tud.link/ad38
Full resolution photos: https://tud.link/gycm