Old cells slow down muscle regeneration

old cells

Senescent cells (colored) in muscle tissue. © Moiseeva et al.

Stem cells normally ensure that damage to our muscles can be repaired by maturing cells. But this regeneration slows down with age. Scientists have now found out why this is so. According to this, old, no longer functional cells accumulate in the niches of the muscle tissue occupied by stem cells. Although these senescent cells are shut down and no longer divide, they still release inflammatory messenger substances. This, in turn, blocks the stem cells from regenerating the tissue, the team found. These findings explain why the muscles shrink with age, but could also open up therapeutic approaches.

The constant repair of cells and tissues is vital for our body. Our organs, muscles and bones only remain functional if cells damaged by injuries, DNA defects or aging are constantly replaced by new ones. Responsible for this are small accumulations of stem cells, so-called stem cell niches, scattered throughout the tissues. When messenger substances and surrounding cells signal them that there is tissue damage, these stem cells become active, divide and differentiate into the required cell types. This allows our body to repair muscle damage and replace defective cells. However, for this to work, the stem cells must be “woken up” and given the appropriate signals. "The reconstruction of damaged tissues requires a precisely timed interaction of different cell types within the regenerative stem cell niche," explain Victoria Moiseeva from Pompeu Fabra University in Barcelona and her colleagues.

Premature cell aging in muscle

This is where the study by Moiseeva and her team comes in. Because the researchers wanted to know what role senescent cells play in tissue regeneration. These cells have reached the end of their lifetime and are therefore shut down by the cell's own programs: they no longer divide to prevent age-related degeneration, but remain in a kind of dormant state in the tissues. "Until now, little was known about the distribution of these senescent cells and their role in tissue regeneration," the scientists explain. This was mainly because there was a lack of clear markers for cells in the senescent stage, they appeared very different and were difficult to isolate. To remedy the situation, Moiseeva and her colleagues first identified some metabolic molecules that may be typical of senescent cells in muscle tissue and visualized their production in living mice using a fluorescent marker.

This allowed the team to monitor the distribution of senescent cells in the muscles of young and old animals, and in animals with a muscle injury. It turned out that there were hardly any old cells to be found in the young, healthy muscles. However, that changed when the mouse muscles aged or became injured. Then senescent cells accumulated, especially in the stem cell niches of the muscles – in the places where tissue repair was supposed to start. Further analysis revealed that this rapid accumulation was triggered by many older but still functional cells in these niches suddenly falling into the senescent state. "After an injury, some muscle cells become senescent, creating a prematurely aged microenvironment," explains co-author Antonio Del Sol from the University of Luxembourg. The affected cells show strong oxidative stress and increased DNA damage, which then drive them into the aging state.

Senescent cells inhibit tissue regeneration

Next, the scientists investigated the processes behind this conversion. They discovered that the senescent cells already present in the muscle change their cell metabolism and upregulate certain genes in the event of injury and also as the muscle ages. As a result, they now release more messenger substances that promote inflammation and the accumulation of hardened connective tissue cells. "Their messenger substances thus reflect the signals normally associated with aging and generate them even in young, injured mice," explains Del Sol. In principle, this leads to premature aging of the cell environment around the stem cells, which are important for tissue repair. Doctors also refer to the age-typical combination of inflammation and tissue scarring as “inflammaging”. While young bodies can partially reverse these effects by allowing the immune system to clear the excess senescent cells, this is not the case as we age. "The weakened immune system in old age no longer removes these senescent cells and as a result they remain longer and accumulate in the damaged old muscle," explain Moiseeva and her colleagues.

This has consequences: As the scientists discovered, the presence of these old cells inhibits the proliferation and differentiation of the stem cells in the muscle. This in turn means that injuries and similar damage can no longer be repaired or can only be repaired slowly. "The senescent cells in the stem cell niches therefore suppress regeneration," say the researchers. This effect was also observed when senescent cells were transplanted into injured muscle tissue. This premature aging of the stem cell niches could also explain why older people often suffer from gradual muscle atrophy: micro-damage and dead tissue areas are no longer repaired, or only slowly, because they naturally have more old, senescent cells in their tissues.

However, the new findings also open up an opportunity to do something about age-related muscle wasting and other disorders in muscle healing. Because when the research team blocked the senescent cells or their messenger substances in their mice, muscle regeneration improved in both the young and old mice. "Because such senescent cells also accumulate in human muscles, this opens up new avenues to improve muscle repair," explain Moiseeva and her colleagues.

Source: Victoria Moiseeva (Universitat Pompeu Fabra, Barcelona) et al., Nature, doi: 10.1038/s41586-022-05535-x)

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