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Why our sense of smell declines in old age

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NEUHERBERG (DE), December 2018 — As mammals age, their sense of smell deteriorates. A recent study investigated why this is the case by tracking the development of stem cells in the brains of mice using what are known as confetti reporters. The researchers then analyzed the complex data obtained using intelligent algorithms.

The results are published in Cell Reports.

In mammals, the generation of new neurons (neurogenesis) is limited mainly to early childhood; it occurs in adulthood in only a few regions of the forebrain. One such exception is olfactory neurons, which develop from stem cells via several intermediate stages.

“The production of these neurons diminishes with advancing age. In our recent study we wanted to find out the cellular basis and what role stem cells play in the process,” said Carsten Marr, Ph.D., research group leader at the Institute of Computational Biology (ICB) of Helmholtz Zentrum München.

To shed light on this question, an interdisciplinary team of experts from the Helmholtz Zentrum München was formed that included the mathematicians Marr and doctoral student dLisa Bast as well as stem cell researchers Filippo Calzolari, Ph.D., (now with the Institute of Physiological Chemistry at the University Mainz) and Jovica Ninkovic, Ph.D. “Our approach utilized what are known as confetti reporters to perform lineage tracing. In mouse brains, we induced individual stem cells and all their descendants – called clones − to light up in a specific color,” Dr. Calzolari said. In this way, the scientists could distinguish clones over time by the different colors that give the technique its name.

“In the next step, we compared clones found in young and older mice to find out what contribution individual stem cells and intermediates make to the neurogenesis of mature olfactory cells,” he added.

The available data were extremely heterogeneous, making a comparison of young and old brains difficult. Here is where the expertise of Dr. Marr and his team came into play. They are specialists in the quantification of single-cell dynamics, i.e., the study of which and how many cells of a large population make which cell fate decisions. To do so, the researchers use artificial intelligence methods, develop mathematical models and deduce algorithms to help analyze the image data.

“We compared the confetti measurements with several mathematical models of neurogenesis,” explained Dr. Bast. “We found that the ability of self-renewal declines in old age, especially in certain intermediate stages called transit amplifying progenitors.”

In addition, the analysis showed that asymmetric cell division and quiescence of stem cells increased in older mice. “That means that fewer cells differentiate into olfactory cells in old age as they tend to remain in the stem cell pool and become less active. Therefore, the production comes to a halt,” Dr. Ninkovic said.

The work is the first in which scientists have been able to quantitatively describe the behavior of neural stem cells in the living mammalian brain using a mathematical model.

The researchers tracked the development of stem cells using so-called confetti reporters. Image courtesy of © Helmholtz Zentrum München.

Learn more:
https://www.helmholtz-muenchen.de/en/aktuelles/latest-news/press-information-news/article/45520/index.html
DOI: 10.1016/j.celrep.2018.11.088a