Dental research: NYU study links life's milestones to a noncircadian biological rhythm in teeth

New York University College of Dentistry researchers provide first experimental evidence of a new multidien chronobiological rhythm responsible for regulating the pace of growth and development in large mammals.

The circadian rhythm, or “daily biological clock,” controls much of an organism’s regular pace of development, and this growth paradigm has been the focus of intense molecular, cellular, pharmacological, and behavioral, research for decades. But then, why do rats mature faster than humans?

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“It is impossible to explain enormous variations in age at maturity and other developmental milestones just by looking at differences in this daily rhythm,” said Dr. Timothy Bromage, a professor of biomaterials and of basic science and craniofacial biology at the New York University College of Dentistry. “This suggests that another biological timing mechanism is at work.”

Through metabolomic analysis of blood plasma, Dr. Bromage and his team have, for the first time, linked these variations to another biological timing mechanism operating on multi-day (multidien) rhythms of growth and degradation. The findings were published earlier this month in the online journal PLOS ONE.

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This study builds upon earlier dental research by Dr. Bromage that observed multi-day biological rhythms within incremental growth lines in tooth enamel and skeletal bone tissue first published in the February 2009 issue of Calcified Tissue International.

“These rhythms, originating in the hypothalamus, a region of the brain that functions as the main control center for the autonomic nervous system, affect bone, body size, and many metabolic processes, including heart and respiration rates,” Dr. Bromage hypothesized. “The rhythms affect an organism’s overall pace of life and its lifespan, so a rat that grows teeth and bone in a fraction of the time of a human, in fact also lives faster and dies at a much younger age.”

In his current research, Dr. Bromage and his team further characterized these rhythms through metabolome and genome analysis of blood plasma from a medium-sized mammal, the domestic pig. The study, “The Swine Plasma Metabolome Chronicles 'Many Days' Biological Timing and Functions Linked to Growth,” is the first-ever use of metabolomics to address a question in evolutionary biology.

The researchers found that blood plasma metabolites and RNA drawn from 33 domestic pigs over a two-week period oscillate on a five-day rhythm. Using microscopic analysis, the investigators also observed a corresponding five-day rhythm in the pigs’ tooth enamel.

Further study revealed two five-day rhythms in tandem—one controlling tissue growth and a second one beginning three days later for degradation of growth-related molecular compounds back to their basic biological entities for use in the next growth round.

“These findings provide new insight into biological processes regulating growth and body size and controlling gestation length, weaning, age at maturity, and other developmental milestones,” said Dr. Bromage. “We believe this to be a key component to what regulates species’ life history evolution.”

In the next stage of this research, Dr. Bromage will use metabolic profiling to reveal the intricacies of a four-day growth rhythm he observed in the rhesus macaque monkey’s teeth. The final stage of research will examine humans, who are expected to clock eight- to nine-day rhythms, reflecting a larger body size and longer average lifespan than the macaque.

Dr. Bromage’s coinvestigators included: Dr. Youssef Idaghdour of the Department of Biology at NYU Abu Dhabi; Dr. Rodrigo S. Lacruz of the Department of Basic Science & Craniofacial Biology at NYU College of Dentistry; Dr. Thomas D. Crenshaw of the Department of Animal Science at the University of Wisconsin at Madison; Dr. Olexandra Ovsiy of the Department of Biomaterials at NYU College of Dentistry; Dr. Björn Rotter and Dr. Klaus Hoffmeier, both of GenXPro GmbH in Frankfurt, Germany; and Dr. Friedemann Schrenk, head of the Palaeoanthropology Division at the Senckenberg Research Institute and professor of Paleobiology at the Institute for Ecology, Evolution, and Diversity at Goethe University, both in Frankfurt.

Acknowledgments
We posthumously thank Dr. Franz Halberg, a long-time explorer of long period rhythms, for many discussions and for his advice during the course of this study. We thank Dr. Germaine Cornelissen for discussions on spectral analyses, for providing assistance with the development of our cosinor algorithm, and for performing an independent validation of its operation. Mass spectrometry and metabolite profiling were generously provided by Metanomics GmbH. We thank Dr. Bin Hu for expert dental histology. We thank anonymous nonpeer reviewers, who helped to clarify several lines of reasoning, and three PLoS ONE reviewers, including Dr. Holly Smith, who helped illuminate several important points and counterpoints of our work.

This study was hosted by the Senckenberg Research Institute, Frankfurt, and funded by the 2010 Max Planck Research Award to TGB, administered by the Max Planck Society and the Alexander von Humboldt Foundation in respect of the Hard Tissue Research Program in Human Paleobiomics.

For more information about New York University College of Dentistry, visit their website.