The toddler of your organs – your liver is just under three years old

Forever young: using retrospective radiocarbon birth dating, researchers have shown that no matter a person’s age, the liver is always on average less than three years old.

The liver has a unique ability to regenerate after damage – however, it was unknown whether this ability decreases as we age. International scientists led by Dr Olaf Bergmann at the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden used a technique known as retrospective radiocarbon birth dating to determine the age of the human liver and demonstrated that no matter the person’s age, the liver is always on average less than three years old.

Longevity.Technology: The liver is an essential organ that takes care of clearing toxins in our bodies. Because it constantly deals with toxic substances, it is likely to be regularly injured, but to overcome this, the liver has a unique capacity among organs to regenerate itself after damage. As much of the body’s ability to heal itself and regenerate decreases as we age, the TU Dresden team wanted to ascertain if the liver’s capacity to renew also diminishes with age.

The results of this interesting study demonstrate that aging does not influence liver renewal, making the liver an organ that replaces its cells equally well in young and old people.

The nature of liver renewal in humans has been poorly understood, with animal models providing contradictory answers.

“Some studies pointed to the possibility that liver cells are long-lived while others showed a constant turnover,” said Dr Olaf Bergmann, CRTD research group leader. “It was clear to us that if we want to know what happens in humans, we need to find a way to directly assess the age of human liver cells [1].”

The nature of liver renewal in humans has been poorly understood, with animal models providing contradictory answers.
Human liver is composed of cells with different amounts of DNA. Most of the cells have just two copies of DNA, as the cell indicated with a white arrow. Some cells accumulate more sets of DNA, like the ones indicated with yellow arrows. Those various types of cells renew differently.

The human liver remains a young organ

The interdisciplinary team of biologists, physicists, mathematicians and clinicians led by Bergmann analysed the livers of multiple individuals who had died aged between 20 and 84. Surprisingly, the team showed that the liver cells of all subjects were more or less the same age [2].

“No matter if you are 20 or 84, your liver stays on average just under three years old,” explained Dr Bergmann [1]. The results show that the adjustment of liver mass to the needs of the body is tightly regulated through the constant replacement of liver cells – and this process is maintained even in older people. This ongoing liver cell replacement is important for various aspects of liver regeneration and cancer formation.

More is less – liver cells with more DNA renew less

However, not all the cells in our liver are that young – a fraction of cells can live up to 10 years before renewing themselves, and this longer-living subpopulation of liver cells carries more DNA than the typical cells.

“Most of our cells have two sets of chromosomes, but some cells accumulate more DNA as they age. In the end, such cells can carry four, eight, or even more sets of chromosomes,” explained Bergmann.

“When we compared typical liver cells with the cells richer in DNA, we found fundamental differences in their renewal,” he added. “Typical cells renew approximately once a year, while the cells richer in DNA can reside in the liver for up to a decade,” says Bergmann. “As this fraction gradually increases with age, this could be a protective mechanism that safeguards us from accumulating harmful mutations. We need to find out if there are similar mechanisms in chronic liver disease, which in some cases can turn into cancer [1].”

Lessons from the nuclear fallout

Determining the biological age of human cells is an enormous challenge, as methods commonly used in animal models cannot be applied to humans.

Bergmann’s group specialises in retrospective radiocarbon birth dating and uses the technique to assess the biological age of human tissues. An ubiquitous element, carbon forms the backbone of life on Earth, and radiocarbon, one of a variety of types of carbon, appears naturally in the atmosphere. Plants incorporate it through photosynthesis, in the same way as typical carbon, and pass it on to animals and humans. Radiocarbon is weakly radioactive and unstable, and these characteristics are taken advantage of in archaeology to determine the age of ancient samples.

“Archaeologists have used the decay of radiocarbon successfully for many years to assess the age of specimens, one example being dating of the shroud of Turin,” explained Bergmann. “The radioactive decay of radiocarbon is very slow. It provides enough resolution for archaeologists but it is not useful for determining the age of human cells. Nevertheless, we can still take advantage of the radiocarbon in our research [1].”

The above-ground nuclear tests carried out in the 1950s introduced massive amounts of radiocarbon into the atmosphere, into the plants, and into the animals, and as a result, cells formed in this period have higher amounts of radiocarbon in their DNA.

Following the official ban of above-ground nuclear testing in 1963, the amounts of atmospheric radiocarbon started to drop and so did the amounts of radiocarbon incorporated into the animal DNA; the values of atmospheric and cellular radiocarbon correspond to each other very well.

“Even though these are negligible amounts that are not harmful, we can detect and measure them in tissue samples. By comparing the values to the levels of atmospheric radiocarbon, we can retrospectively establish the age of the cells,” added Bergmann [1].

Insights directly from the source

The Bergmann group also explores the mechanisms that drive the regeneration of other tissues considered as static, such as the brain or the heart. The team has previously used their expertise in retrospective radiocarbon birth dating to show that the formation of new brain and heart cells is not limited to prenatal time 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 studying cell renewal directly in humans is technically very challenging but it can provide unparalleled insights into the underlying cellular and molecular mechanisms of human organ regeneration,” concluded Bergmann [1].

[1] https://tu-dresden.de/tu-dresden/newsportal/news/die-menschliche-leber-ist-nicht-einmal-drei-jahre-alt
[2] https://www.cell.com/cell-systems/fulltext/S2405-4712(22)00171-5

Photograph: Paula Heinke

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