New insights into a family of metabolites, acylspermidines, could change how we understand aging and fight disease. A new study presents an unexpected connection between spermidine, a long-known compound present in all living cells, and sirtuins, an enzyme family that regulates many life-essential functions.

The study is recently published in Nature Chemical Biology, in a paper titled, “Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.

Sirtuins (nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases) have been the subject of significant attention over the past two decades. Studies indicate that sirtuins play a role in various age-related diseases. As a result, there is growing interest in the link between sirtuins and aging, and their potential as a promising target for therapeutic interventions aimed at improving health span and longevity.

Sirtuins are known to regulate metabolism and stress responses. Despite being the subject of intense study, a characterization of the removed acyl groups and their downstream metabolic fates has remained incomplete.

“We were excited to uncover this unexpected branch of cellular metabolism related to sirtuins,” said Frank Schroeder, PhD, professor at Boyce Thompson Institute at Cornell University. “Discovering these previously uncharacterized spermidine derivatives provides insight into the inner workings of this critical pathway and brings us a step closer to understanding the physiological functions of mitochondrial sirtuins.”

The researchers took an unbiased approach and used comparative metabolomics to screen for sirtuin-dependent metabolic changes. The study revealed a novel family of metabolites called acylspermidines, which are derived from modifications of diverse proteins, many of which play essential roles in growth and cell survival.

More specifically, the authors noted that they “identified N-glutarylspermidines as metabolites downstream of the mitochondrial sirtuin SIR-2.3 in Caenorhabditis elegans and demonstrated that SIR-2.3 functions as a lysine deglutarylase and that N-glutarylspermidines can be derived from O-glutaryl-ADP-ribose.”

Following the discovery of sirtuin-linked acylspermidines in C. elegans, the researchers further demonstrated that the same compounds are also present in mammals—including humans. Lastly, the research team demonstrates the direct impact of these metabolites on lifespan in C. elegans and cell proliferation in mammals.

They found that “mouse and human metabolomes revealed a chemically diverse range of N-acylspermidines, and formation of N-succinylspermidines and/or N-glutarylspermidines was observed downstream of mammalian mitochondrial sirtuin SIRT5 in two cell lines, consistent with annotated functions of SIRT5.”

Lastly, they asserted that “N-glutarylspermidines were found to adversely affect C. elegans lifespan and mammalian cell proliferation.”

“Important physiological functions are reflected in many molecular fingerprints, including tens of thousands of small molecule metabolites that remain to be discovered,” said Bingsen Zhang, a graduate student in the Schroeder lab. “This work is a step towards uncovering the biological roles and functions of the vast space of chemical dark matter in our bodies.”

Future research will explore the mechanisms and pharmacological aspects of these findings, particularly how acylspermidines affect lifespan, cell growth, and their potential interactions with other metabolic pathways.

“Nearly 350 years after spermidine was isolated and 100 years after its structure was understood, our work further advances the collective knowledge of the spermidine family, connecting it to other vital biochemical processes, including central energy metabolism and amino acid metabolism,” added Zhang.

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