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FOCUS cell biology macrophages are actually lining the nerve,” she said. “They almost look like they’re hugging it.” This configuration led Camell to conclude that she had discovered an entirely new subset of macrophages, termed nerve-associated macrophages, that represents the intersection of the nervous, immune, and metabolic systems. These immune cells directly access the catecholamines from the nerves, which allows them to regulate levels of these hormones in the adipose tissue. Where before, the exact relationship of the nerve, the released catecholamine, and the adipocyte was unclear, now macrophages have been established as a direct and crucial link. This immediate connection allows the nerve-associated macrophages to influence both lipid metabolism and inflammation, two primary factors that contribute to aging, via their control over the concentration of catecholamines present in the adipose tissue. Learning how to manipulate this system was a final step to cement the validity of these findings. Aged macrohpages were found to overexpress an enzyme called MAOA that is implicated in catecholamine degradation, so the researchers treated aged mice with a MAOA inhibitor and saw increased fat breakdown. This result confirms the link between catecholamine degradation and resistance to lipolysis in aging. To sum up the model, when catecholamines are released by still functional nerves in aged individuals, inflamed macrophages have excess biological “machinery” like MAOA that degrades the catecholamines, so the hormones are broken down before they can act on the adipocyte to promote lipolysis. This more complete picture gives researchers a better comprehension of the complicated crosstalk between the nervous, immune, and metabolic systems and how it influences fat breakdown in aging. The life in your years Down the road, an understanding of these intersecting communication patterns has far-reaching applications in treatment for aging in line with its classification as a chronic disease. The aforementioned class of MAOA inhibitors is currently used as treatment for depression, but if research worked to localize these drugs such that they do not affect the brain, this therapeutic avenue would be promising. With lower levels of MAOA comes higher levels of catecholamines, which can restore lipolysis in aging individuals. An IMAGE COURTESY OF CHRISTINA CAMELL ►Nerve-associated macrophages, shown in green, seem to hug sympathetic nerves, shown in white. alternative target is GDF3, the NLRP3-dependent protein that inhibits fat breakdown. While GDF3 is a single upregulated protein under the overarching control of the NLRP3 inflammasome, NLRP3 itself is required for fighting off infection, so drugs to block this protein can increase the risk of certain infections. Instead, neutralization of GDF3 is an indirect way to achieve the same goal. If aberrant inflammation via GDF3 can be prevented, cells of the adipose tissue will show better lipolysis. Regardless of the mechanism, these strategies work to influence the crosstalk between macrophages and their associated nerves, which, in turn, influences fat metabolism. The communication between the nervous, immune, and metabolic systems that this research establishes integrates almost every organ system and so has clear potential to address the disease of aging as a condition that impacts all aspects of human health. When viewed through an even broader lens, this research is about improving people’s healthspan, the time during which an individual is in good health. To clarify the relationship between catecholamine degradation and inflammation is to draw the links between the immune, nervous, and metabolic systems that, for example, can be implemented to mitigate neurodegenerative and other age-related diseases. Ultimately this research may represent a key to healthier aging. “Our goal is not to simply increase lifespan,” Dixit said, “but to add life to the years that exist.” An understanding of the mechanisms controlling lipolysis, however narrow of a focus, can help to achieve this universal ideal: to add life to your years. ABOUT THE AUTHOR CHARLIE MUSOFF CHARLIE MUSOFF is a sophomore molecular, cellular, and developmental biology major in Davenport College. Besides being Yale Scientific’s Outreach Designer, Charlie enjoys running, singing with the Baker’s Dozen, and teaching with Community Health Educators. THE AUTHOR WOULD LIKE TO THANK Christina Camell and Professor Vishwa Deep Dixit for their time and insights. FURTHER READING Pirzgalska, Roksana M, et al. “Sympathetic Neuron-Associated Macrophages Contribute to Obesity by Importing and Metabolizing Norepinephrine.” Nature Medicine, 9 Oct. 2017, doi:10.1038/nm.4422. 24 Yale Scientific Magazine December 2017 www.yalescientific.org
materials science FEATURE IMAGING OF DYNAMIC SURFACES A new microscope images surfaces 5000 times faster ►BY JAU TUNG CHAN IMAGE COURTESY OF ALAIN HERZOG ►The second harmonic microscope constructed by the researchers, used to image a glass capillary. Many industrial processes rely on chemical reactions occurring along surfaces, such as the Haber-Bosch process that produces ammonia on the surface of iron for fertilizer and other industrial products. It may seem surprising, then, that there are presently no good ways to observe these reactions on the molecular level in real-time because of their speed and scale (they occur on a scale smaller than the width of a human hair). Earlier this year, however, researchers at the École Polytechnique Fédérale de Lausanne, a research institution in Lausanne, Switzerland, constructed and tested of a new type of microscope that can do just that—look at surface chemistry on the micro-scale in real-time. Using their microscope, the researchers measured, in a matter of milliseconds, the variation in chemical properties of a glass surface over micrometers. Their results were published in August 2017 in Science. The first of its kind, this microscope is known as a “wide-field, structured illumination, second harmonic microscope,” which, as its name suggests, utilizes a phenomenon called second harmonic generation (SHG). SHG is a process that allows two photons— particles of light—to combine under certain conditions, resulting in a new photon with exactly twice the frequency. This is similar to how two water droplets, when colliding with suitable orientations and speeds, can combine to form a droplet with precisely twice the volume. For SHG, the new photon forms only when two original photons interact with a non-centrosymmetric material—a material without a central point about which the molecules can be reflected. For example, a pizza in five slices is non-centrosymmetric, while a pizza in six slices is centrosymmetric. The net number of photons generated by SHG depends on the orientation of this non-centrosymmetric material. This property is what allows the researchers to use SHG in their microscope. First, to reveal underlying chemical structures of a glass-water interface, the researchers wetted the surface, causing water molecules to selectively cluster on areas to which they were more attracted, akin to how shaking a tray of sand with a strip of glue collects sand along that strip. Next, the researchers shined light onto the whole surface, showering it with photons. Because water molecules are non-centrosymmetric, the amount of SHG depends on the orientation of the water molecules, which in turn depends on the surface’s underlying chemical structure. By measuring the output of SHG photons coming from different positions on the curved glass surface, the researchers were able to reconstruct the chemical properties of the different parts of the surface in 3D. Since this microscope captures the entire surface all at once, it captures images more than 5000 times faster than current second harmonic microscopes. Most importantly, this increase in speed does not sacrifice image quality. Sylvie Roke, the principle investigator of the project, was herself pleasantly surprised about the sensitivity of the microscope. “What I find amazing is that there are so few oriented water molecules—just one nanometer of oriented water molecules—and I can see them so brightly,” Roke said. The advantages of this new microscope hardly end there. Sapun H. Parekh of the Max Planck Institute for Polymer Research in Mainz, Germany, added that this microscope offers the additional benefit of being operational even without precise control of the environment—unlike most other methods to study surface chemistry that require ultrahigh vacuums to operate. One straightforward application of this microscope could be to improve the industrial manufacturing of surfaces, such as solar cells. By examining the surface chemistry of manufactured surfaces in real-time, we can get immediate feedback on the manufacturing processes, making its optimization easier and more efficient. Roke foresees even more exciting applications for the new microscope, such as imaging biological processes like neurons firing. “Neurons communicate by electrostatic signals that travel across the membrane,” Roke said. “What if I could use this method to [image the] membrane of the neuron while it is signaling to other neurons, without modifying the neuron?” This would be an impressive step forward to understanding how neurons function, since current technologies only allow us to observe neurons by modifying them. While there are still some nuances in second harmonic microscopy that remain to be explicitly addressed, the researchers have certainly accomplished a proof of concept with the new instrument. As Parekh puts it, “What they showed is not the end application—it’s just the beginning.” www.yalescientific.org December 2017 Yale Scientific Magazine 25
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Page 5 and 6: F R O M T H E E D I T O R NEW LETTE
Page 7 and 8: in brief NEWS Solarizing Through So
Page 9 and 10: medicine NEWS HOW GENES AFFECT YOUR
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Page 18 and 19: Studying the Few to Serve the Many
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