Gene therapy extends mice’s lives for the first time – what it means for humans

The world’s population is getting older. The median age between 1900 and 2020 has doubled, increasing the social burden. This is due to the fact that aging is the biggest risk factor for most human diseases. For this reason, it is imperative to slow down or even reverse the aging process, researchers believe.

Although people’s longevity has increased in recent decades, this has not been accompanied by a better quality of life. Although people are living longer, they still suffer from age-related diseases – and then only for a longer period of time.

A problem that has occupied research for some time. Her goal is therefore to slow down the aging process in humans at a cellular level. He lives longer and at the same time can postpone age-related diseases.

Two independent research teams claim to have achieved such cell rejuvenation. At least in mice.

To make the research results understandable, a brief digression into the past is necessary. The Japanese biologist and stem cell researcher Shinya Yamanaka laid the foundation for the research results 10 years ago. During that time he discovered a gene cocktail that can reprogram adult cells into versatile stem cells. huh what?

Bee adult stem cells are already specialized stem cells that are present in humans after birth. These cells can only form certain cell types in the human body. A skin stem cell can therefore only produce different cell types of the skin, but not blood or nerve cells.

Unlike adult stem cells, the embryonic stem cells (ES cells) more versatile. These only occur in a very early stage of embryonic development – ​​the so-called blastocyst. This is a developmental stage of the human embryo on the 5th day after fertilization. At this point, the embryo is just a cell cluster.

These cells are pluripotent. This means they have the property to become any cell type of the human body to develop.

In 2006, Shinya Yamanaka succeeded in reprogramming adult stem cells in mice to their embryonic state. From then on, he fed the stem cells with a gene cocktail of four different genes the 4 Yamanaka factors called at. These have reawakened the dormant pluripotent property of stem cells. In other words, the stem cells are back in their original embryonic state and can develop into any cell type.

The same experiment was also successful in human cells in 2007. The induced pluripotent stem cells (iPS cells) produced in this way represented a major breakthrough for the research.

Yamanaka received the 2012 Nobel Prize in Physiology or Medicine for this discovery of reprogrammable stem cells.

And what does that have to do with getting older? And anyway: Why do we actually age? Of course, because the muscles and bones become weaker and the organs don’t work as smoothly as they used to. It is correct. However, these factors are related to aging processes. However, it does not answer the question ‘why’.

This question is much less well researched than the “how”. From an evolutionary point of view, it actually makes no sense that harmful processes predominate. So aging does not develop because it would be useful. Dr Sebastian Grönke from the Max Planck Institute for the Biology of Aging in Cologne explains in an interview:

One of the theories of such a side effect is the harm theory. It states that the body ages due to all the accumulated damage in the body. Our genomes, which contain our DNA, are constantly exposed to harmful influences (such as UV radiation). Although our cells have the ability to repair damage to the genetic material, this is not always possible. For example, DNA damage is anchored in our genome as mutations. These accumulate over the years, accelerating the aging process and contributing to the onset of diseases such as cancer.

The study published last Thursday challenges this scientific assumption. For example, geneticist David Sinclair of Harvard Medical School does not believe that it is directly the damage that makes us old. At a health event hosted by “CNN” last year, he said:

While the DNA is the hardware in its equation, the epigenome is the software. The epigenome is located on the genome and is composed of so-called epigenetic factors. According to the National Human Genome Research Institute, these are waiting to tell the genome “what it should do, and where and when it should do it.” The epigenome can turn genes on and off like a computer. In this way, only those genes with the information needed by the cell in question are active.

When DNA is damaged, which happens millions of times every day, it is the epigenetic factors that coordinate the repair. They then pause their normal job of regulating genes and proceed to DNA damage. Then they return to their original location. Here, according to Sinclair, lies the crux of the matter. He found that the epigenetic factors do not return over time and lose their original information – epigenetic disturbances occur. Without the commands of the epigenetic factors, cells (such as muscle or skin cells) lose their identity and their function is disrupted. This eventually leads to signs of aging and diseases such as cancer.

To test his informational theory of aging, his team cut the DNA of a mouse genome in 20 places. So they created DNA damage that the mouse would have accumulated on its own over time. Sinclair then noted that while the damage was repaired, the epigenetic factors suffered significantly. As a result, they resembled those of much older animals. And indeed: Within weeks, the animals lost hair and pigment and became more fragile. This while their DNA was no longer damaged.

Now Sinclair wanted to reverse the whole process and repair the damaged cells in these older-looking mice. To do this, he resorted to the Yamanaka Factors mentioned at the beginning and used them to inject different cells to restore them to a rejuvenated state. Subsequent analyzes of the mice’s muscles, kidneys and retinas yielded promising results: The gene cocktail was able to reverse some of the epigenetic changes caused by the DNA breaks.

What surprised Sinclair was that the treated cells had only been reduced to about 50 to 75 percent of their original age. Thus, they did not fully return to their embryonic state as they did in Yamanaka’s original experiment. Sinclair says he still doesn’t understand why. But: if the cell had returned to the embryonic state, it would have lost all of its identity. An aging muscle cell would not even know it was once a muscle cell. According to Sinclair, this defect in hereditary function would lead to cancer. To Sinclair’s surprise, the cells seemed to have stopped rejuvenation at just the right time.

Sinclair therefore sees a lot of potential in this treatment. His team is now looking for a way to achieve this rejuvenation evenly in every cell, so that the entire mouse rejuvenates at once. This appears to have been the case in another study.

The second study also used the Yamanaka factors. It was published as a preprint on the BioTxiv website on Jan. 5 and has not yet been peer-reviewed. San Diego-based company Rejuvenate Bio’s claim is bold: They can extend the life of rodents. as the?

As part of their study, the researchers injected very old mice (124 weeks) with three of the four Yamanaka factors and then observed how long they lived. Unlike Sinclair, the mice were not artificially aged before. Until the gene cocktail was injected, the mice were healthy, naturally old.

The result: the treated mice lived an average of 18 weeks, while the untreated mice in the control group, as expected, died after 9 weeks. Like Sinclar, they were able to identify epigene rejuvenation in the context of gene therapy. So the mice not only lived longer, they were also healthier for longer.

While the life extension is only modest, says Noah Davidsohn, head of science at Rejuvenate Bio, it’s still groundbreaking:

But when will it be?

Scientists who are not connected to the studies call them milestones. But they also warn that whole-body rejuvenation through gene therapy is still a poorly understood concept and carries many risks. One of them causes cancer.

For example, Professor Vittorio Sebastiano of Stanford University is quoted in an article entitled “MIT Technology Review”:

Sebastiano, an expert in stem cell biology, also criticizes the fact that Rejuvenate Bio did not document which and how many cells were changed during the gene treatment. The extended lifespan could therefore be due to the changes in a single organ and not an overall rejuvenation effect of the mouse.

In fact, the focus of rejuvenation research in many studies is on individual organs. Sinclair is currently testing Yamanaka factors on blind monkey eyes. They have already had success with this in mice: the affected genes in the eye that no longer worked were ‘turned on’ again, and the mouse could see again. Meanwhile, Professor Sebastation is working on rejuvenating injections that should fight wrinkles or stimulate new hair growth.

Rejuvenate Bio is investigating, among other things, a gene therapy drug intended to treat heart failure.

However, Head of Science Davidsohn firmly believes that it will eventually be possible to holistically rejuvenate people. He says with conviction: