obesity
Saving Fat for Lean Times
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Humans and all multi-celled organisms, or metazoans, have evolved through millennia into a variety of competing shapes, sizes, and survival strategies. But all metazoans still share lots of intriguing cell biology, including the ability to store excess calories as fat. In fact, many researchers now consider fat-storing cells to be “nutrient sinks,” or good places for the body to stash excess sugars and lipids. Not only can these provide energy needed to survive a future famine, this is a good way to sequester extra molecules that could prove toxic to cells and organs.
Here’s something to think about the next time you skip a meal. Fat-storing cells organize their fat reserves spatially, grouping them into specific pools of lipid types, in order to generate needed energy when food is scarce.
That’s the story behind this striking image taken in a larval fruit fly (Drosophila melanogaster). The image captures fat-storing adipocytes in an organ called a fat body, where a larval fruit fly stores extra nutrients. It’s like the fat tissue in mammals. You can see both large and small lipid droplets (magenta) inside polygon-shaped fat cells, or adipocytes, lined by their plasma membranes (green). But notice that the small lipid droplets are more visibly lined by green, as only these are destined to be saved for later and exported when needed into the fly’s bloodstream.
Working in Mike Henne’s lab at the University of Texas Southwestern Medical Center, Dallas, research associate Rupali Ugrankar discovered how this clever fat-management system works in Drosophila [1]. After either feeding flies high-or-extremely low-calorie diets, Ugrankar used a combination of high-resolution fluorescence confocal microscopy and thin-section transmission electron microscopy to provide a three-dimensional view of adipocytes and their lipid droplets inside.
She observed two distinct sizes of lipid droplets and saw that only the small ones clustered at the cell surface membrane. The adipocytes contorted their membrane inward to grab these small droplets and package them into readily exportable energy bundles.
Ugrankar saw that during times of plenty, a protein machine could fill these small membrane-wrapped fat droplets with lots of triacylglycerol, a high-energy, durable form of fat storage. Their ready access at the surface of the adipocyte allows the fly to balance lipid storage locally with energy release into its blood in times of famine.
Ugrankar’s adeptness at the microscope resulted in this beautiful photo, which was earlier featured in the American Society for Cell Biology’s Green Fluorescent Protein Image and Video Contest. But her work and that of many others help to open a vital window into nutrition science and many critical mechanistic questions about the causes of obesity, insulin resistance, hyperglycemia, and even reduced lifespan.
Such basic research will provide the basis for better therapies to correct these nutrition-related health problems. But the value of basic science must not be forgotten—some of the most important leads could come from a tiny insect in its larval state that shares many aspects of mammalian metabolism.
Reference:
[1] Drosophila Snazarus regulates a lipid droplet population at plasma membrane-droplet contacts in adipocytes. Ugrankar R, Bowerman J, Hariri H, Chandra M, et al. Dev Cell. 2019 Sep 9;50(5):557-572.e5.
Links:
The Interactive Fly (Society for Developmental Biology, Rockville, MD)
Henne Lab (University of Texas Southwestern Medical Center, Dallas)
NIH Support: National Institute of General Medical Sciences
Large Study Reveals Prevalence, Health Benefits of Brown Fat
Posted on by Dr. Francis Collins
It’s pretty easy to spot differences between the two people on these positron emission tomography (PET) scans. In the scan of the male individual on the left, you see lots of small, dark spots around the neck and shoulders. But you can’t see any on the female on the right. What’s the explanation? Is this a sex difference? No! Brown fat!
This energy-burning type of fat happens to show up as small, dark spots in the neck and shoulder area on PET scan studies. So, as these scans reveal, the individual on the left possesses an abundance of brown fat, while the person on the right has essentially none. This wide range of difference in abundance is true for both men and women.
Researchers’ interest in brown fat began to heat up (sorry about that!) more than a decade ago when it was discovered that certain adults have persistently high levels of brown fat. It’s long been known that babies have brown fat, but it had been thought this fat generally vanished as children grew up. It turns out that adults who hold onto their brown fat are less likely to be overweight than adults who do not. That’s because brown fat actually burns extra calories, instead of storing it in the way the more familiar white fat does.
But are people with more brown fat actually any healthier? After studying about 130,000 PET scans from more than 52,000 people, researchers led by Paul Cohen, The Rockefeller University Hospital, New York, NY, say that the answer is “yes” in certain key areas. In a recent study in the journal Nature Medicine, they found that people with detectable brown fat had a lower incidence of many cardiovascular and metabolic conditions, including type 2 diabetes, congestive heart failure, and high blood pressure.
Studies to explore the health benefits of brown fat have been challenging to do. That’s because brown fat only shows up on PET scans, which measure how much glucose various tissues consume, an indication of their metabolic activity. What’s more, PET scans are quite costly and involve radiation exposure. So, researchers have been reluctant to ask healthy people to undergo a PET scan just to look at brown fat. But a solution occurred to the study’s first author Tobias Becher, who was aware that thousands of patients at nearby Memorial Sloan Kettering Cancer Center were undergoing PET scans each year as part of routine evaluation and care. In fact, cancer doctors often make note of brown fat on PET scans, if only to make sure it’s not mistaken for cancer.
So, the Cohen lab teamed up with Memorial Sloan Kettering Cancer Center radiologists Heiko Schöder and Andreas G. Wibmer to review many thousands of PET scans for the presence of brown fat. And they found it in about one of 10 people.
Next, they looked for health differences between the 10 percent of people with brown fat and the 90 percent who lack it. The differences turned out be striking. Type 2 diabetes was about half as prevalent in folks with detectable brown fat compared to those without. Individuals with brown fat also were less likely to have high cholesterol, high blood pressure, congestive heart failure, and coronary artery disease.
The findings suggest that brown fat may even help to offset the negative health effects of obesity. The researchers found that obese people with brown fat had a health profile that otherwise appeared more similar to individuals who weren’t obese. In fact, the benefits of brown fat were more pronounced in individuals who were overweight or obese than they were in people of normal weight.
Still, the researchers note that people with cancer might tend to show differences in brown fat compared to healthy adults. There’s some evidence also that prevalence may vary across cancer types and stages. The researchers took those variables into account in their studies. It’s also known that women are more likely to have brown fat than men and that the amount of brown fat tends to decline with age. What’s not yet well understood is whether differences in brown fat exist among people of different racial and ethnic backgrounds, and whether specific genetic factors are involved.
So, plenty of questions remain! Researchers not only want to figure out why some adults have so much more brown fat than others, they want to explore whether brown fat produces hormones that may add to its calorie-burning benefits. The hope is that these and other discoveries could eventually lead to new strategies for treating obesity, diabetes, and other metabolic conditions.
Reference:
[1] Brown adipose tissue is associated with cardiometabolic health. Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, Butler SD, Jiang CS, Vaughan R, Schöder H, Mark A, Cohen P. Nat Med. 2021 Jan;27(1):58-65.
Links:
Paul Cohen (The Rockefeller University, New York, NY)
Heiko Schöder (Memorial Sloan Kettering Cancer Center, NY)
Andreas Wibmer (Memorial Sloan Kettering Cancer Center, NY)
NIH Support: National Center for Advancing Translational Sciences
The People’s Picks for Best Posts
Posted on by Dr. Francis Collins
It’s 2021—Happy New Year! Time sure flies in the blogosphere. It seems like just yesterday that I started the NIH Director’s Blog to highlight recent advances in biology and medicine, many supported by NIH. Yet it turns out that more than eight years have passed since this blog got rolling and we are fast approaching my 1,000th post!
I’m pleased that millions of you have clicked on these posts to check out some very cool science and learn more about NIH and its mission. Thanks to the wonders of social media software, we’ve been able to tally up those views to determine each year’s most-popular post. So, I thought it would be fun to ring in the New Year by looking back at a few of your favorites, sort of a geeky version of a top 10 countdown or the People’s Choice Awards. It was interesting to see what topics generated the greatest interest. Spoiler alert: diet and exercise seemed to matter a lot! So, without further ado, I present the winners:
2013: Fighting Obesity: New Hopes from Brown Fat. Brown fat, one of several types of fat made by our bodies, was long thought to produce body heat rather than store energy. But Shingo Kajimura and his team at the University of California, San Francisco, showed in a study published in the journal Nature, that brown fat does more than that. They discovered a gene that acts as a molecular switch to produce brown fat, then linked mutations in this gene to obesity in humans.
What was also nice about this blog post is that it appeared just after Kajimura had started his own lab. In fact, this was one of the lab’s first publications. One of my goals when starting the blog was to feature young researchers, and this work certainly deserved the attention it got from blog readers. Since highlighting this work, research on brown fat has continued to progress, with new evidence in humans suggesting that brown fat is an effective target to improve glucose homeostasis.
2014: In Memory of Sam Berns. I wrote this blog post as a tribute to someone who will always be very near and dear to me. Sam Berns was born with Hutchinson-Gilford progeria syndrome, one of the rarest of rare diseases. After receiving the sad news that this brave young man had passed away, I wrote: “Sam may have only lived 17 years, but in his short life he taught the rest of us a lot about how to live.”
Affecting approximately 400 people worldwide, progeria causes premature aging. Without treatment, children with progeria, who have completely normal intellectual development, die of atherosclerotic cardiovascular disease, on average in their early teens.
From interactions with Sam and his parents in the early 2000s, I started to study progeria in my NIH lab, eventually identifying the gene responsible for the disorder. My group and others have learned a lot since then. So, it was heartening last November when the Food and Drug Administration approved the first treatment for progeria. It’s an oral medication called Zokinvy (lonafarnib) that helps prevent the buildup of defective protein that has deadly consequences. In clinical trials, the drug increased the average survival time of those with progeria by more than two years. It’s a good beginning, but we have much more work to do in the memory of Sam and to help others with progeria. Watch for more about new developments in applying gene editing to progeria in the next few days.
2015: Cytotoxic T Cells on Patrol. Readers absolutely loved this post. When the American Society of Cell Biology held its first annual video competition, called CellDance, my blog featured some of the winners. Among them was this captivating video from Alex Ritter, then working with cell biologist Jennifer Lippincott-Schwartz of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The video stars a roving, specialized component of our immune system called cytotoxic T cells. Their job is to seek out and destroy any foreign or detrimental cells. Here, these T cells literally convince a problem cell to commit suicide, a process that takes about 10 minutes from detection to death.
These cytotoxic T cells are critical players in cancer immunotherapy, in which a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. Cancer immunotherapy remains a promising area of research that continues to progress, with a lot of attention now being focused on developing immunotherapies for common, solid tumors like breast cancer. Ritter is currently completing a postdoctoral fellowship in the laboratory of Ira Mellman, Genentech, South San Francisco. His focus has shifted to how cancer cells protect themselves from T cells. And video buffs—get this—Ritter says he’s now created even cooler videos that than the one in this post.
2016: Exercise Releases Brain-Healthy Protein. The research literature is pretty clear: exercise is good for the brain. In this very popular post, researchers led by Hyo Youl Moon and Henriette van Praag of NIH’s National Institute on Aging identified a protein secreted by skeletal muscle cells to help explore the muscle-brain connection. In a study in Cell Metabolism, Moon and his team showed that this protein called cathepsin B makes its way into the brain and after a good workout influences the development of new neural connections. This post is also memorable to me for the photo collage that accompanied the original post. Why? If you look closely at the bottom right, you’ll see me exercising—part of my regular morning routine!
2017: Muscle Enzyme Explains Weight Gain in Middle Age. The struggle to maintain a healthy weight is a lifelong challenge for many of us. While several risk factors for weight gain, such as counting calories, are within our control, there’s a major one that isn’t: age. Jay Chung, a researcher with NIH’s National Heart, Lung, and Blood Institute, and his team discovered that the normal aging process causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies showed it also slows down metabolism, making it more difficult to burn fat.
Since publishing this paper in Cell Metabolism, Chung has been busy trying to understand how aging increases the activity of DNA-PK and its ability to suppress renewal of the cell’s energy-producing mitochondria. Without renewal of damaged mitochondria, excess oxidants accumulate in cells that then activate DNA-PK, which contributed to the damage in the first place. Chung calls it a “vicious cycle” of aging and one that we’ll be learning more about in the future.
2018: Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic? This impressive bit of microbial detective work had blog readers clicking and commenting for several weeks. So, it’s no surprise that it was the runaway People’s Choice of 2018.
Clostridium difficile (C. diff) is a common bacterium that lives harmlessly in the gut of most people. But taking antibiotics can upset the normal balance of healthy gut microbes, allowing C. diff. to multiply and produce toxins that cause inflammation and diarrhea.
In the 2000s, C. diff. infections became far more serious and common in American hospitals, and Robert Britton, a researcher at Baylor College of Medicine, Houston, wanted to know why. He and his team discovered that two subtypes of C. diff have adapted to feed on the sugar trehalose, which was approved as a food additive in the United States during the early 2000s. The team’s findings, published in the journal Nature, suggested that hospitals and nursing homes battling C. diff. outbreaks may want to take a closer look at the effect of trehalose in the diet of their patients.
2019: Study Finds No Benefit for Dietary Supplements. This post that was another one that sparked a firestorm of comments from readers. A team of NIH-supported researchers, led by Fang Fang Zhang, Tufts University, Boston, found that people who reported taking dietary supplements had about the same risk of dying as those who got their nutrients through food. What’s more, the mortality benefits associated with adequate intake of vitamin A, vitamin K, magnesium, zinc, and copper were limited to amounts that are available from food consumption. The researchers based their conclusion on an analysis of the well-known National Health and Nutrition Examination Survey (NHANES) between 1999-2000 and 2009-2010 survey data. The team, which reported its data in the Annals of Internal Medicine, also uncovered some evidence suggesting that certain supplements might even be harmful to health when taken in excess.
2020: Genes, Blood Type Tied to Risk of Severe COVID-19. Typically, my blog focuses on research involving many different diseases. That changed in 2020 due to the emergence of a formidable public health challenge: the coronavirus disease 2019 (COVID-19) pandemic. Since last March, the blog has featured 85 posts on COVID-19, covering all aspects of the research response and attracting more visitors than ever. And which post got the most views? It was one that highlighted a study, published last June in the New England Journal of Medicine, that suggested the clues to people’s variable responses to COVID-19 may be found in our genes and our blood types.
The researchers found that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death. The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system.
In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.
That’s it for the blog’s year-by-year Top Hits. But wait! I’d also like to give shout outs to the People’s Choice winners in two other important categories—history and cool science images.
Top History Post: HeLa Cells: A New Chapter in An Enduring Story. Published in August 2013, this post remains one of the blog’s greatest hits with readers. The post highlights science’s use of cancer cells taken in the 1950s from a young Black woman named Henrietta Lacks. These “HeLa” cells had an amazing property not seen before: they could be grown continuously in laboratory conditions. The “new chapter” featured in this post is an agreement with the Lacks family that gives researchers access to the HeLa genome data, while still protecting the family’s privacy and recognizing their enormous contribution to medical research. And the acknowledgments rightfully keep coming from those who know this remarkable story, which has been chronicled in both book and film. Recently, the U.S. Senate and House of Representatives passed the Henrietta Lacks Enhancing Cancer Research Act to honor her extraordinary life and examine access to government-funded cancer clinical trials for traditionally underrepresented groups.
Top Snapshots of Life: A Close-up of COVID-19 in Lung Cells. My blog posts come in several categories. One that you may have noticed is “Snapshots of Life,” which provides a showcase for cool images that appear in scientific journals and often dominate Science as Art contests. My blog has published dozens of these eye-catching images, representing a broad spectrum of the biomedical sciences. But the blog People’s Choice goes to a very recent addition that reveals exactly what happens to cells in the human airway when they are infected with the coronavirus responsible for COVID-19. This vivid image, published in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. This image squeezed in just ahead of another highly popular post from Steve Ramirez, Boston University, in 2019 that showed “What a Memory Looks Like.”
As we look ahead to 2021, I want to thank each of my blog’s readers for your views and comments over the last eight years. I love to hear from you, so keep on clicking! I’m confident that 2021 will generate a lot more amazing and bloggable science, including even more progress toward ending the COVID-19 pandemic that made our past year so very challenging.
See the Human Cardiovascular System in a Whole New Way
Posted on by Dr. Francis Collins
Watch this brief video and you might guess you’re seeing an animated line drawing, gradually revealing a delicate take on a familiar system: the internal structures of the human body. But this movie doesn’t capture the work of a talented sketch artist. It was created using the first 3D, full-body imaging device using positron emission tomography (PET).
The device is called an EXPLORER (EXtreme Performance LOng axial REsearch scanneR) total-body PET scanner. By pairing this scanner with an advanced method for reconstructing images from vast quantities of data, the researchers can make movies.
For this movie in particular, the researchers injected small amounts of a short-lived radioactive tracer—an essential component of all PET scans—into the lower leg of a study volunteer. They then sat back as the scanner captured images of the tracer moving up the leg and into the body, where it enters the heart. The tracer moves through the heart’s right ventricle to the lungs, back through the left ventricle, and up to the brain. Keep watching, and, near the 30-second mark, you will see in closer focus a haunting capture of the beating heart.
This groundbreaking scanner was developed and tested by Jinyi Qi, Simon Cherry, Ramsey Badawi, and their colleagues at the University of California, Davis [1]. As the NIH-funded researchers reported recently in Proceedings of the National Academy of Sciences, their new scanner can capture dynamic changes in the body that take place in a tenth of a second [2]. That’s faster than the blink of an eye!
This movie is composed of frames captured at 0.1-second intervals. It highlights a feature that makes this scanner so unique: its ability to visualize the whole body at once. Other medical imaging methods, including MRI, CT, and traditional PET scans, can be used to capture beautiful images of the heart or the brain, for example. But they can’t show what’s happening in the heart and brain at the same time.
The ability to capture the dynamics of radioactive tracers in multiple organs at once opens a new window into human biology. For example, the EXPLORER system makes it possible to measure inflammation that occurs in many parts of the body after a heart attack, as well as to study interactions between the brain and gut in Parkinson’s disease and other disorders.
EXPLORER also offers other advantages. It’s extra sensitive, which enables it to capture images other scanners would miss—and with a lower dose of radiation. It’s also much faster than a regular PET scanner, making it especially useful for imaging wiggly kids. And it expands the realm of research possibilities for PET imaging studies. For instance, researchers might repeatedly image a person with arthritis over time to observe changes that may be related to treatments or exercise.
Currently, the UC Davis team is working with colleagues at the University of California, San Francisco to use EXPLORER to enhance our understanding of HIV infection. Their preliminary findings show that the scanner makes it easier to capture where the human immunodeficiency virus (HIV), the cause of AIDS, is lurking in the body by picking up on signals too weak to be seen on traditional PET scans.
While the research potential for this scanner is clearly vast, it also holds promise for clinical use. In fact, a commercial version of the scanner, called uEXPLORER, has been approved by the FDA and is in use at UC Davis [3]. The researchers have found that its improved sensitivity makes it much easier to detect cancers in patients who are obese and, therefore, harder to image well using traditional PET scanners.
As soon as the COVID-19 outbreak subsides enough to allow clinical research to resume, the researchers say they’ll begin recruiting patients with cancer into a clinical study designed to compare traditional PET and EXPLORER scans directly.
As these researchers, and other researchers around the world, begin to put this new scanner to use, we can look forward to seeing many more remarkable movies like this one. Imagine what they will reveal!
References:
[1] First human imaging studies with the EXPLORER total-body PET scanner. Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, Ding Y, Spencer BA, Nardo L, Liu W, Bao J, Jones T, Li H, Cherry SR. J Nucl Med. 2019 Mar;60(3):299-303.
[2] Subsecond total-body imaging using ultrasensitive positron emission tomography. Zhang X, Cherry SR, Xie Z, Shi H, Badawi RD, Qi J. Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2265-2267.
[3] “United Imaging Healthcare uEXPLORER Total-body Scanner Cleared by FDA, Available in U.S. Early 2019.” Cision PR Newswire. January 22, 2019.
Links:
Positron Emission Tomography (PET) (NIH Clinical Center)
EXPLORER Total-Body PET Scanner (University of California, Davis)
Cherry Lab (UC Davis)
Badawi Lab (UC Davis Medical Center, Sacramento)
NIH Support: National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; Common Fund
Why When You Eat Might Be as Important as What You Eat
Posted on by Dr. Francis Collins
About 1 in 3 American adults have metabolic syndrome, a group of early warning signs for increased risk of type 2 diabetes, heart disease, and stroke. To help avoid such health problems, these folks are often advised to pay close attention to the amount and type of foods they eat. And now it seems there may be something else to watch: how food intake is spaced over a 24-hour period.
In a three-month pilot study, NIH-funded researchers found that when individuals with metabolic syndrome consumed all of their usual daily diet within 10 hours—rather than a more customary span of about 14 hours—their early warning signs improved. Not only was a longer stretch of daily fasting associated with moderate weight loss, in some cases, it was also tied to lower blood pressure, lower blood glucose levels, and other improvements in metabolic syndrome.
The study, published in Cell Metabolism, is the result of a joint effort by Satchidananda Panda, Salk Institute for Biological Sciences, La Jolla, CA, and Pam R. Taub, University of California, San Diego [1]. It was inspired by Panda’s earlier mouse studies involving an emerging dietary intervention, called time-restricted eating (TRE), which attempts to establish a consistent daily cycle of feeding and fasting to create more stable rhythms for the body’s own biological clock [2, 3].
But would observations in mice hold true for humans? To find out, Panda joined forces with Taub, a cardiologist and physician-scientist. The researchers enlisted 19 men and women with metabolic syndrome, defined as having three or more of five specific risk factors: high fasting blood glucose, high blood pressure, high triglyceride levels, low “good” cholesterol, and/or extra abdominal fat. Most participants were obese and taking at least one medication to help manage their metabolic risk factors.
In the study, participants followed one rule: eat anything that you want, just do so over a 10-hour period of your own choosing. So, for the next three months, these folks logged their eating times and tracked their sleep using a special phone app created by the research team. They also wore activity and glucose monitors.
By the pilot study’s end, participants following the 10-hour limitation had lost on average 3 percent of their weight and about 3 percent of their abdominal fat. They also lowered their cholesterol and blood pressure. Although this study did not find 10-hour TRE significantly reduced blood glucose levels in all participants, those with elevated fasting blood glucose did have improvement. In addition, participants reported other lifestyle improvements, including better sleep.
The participants generally saw their metabolic health improve without skipping meals. Most chose to delay breakfast, waiting about two hours after they got up in the morning. They also ate dinner earlier, about three hours before going to bed—and then did no late night snacking.
After the study, more than two-thirds reported that they stuck with the 10-hour eating plan at least part-time for up to a year. Some participants were able to cut back or stop taking cholesterol and/or blood-pressure-lowering medications.
Following up on the findings of this small study, Taub will launch a larger NIH-supported clinical trial involving 100 people with metabolic syndrome. Panda is now exploring in greater detail the underlying biology of the metabolic benefits observed in the mice following TRE.
For people looking to improve their metabolic health, it’s a good idea to consult with a doctor before making significant changes to one’s eating habits. But the initial data from this study indicate that, in addition to exercising and limiting portion size, it might also pay to watch the clock.
References:
[1] Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, Wang X, Fleisher JG, Panda S, Taub PR. Cell Metab. 2019 Jan 7; 31: 1-13. Epub 2019 Dec 5.
[2] Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Cell Metab. 2012 Jun 6;15(6):848-60.
[3] Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Chaix A, Zarrinpar A, Miu P, Panda S. Cell Metab. 2014 Dec 2;20(6):991-1005.
Links:
Metabolic Syndrome (National Heart, Lung, and Blood Institute/NIH)
Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Body Weight Planner (NIDDK/NIH)
Satchidananda Panda (Salk Institute for Biological Sciences, La Jolla, CA)
Taub Research Group (University of California, San Diego)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
Connecting Senescent Cells to Obesity and Anxiety
Posted on by Dr. Francis Collins
Obesity—which affects about 4 in 10 U.S. adults—increases the risk for lots of human health problems: diabetes, heart disease, certain cancers, and even anxiety and depression [1]. It’s also been associated with increased accumulation of senescent cells, which are older cells that resist death even as they lose the ability to grow and divide.
Now, NIH-funded researchers have found that when lean mice are fed a high-fat diet that makes them obese, they also have more senescent cells in their brain and show more anxious behaviors [2]. The researchers could reduce this obesity-driven anxiety using so-called senolytic drugs that cleared away the senescent cells. These findings are among the first to provide proof-of-concept that senolytics may offer a new avenue for treating an array of neuropsychiatric disorders, in addition to many other chronic conditions.
As we age, senescent cells accumulate in many parts of the body [3]. But cells can also enter a senescent state at any point in life in response to major stresses, such as DNA damage or chronic infection. Studies suggest that having lots of senescent cells around, especially later in life, is associated with a wide variety of chronic conditions, including osteoporosis, osteoarthritis, vascular disease, and general frailty.
Senescent cells display a “zombie”-like behavior known as a senescence-associated secretory phenotype (SASP). In this death-defying, zombie-like state, the cells ramp up their release of proteins, bioactive lipids, DNA, and other factors that, like a zombie virus, induce nearby healthy cells to join in the dysfunction.
In fact, the team behind this latest study, led by James Kirkland, Mayo Clinic, Rochester, MN, recently showed that transplanting small numbers of senescent cells into young mice is enough to cause them weakness, frailty, and persistent health problems. Those ill effects were alleviated with a senolytic cocktail, including dasatinib (a leukemia drug) and quercetin (a plant compound). This drug cocktail overrode the zombie-like SASP phenotype and forced the senescent cells to undergo programmed cell death and finally die.
Previous research indicates that senescent cells also accumulate in obesity, and not just in adipose tissues. Moreover, recent studies have linked senescent cells in the brain to neurodegenerative conditions, including Alzheimer’s disease, and showed in mice that dasatinib and quercetin helps to alleviate neurodegenerative disease [4,5]. In the latest paper, published in the journal Cell Metabolism, Kirkland and colleagues asked whether senescent cells in the brain also could explain anxiety-like behavior in obesity.
The answer appears to be “yes.” The researchers showed that lean mice, if allowed to feast on a high-fat diet, grew obese and became more anxious about exploring open spaces and elevated mazes.
The researchers also found that the obese mice had an increase in senescent cells in the white matter near the lateral ventricle, a part of the brain that offers a pathway for cerebrospinal fluid. Those senescent cells also contained an excessive amount of fat. Could senolytic drugs clear those cells and make the obesity-related anxiety go away?
To find out, the researchers treated lean and obese mice with a senolytic drug for 10 weeks. The treatment didn’t lead to any changes in body weight. But, as senescent cells were cleared from their brains, the obese mice showed a significant reduction in their anxiety-related behavior. They lost their anxiety without losing the weight!
More preclinical study is needed to understand more precisely how the treatment works. But, it’s worth noting that clinical trials testing a variety of senolytic drugs are already underway for many conditions associated with senescent cells, including chronic kidney disease [6,7], frailty [8], and premature aging associated with bone marrow transplant [9].
As a matter of fact, just after the Cell Metabolism paper came out, Kirkland’s team published encouraging though preliminary, first-in-human results of the previously mentioned senolytic drug dasatinib in 14 people with age-related idiopathic pulmonary fibrosis, a condition in which lung tissue becomes damaged and scarred [10]. Caution is warranted as we learn more about the associated risks and benefits, but it’s safe to say we’ll be hearing a lot more about senolytics in the years ahead.
References:
[1] Adult obesity facts (Centers for Disease Control and Prevention)
[2] Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Ogrodnik M et al. Cell Metabolism. 2019 Jan 3.
[3] Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. Tchkonia T, Kirkland JL. JAMA. 2018 Oct 2;320(13):1319-1320.
[4] Tau protein aggregation is associated with cellular senescence in the brain. Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Aging Cell. 2018 Dec;17(6):e12840.
[5] Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Nature. 2018 Oct;562(7728):578-582.
[6] Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease. ClinicalTrials.gov, Sep 2018.
[7] Senescence in Chronic Kidney Disease. Clinicaltrials.gov, Sep 2018.
[8] Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (AFFIRM-LITE). Clinicaltrials.gov, Dec 2018.
[9] Hematopoietic Stem Cell Transplant Survivors Study (HTSS Study). Clinicaltrials.gov, Sep 2018.
[10] Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. Justice JN, Nambiar AN, Tchkonia T, LeBrasseur K, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. EBioMed. 5 Jan. 2019. [Epub ahead of print]
Links:
Healthy Aging (National Institute on Aging/NIH)
Video: Vail Scientific Summit James Kirkland Interview (Youtube)
James Kirkland (Mayo Clinic, Rochester, MN)
NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke
Using Frogs to Tackle Kidney Problems
Posted on by Dr. Francis Collins
Many human cells are adorned with hair-like projections called cilia. Scientists now realize that these specialized structures play many important roles throughout the body, including directing or sensing various signals such as fluid flow. Their improper function has been linked to a wide range of health conditions, such as kidney disease, scoliosis, and obesity.
Studying cilia in people can be pretty challenging. It’s less tricky in a commonly used model organism: Xenopus laevis, or the African clawed frog. This image highlights a healthy patch of motile cilia (yellow) on embryonic skin cells (red) of Xenopus laevis. The cilia found in humans and all other vertebrates are built from essentially the same elongated structures known as microtubules. That’s why researchers can learn a lot about human cilia by studying frogs.
Poor Sleep Habits in Adolescence Correlated with Cardiovascular Risk
Posted on by Dr. Francis Collins
Thinkstock/pixelheadphoto
Just ask any parent or teacher, most of today’s teens and pre-teens don’t seem to get enough sleep. And what sleep they do get is often poor quality—no great surprise, given that smartphones and other electronic devices are usually never far from their reach. Now, an NIH-funded team has uncovered the strongest evidence yet that this lack of quality sleep may be setting our kids up for some serious health issues later in life.
The team’s study of more than 800 adolescents, ages 11 through 13, confirmed that many are getting an insufficient amount of undisturbed, restful sleep each night. While earlier studies had found a link between sleep duration and obesity [1], the new work shows that a wide range of other cardiovascular risk factors are affected by both too little sleep and poor sleep quality [2]. When compared to well-rested kids, sleep-deprived youth were found to have higher blood pressure, bigger waistlines, and lower levels of high density lipoprotein (HDL) cholesterol, which is associated with lower risk of cardiovascular disease.
Does Gastric Bypass Reduce Cardiovascular Complications of Diabetes?
Posted on by Dr. Francis Collins
Thinkstock/IPGGutenbergUKLtd
For obese people with diabetes, doctors have increasingly been offering gastric bypass surgery as a way to lose weight and control blood glucose levels. Short-term results are often impressive, but questions have remained about the long-term benefits of such operations. Now, a large, international study has some answers.
Soon after gastric bypass surgery, about 50 percent of folks not only lost weight but they also showed well-controlled blood glucose, cholesterol, and blood pressure. The good news is that five years later about half of those who originally showed those broad benefits of surgery maintained that healthy profile. The not-so-good news is that the other half, while they generally continued to sustain weight loss and better glucose control, began to show signs of increasing risk for cardiovascular complications.
Unraveling the Biocircuitry of Obesity
Posted on by Dr. Francis Collins
Caption: Mouse neurons (purple), with their nuclei (blue) and primary cilia (green).
Credit: Yi Wang, Vaisse Lab, UCSF
Obesity involves the complex interplay of diet, lifestyle, genetics, and even the bacteria living in the gut. But there are other less-appreciated factors that are likely involved, and a new NIH-supported study suggests one that you probably never would have imagined: antenna-like sensory projections on brain cells.
The study in mice, published in the journal Nature Genetics [1], suggests these neuronal projections, called primary cilia, are a key part of a known “hunger circuit,” which receives signals from other parts of the body to control appetite. The researchers add important evidence in mouse studies showing that changes in the primary cilia can produce a short circuit, impairing the brain’s ability to regulate appetite and leading to overeating and obesity.
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