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Scientists have already thought that neurons, or even heart cells, were the oldest cells in the body. Researchers at the Salk Institute have found that the mouse brain, liver and pancreas contain extremely long cell and protein populations, some as old as neurons. The results, demonstrating "mosaicism by age", were published in Cell metabolism June 6, 2019. The team's methods could be applied to almost all body tissues to provide valuable information about the lifetime function of non-dividing cells and the loss of cell control over the body. quality and integrity of proteins and important cell structures during aging.
"We were quite surprised to find cell structures that are essentially as old as the organism in which they reside," said Salk's vice president, chief scientist, Martin Hetzer, author and senior lecturer. "This suggests an even greater cellular complexity than we had imagined before and has intriguing implications for how we think about aging organs, such as the brain, heart and pancreas."
Most neurons in the brain do not divide in adulthood and therefore have a long lifespan and an age-related decline. However, largely because of technical limitations, the lifespan of cells outside the brain was difficult to determine.
"Biologists have asked: how old are the cells in an organism?" There is this general idea that neurons are old, while other cells in the body are relatively young and regenerate throughout the life of the body. organization, "says Rafael Arrojo e Drigo, first author Scientific Salk. "We sought to find out if it is possible that some organs also have cells that have a life span as long as brain neurons."
Researchers know that most neurons are not replaced during life, so they used them as "age-based" to compare other non-dividing cells. The team has combined electron isotopic labeling with a hybrid imaging method (MIMS-EM) to visualize and quantify the age and turnover of cells and proteins in the brain, pancreas and the body. liver in young and old rodent models.
To validate their method, the scientists first determined the age of the neurons and discovered that, as one might suspect, they were as old as the body. Yet, surprisingly, the cells lining the blood vessels, called endothelial cells, were as old as the neurons. This means that some non-neuronal cells do not replicate and do not replace themselves throughout life.
The pancreas, the organ responsible for maintaining glycemia and the secretion of digestive enzymes, also had cells of different ages. A small part of the pancreas, called islets of Langerhans, appeared to researchers as a puzzle of interconnected young and old cells. Some beta cells, which release insulin, replicated in their lifetime and were relatively young, while others did not divide and had a long life, similar to neurons. Another type of cell, called delta cells, does not divide at all. The pancreas was a striking example of mosaicism by age, that is, a population of identical cells that are distinguished by their life span.
Previous studies have suggested that the liver has the ability to regenerate in adulthood. The researchers therefore selected this organ in the hope of observing relatively young liver cells. To their surprise, the vast majority of liver cells in healthy adult mice were as old as the animal, while the cells lining the blood vessels and star-shaped cells, another type of liver cells, had a much shorter life. Thus, unexpectedly, the liver has also demonstrated mosaicism by age, indicating new potential pathways for regenerative research for this organ.
At the molecular level, a selection of long-lived cells observed contained protein complexes exhibiting mosaicism by age. For example, primary eyelashes (hair-like appendages located outside of cells) of pancreatic beta cells and neurons contained protein regions of a very different lifespan. In contrast, liver cells contained no long-lived protein.
"Thanks to new visualization technologies, we are able to determine the age of cells and their supramolecular complexes more accurately than ever before, which opens new doors for the study of all cells, tissues and tissues. and organs in normal states and pathological states, "says Mark Ellisman, a distinguished Professor of Neuroscience at the University of San Diego School of Medicine and co-head of the study with Hetzer. His laboratory, the National Research Center for Microscopy and Imaging, has developed and provided new tissue imaging methods for multi-scale and multi-modal correlated microscopy. These methods provided the main new and enabling technologies that made this study possible.
"The determination of the age of cells and subcellular structures in adult organisms will provide new information on cell maintenance and repair mechanisms and on the impact of cumulative changes occurring at an early age. on the health and development of the disease, "says Hetzer. "The ultimate goal is to use these mechanisms to prevent or delay the decline of organ-restricted, age-related cell renewal."
Next, the authors plan to decipher the difference in life span of nucleic acids and lipids. They also want to understand the link between mosaicism by age, health and diseases such as type 2 diabetes.
Swati Tyagi of Salk; Varda Lev-ram, Ranjan Ramachandra, Thomas Deerinck, Eric Bushong and Sebastien Phan of UC San Diego; Victoria Orphan from the California Institute of Technology; and Claude Lechene from Brigham and Women's Hospital.
The work was funded by the National Institutes of Health (R01 NS096786, NINDS NIH RO1 NS027177-30, NIGMS 5P41 GM103412-29), the Keck Foundation, the NOMIS Foundation, the US Department of Energy (DE-SC0016469), NINDS Neuroscience Core (NS072031), the Waitt Foundation, the Chapman Foundation, the Helmsley Charitable Trust, a postdoctoral fellowship of the American Diabetes Association (# 1-18-PMF-007), and the Cell and Tissue Imaging Center of the American Diabetes Association. Institut Curie (PICT), member of France BioImaging National Infrastructure (ANR-10-INBS-04).
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