Cornell researchers recently discovered a novel metabolite — a byproduct of life-sustaining chemical processes called metabolism — that is connected to the lifespan of a species of roundworm.
According to the study published in Nature Chemical Biology, the new classification of metabolite — acylspermidine — is produced through interactions between sirtuins and spermidines. Sirtuins are an enzyme family that is involved in many essential processes like DNA damage repair, and spermidine is a compound found in all cells responsible for life-sustaining functions. Researchers found that when the roundworm Caenorhabditis elegans did not produce acylspermidine, its lifespan increased. This discovery helped to focus research into aging and age-related diseases like cancer, according to Prof. Robert Weiss, biomedical sciences.
The researchers first discovered acylspermidines after the Schroeder lab, led by Prof. Frank Schroeder, chemistry and chemical biology, created a version of C. elegans without the gene responsible for producing sirtuins in the mitochondria — the part of the cell responsible for energy production. This technique of removing genes is known as a knockout and is a tool commonly used to better understand the role of a particular gene.
When they compared the molecules present in the C. elegans lacking the sirtuin gene to a wild type C. elegans with no knockouts, the researchers found that it had a reduced production of an unknown metabolite — an intermediate they would later identify as an acylspermidine. First author Bingsen Zhang grad discovered the makeup of this unknown intermediate through the use of tandem mass spectrometry and structural analysis.
Tandem mass spectrometry is a technique to measure the weight of a molecule by breaking it into smaller fragments through the use of high energy. This process allows researchers to understand the fragments individually before determining the chemical makeup of the whole molecule. Verifying chemical makeup was troublesome due to the presence of multiple metabolites, according to Zhang.
“It was conceptually very challenging to say what [the metabolite] is because [the fragments were] actually coming from two molecules and not coming from one molecule,” Zhang said.
However, despite this difficulty, the researchers confirmed that the unknown intermediate was a new type of metabolite that they called N-acylsperminide, with the ‘N’ prefix referring to the attachment of particular components of the metabolite to nitrogen.
In order to further investigate N-acylspermidine, the researchers consulted the lab led by Weiss, which focuses on studying sirtuin in the context of cancer. Weiss supplied the Schroeder lab with cultured mouse cells to continue studying the interaction between the sirtuin and spermidine.
In the mouse cells, the researchers observed a similar effect on lifespan to the one that had been noticed within C. elegans. When the gene that produced sirtuin was knocked out, the number of mouse cell colonies decreased.
The results of the knockout indicated that the regular functions of sirtuins are necessary for producing N-acylspermidine and therefore prolonging lifespan, Weiss explained. Without sirtuin to interact with spermidine, N-acylspermidine is not produced.
According to Weiss, many avenues of exploration are being considered. Sirtuin enzymes and spermidine proteins are present over a multitude of species, and the discovery that they interact to prolong lifespan has helped guide researchers in a new direction. Going forward, both Zhang and Weiss plan to look at all aspects of the pathway of metabolism, and not just the final outcome of the process.
“Right now, it’s a pretty wide-open question of how [N-acylspermidine] influences lifespan and cancer cell proliferation,” Weiss said. “I think it’s a great question for future study — it’s really opening a new avenue for research.”
Cristina Torres can be reached at [email protected].
Correction, Feb. 16, 1:20 p.m.: A previous version of this article incorrectly stated that researchers found that when the roundworm Caenorhabditis elegans did not produce acylspermidine, its lifespan decreased. The researchers found that lifespan increased in this situation. The Sun regrets this error, and the article has been corrected.