Animal Lifespans Linked To Nucleoli Size, Prompting A Firestorm Of New Research

Biologics

Scientists of all stripes, prepare to be stunned. According to new research published in Nature Communications, the mere size of animal cell nucleoli is strongly correlated with longevity.1 The culprit, naturally, is a tumor suppressor gene called NCL-1/TRIM2/Brat. The sequence of the “Brat” allele controls nucleoli size in C. elegans, and its discovery effectively opens up a new area of investigation for longevity scientists. If longevity researchers of any stripe are interested in exploring how different genotypes of Brat affect longevity, they’re going to have to seamlessly team up and perform cross-disciplinary research enabled by a powerful software platform for knowledge sharing.

Brat, the new kid on the longevity block

Brat isn’t the first gene or pathway to be discovered with direct implications on longevity.2 Studies on the mTOR pathway have been particularly fruitful in linking allele to longevity outcomes across many models. The consensus is clear: metabolism is directly linked with longevity, and so understanding longevity is in many ways a process of understanding the accumulated consequences of metabolism within the cell. Brat is, however, the latest in a series of genes associated with autophagy to be implicated in longevity.3

Autophagy’s relationship with longevity may not seem immediately clear– cellular housekeeping is a stable process, and, in the event that it isn’t, apoptotic signalling pathways will take care of the rest. There’s more to this story, though. Autophagy within the nucleolus is made up of some very specific process which merit further exploration.

The nucleoli are hotspots of ribosomal activity and metabolic function, meaning that their autophagy causes a few core events to occur:4

  • Ribosomal machinery is broken down and presumably reformed anew, removing the effects of any accumulated defects in their conformation
  • Cellular building blocks tied up in nucleoli are released back into the cytosol, allowing their repurposing for non-ribosomal metabolic activity
  • The genes for ribosomal production of other ribosomes are upregulated to reflect the need to replace the digested members in the nucleoli

Autophagy of the nucleoli is a natural process which cells can use to regulate their level of activity and respond to environmental stressors, meaning that it’s a core process to the functioning of the entire cell.5  When the new research thus uncovered that nucleoli size is related to their rate of metabolic activity, autophagy, and the longevity of the entire organism, it added an entirely new dimension of understanding to a deep cellular pathway that has yet to be fully understood. Brat will be the subject of a huge amount of follow up research, as the authors of the study note.

The huge upshot of nucleolar size being correlated with longevity is that it’s an extremely easy metric to assay, as anyone who has ever stained nuclei for visualization could tell you. It’s entirely possible that a drop-dead-simple assay for model organism longevity could be designed based off of the new research, which is extremely exciting for other longevity researchers who are accustomed to performing deep gene analyses to make guesses at the relative longevity that their experimental changes impact. In this sense, the new research not only adds depth to the working hypotheses of cellular longevity, but also to the day-to-day physical practice of executing laboratory experiments assaying longevity– a rare and extremely valuable coincidence.

Teaming up to exploit small nucleoli

There’s quite a bit of data and understanding that will need to be shifting hands rapidly and repeatedly if researchers want to start turning knowledge of Brat into further research which will relate it to longevity in humans. Part of the reason that taking on Brat will be such a huge research project is that impacts the way that cells respond to environmentally induced changes to their other longevity associated genes– another new finding that will require re-examination and re-integration of old knowledge.6

Longevity research is already a multidisciplinary effort, and the new research’s discovery of Brat complicates matters even further. Cellular and molecular biologists will need to join forces with geneticists, physiologists, practitioners of gerontology, and ultimately, human subjects if they have any hope of fully understanding Brat. All former research involving the autophagy of nucleoli can now be seen in a new light, so much of the new research effort will be rehashing old information to understand it at a deeper level.

If researchers assemble the right collaborative team and figure out the technical details of how to work together, they’ll be able to answer critical questions like:

  • How do DNA methylation patterns affect Brat?
  • How do post-translational protein alterations to Brat’s output affect nucleoli size, and therefore ribosomal characteristics?
  • Are there physiological consequences to varying Brat alleles independent of those caused by nucleoli size?
  • Which physiological, metabolic, or genetic events cause upregulation or downregulation of Brat?
  • Does the Brat pathway operate the same way in model organisms such as C. elegans and mammalian model organisms, or in humans?

Only the most diverse research teams will be able to approach more than a  single one of these questions, and it’s more than likely that multiple groups will need to work in concert to answer certain individual questions. Given that the new metric of nucleoli size has been validated as correlative with longevity, entire new research groups will form with size as their only area of study. These groups would do well to share their data to accelerate the pace of research, too.

BIOVIA’s Collaborative Science Solutions is the collaboration, predictive analytics and data analysis platform that will be necessary for the longevity researchers of the near future to create a new working longevity hypothesis including Brat. Using Collaborative Science Solutions, your team can easily collaborate with other groups by sharing data, experiment plans, and laboratory practices. Contact us today to find out how BIOVIA can help you join the new wave of research into nucleolar autophagy as defined by Brat.

  1.  “Small Nucleoli Are A Cellular Hallmark Of Longevity.” August 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582349/.
  2. “A Role For Autophagy In The Extension Of Lifespan By Dietary Restriction In C. elegans.” February 2008, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2242811/.
  3. “Autophagy Genes Are Essential For Dauer Development And Life-Span Extension In C. elegans.” September 2003, https://www.ncbi.nlm.nih.gov/pubmed/12958363.
  4. “The Nucleolus Of Caenorhabditis elegans.” April 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345250/.
  5. “The Nucleolus Under Stress.” October 2010, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987465/.
  6. “Lifespan Extension By Conditions That Inhibit Translation In Caenorhabditis elegans.” February 2007, https://www.ncbi.nlm.nih.gov/pubmed/17266679.