Researchers have discovered an epigenetic mechanism that appears to have a major impact on healthy aging. It is a protein that controls muscle function, life expectancy and the level of an essential sugar.
Researchers at the Max Delbrück Center’s Berlin Institute of Medical Systems Biology (BIMSB) have discovered a protein that has a significant impact on healthy muscle and life expectancy. When animals lack the protein called LIN-53, they have severe muscle damage and limited mobility. They die earlier compared to animals that have this protein.
Dr. Baris Tursun, head of the laboratory for "Gene Regulation and Cell Type Specification in C. elegans" at BIMSB, and his colleagues have discovered two specific signaling pathways through which LIN-53 works in roundworms. Their results, published in the journal Aging Cell, lay the foundation for further studies on the human version of the protein.
"We want to identify the genetic factors that link lifespan and healthspan. This is a key to understanding human health and age-related diseases such as muscular dystrophy," said Dr. Tursun.
Dr. Tursun and his team wanted to understand whether an epigenetic factor has an influence on how long an organism lives and how long the organism is healthy. They also wanted to find out whether lifespan and healthspan are directly related.
"As we get older, we usually notice signs of aging accompanied by a loss of muscle mass," said Dr. Tursun. "Are they coincidences or is there a connection? If there is a connection, how are these factors linked exactly? Our study is one of the first publications to show an epigenetic connection" he explained.
The team investigated the role of LIN-53 in Caenorhabditis elegans. "It is such a small organism and yet human tissues, signaling pathways, and gene regulation are similar. Therefore, we can transfer the results from the nematode to humans," said Stefanie Müthel, first author of the publication and postdoctoral fellow at the Laboratory for Myology in the Experimental and Clinical Research Center (ECRC), a joint facility of the Berlin-based Charité University Hospital and Max Delbrück Center.
When the scientists removed the gene for LIN-53, the worms moved less and did not live as long as the representatives who still had this gene.
This shows that LIN-53 plays an important role in healthy musculature and lifespan. The team continued their research and discovered that LIN-53 influences muscle development through the molecular complex NuRD and lifespan through another complex, Sin3. The fact that LIN-53 is involved in two different signaling pathways is particularly intriguing and strongly suggests the importance of LIN-53 as a link between life span and healthspan.
"LIN-53 is part of seven different molecular complexes that regulate the modification and structure of chromatin," said Müthel. "I was surprised and happy that we were able to clearly define the complexes that are important for health and life span.
Further analysis provided a possible explanation of why LIN-53 is so powerful. Animals without LIN-53 had only low levels of a sugar called trehalose. The interaction between LIN-53 and Sin3 concerned genes that regulate metabolism, including the production of this sugar. Further studies are needed to understand how LIN-53 interacts with NuRD and Sin3 and inhibits sugar production.
Since the protein LIN-53 and the human protein RBBP4/7 are almost identical, scientists can use the knowledge they have gained from the microscopic worm as a guide to find answers to similar questions in humans.
"We all want to age healthily," says Tursun. "Once we know the relationship between aging and any associated adverse effects, we can consider how to decouple them from each other.
Stefanie Müthel et al (2019): "The conserved histone chaperone LIN-53 is required for normal lifespan and maintenance of muscle integrity in Caenorhabditis elegans" Aging Cell, https://doi.org/10.1111/acel.13012