Through the ages

Two unique research paths emerge, looking at the fundamentals of aging and ancient origins of disease

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SAN DIEGO & LA JOLLA, Calif.—Researchers are both reaching way back into humanity’s history and heading toward the future in order to learn more about aging and the effects that aging and other factors can have on our minds. From the potential of staying alive longer to strengthening our mental health if we do, research about aging is branching out to study the effects of a carbamate compound within lifespan research, and to discover how a genome dataset that proposes to decode the origins and evolution of mental illnesses can help us learn about the development of diseases.
According to scientists at Scripps Research, an enzyme-blocking molecule can extend the lifespan of Caenorhabditis elegans roundworms by up to 45 percent, largely by modulating a cannabinoid biological pathway. The scientists’ work, entitled “Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan” and published in Nature Chemical Biology, showed that the lifespan-extending cannabinoid pathway in C. elegans is related in unexpected ways to cannabinoid pathways found in humans and other mammals.
“This study reveals a new life-extension pathway, but more broadly, it introduces a powerful method for applying chemical probes to lab animals such as worms to discover biology that may be relevant to humans,” said study senior author Dr. Benjamin Cravatt, professor and Gilula Chair of Chemical Biology, Scripps Research. Cravatt is known for his development of advanced chemical proteomics methods for studying enzymes and the biological pathways they regulate. In this study, his team deployed these methods to investigate aging in C. elegans roundworms. The tiny worms normally live for a few weeks, compared to the two or three years that lab mice attain, making them more practical to study.
Lifespan studies using C. elegans worms typically involve the deletion or silencing of a gene in the embryonic stage of life, to see if that extends the average lifespan of the affected animals. The team’s approach, by contrast, was to use small-molecule compounds to disrupt enzyme-related pathways in adult worms, hoping to uncover pathways that regulate lifespan.
“The beauty of this approach is that any lifespan-extending compounds we identify can be useful tools to study whether the same mechanisms and targets also modulate aging in mammals,” added study co-author Dr. Michael Petrascheck, associate professor in the Department of Molecular Medicine at Scripps Research.
Researchers used a library of about 100 compounds known to inhibit enzymes called serine hydrolases in mammals. The study’s first author Alice Chen, a graduate student in the Cravatt lab, noted that “Metabolic processes are very important in determining the rate of aging and lifespan, and serine hydrolases are major metabolic enzymes, so we thought there was a good chance we’d find an important aging-related enzyme this way.”
After finding ways to get the compounds through the worms’ tough outer skin, Chen tested them on worms that were one day into adulthood, and found that some of the compounds extended average worm lifespan by at least 15 percent. One, a carbamate compound called JZL184, extended worm lifespan by 45 percent at the optimal dose. More than half the worms treated with JZL184 were still alive and apparently healthy at 30 days, when virtually all untreated worms had died. JZL184 was originally developed by the Cravatt lab as an inhibitor of the mammalian enzyme monoacylglycerol lipase (MAGL). Its normal job includes the breakdown of a molecule called 2-AG, an important neurotransmitter and endogenous cannabinoid (endocannabinoid) which activates one of the receptors hit by the main psychoactive component in cannabis.
A corresponding MAGL enzyme doesn’t exist in C. elegans worms, so JZL184’s target was a mystery. Chen found that one of the main target enzymes for JZL184 in worms was fatty acid amide hydrolase 4 (FAAH-4). Although FAAH-4 and MAGL are not related in terms of their amino-acid sequences or 3-D folds, further experiments revealed that FAAH-4 breaks down 2-AG.
2-AG has been linked to aging in mammals; one recent study found evidence that its levels fall in the brains of aging mice, likely due to greater MAGL activity. The results suggest that studying the FAAH-4/2-AG pathway in worms might produce lifespan-extending strategies for humans.
“It seems at least plausible at this point that both worms and mammals have a cannabinoid-related signaling pathway that affects longevity and possibly aging-related disorders,” Cravatt pointed out.
The study more generally demonstrates how libraries of small-molecule compounds and associated proteomics techniques can be used to reveal biological pathways that evolutionarily distant lab animals such as worms have in common with humans.
“In principle, with this approach one can quickly find a compound that has a desired biological effect and also find the target through which it works, all in a live and relatively complex model organism,” Cravatt said.
And now we go from small creatures to much bigger ones, as researchers create an ambitiously large ancient genome dataset intended to decode the genetic origins and evolution of neuropsychiatric illnesses.
Illumina and the Lundbeck Foundation GeoGenetics Centre at the University of Copenhagen, Denmark have partnered to explore the relationship between infectious pathogens and the evolutionary history of select mental and neurological disorders. The endeavor seeks new knowledge of underlying factors in the development of human neuropsychiatric diseases throughout history.
Prof. Eske Willerslev, Lundbeck Foundation Professor at the University of Copenhagen and Prince Philip Professor at the University of Cambridge, and his team will build one of the largest genomic datasets of its kind to hopefully shed light on the role of microbes in the pathogenesis of neuropsychiatric illnesses like Alzheimer’s disease and schizophrenia. The dataset involves complete DNA mapping of thousands of ancient Eurasian human remains, the oldest remains dating back 10,000 years.
“Over the past 10,000 years, mankind has experienced some of the greatest lifestyle changes in the history of our species. Our diet changed as we developed from hunter-gatherers into farmers, our settlement patterns changed, and there have been changes in pressure of infection from the pathogenic micro-organisms to which we were exposed due to altered living conditions,” Willerslev explained.
“We also know that chronic viral, bacterial and fungal infections might be causative factors in neuropsychiatric diseases, so there is every reason to believe that the analyses of DNA from this period will show significant trends, giving us the ability to create new, publicly available reference sets, to enhance both the scientific and healthcare communities’ understanding of disease evolution,” Willerslev added.
To decode the genetic origins and human disease evolution, the team will utilize Illumina’s NovaSeq 6000 system, which was designed to provide the throughput to properly power large-cohort studies. Projects of this scale benefit from speed, throughput and data quality, and this project will use the S4 flow cell to sequence up to 20 billion ancient DNA fragments every two days.
“The NovaSeq 6000 was the obvious choice for this project, with its unrivaled data quality and high-throughput capabilities. While we conceived this project to explore the evolutionary origins of genetic disorders years ago, it was simply impossible to realize before Illumina’s NovaSeq System came on the market,” specified Willerslev. “We are delighted that Lundbeck Foundation had the foresight to see the importance of our project, and that Illumina’s technology will make the research possible.”
The international team of scientists—including specialists in ancient genomics, neuro-genetics, population genetics, archaeology, linguistics and experts in brain health—will focus on creating two subsets of genomic data. The first panel will be comprised of 5,000 ancient human genomes. The second panel will consist of ancient pathogen DNA associated with human diseases. Both panels will be made publicly available. The project will generate and analyze one of the largest sets of ancient human and pathogen genome panels ever created.
“It will be extremely valuable if, by going back 10,000 years, we can acquire new information about when, and under which environmental conditions, a brain disorder may have been introduced into human DNA. This project has the potential to influence future product developments in genetics and precision medicine by providing invaluable insights to those affected by mental health issues,” concluded Paula Dowdy, senior vice president and general manager for Europe, Middle East and Africa at Illumina.

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