Category Archives: Uncategorized

Zika virus in Brazil may be mutated strain

Zika-462x326The mosquito-borne Zika virus has been linked to a surge in cases of birth defects in Brazil, and is spreading in other countries in the southern hemisphere. Flaminia Catteruccia, associate professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health, says the virus may have adapted to the human environment and mutated.

What do we know about the Zika virus?

Zika is very similar to other viruses that are transmitted by the Aedes mosquitoes, including dengue and chikungunya. It was first discovered in 1947 in monkeys in Africa, and there have been several outbreaks since then. But it has not been studied much because, normally, the symptoms are quite mild—fever, headaches, joint pain. People get over it in a few days.

It seems like there is something different about the virus in the current outbreak in Brazil. It has coincided with a dramatic rise in cases of microcephaly, a birth defect that results in babies born with unusually small heads. The increase in babies born with this condition has been more than 20-fold compared with previous years—from maybe 150 cases to more than 3,000 cases in a few months.

What are the major research questions around Zika?

If Zika is the causative agent behind the surge in microcephaly—and possibly also Guillain-Barré syndrome, an autoimmune disease of the nervous system now on the rise among adults in Brazil—this may demonstrate that the virus has adapted to the human environment and may have mutated to become more pathogenic to humans. A correlation between Zika and these conditions has not been confirmed, but previous studies have shown that it can be passed from mothers to babies in utero and also that it can infect the nervous system. What is worrying is that we don’t know what may have changed, and why.

There need to be genetic studies to understand the origin of this virus. It appears that there are two different strains, one originating in Africa and one from Asia. The outbreak in Brazil seems to be from the Asian strain, which may have evolved to be better at invading nerve cells or at evading the immune system.

Should pregnant women in the U.S. be concerned about Zika?

Other viruses in the same family, like dengue and chikungunya, have not proven to be a major problem in the U.S. Most of the cases of these diseases have been imported by travelers. There have only been a few cases of direct transmission of those two diseases from one person to another through a mosquito. These examples are reassuring. For Zika, it should be the same. The only warning from the Centers for Disease Control has been to advise pregnant women not to travel to affected countries. The situation here is quite different from Brazil and Colombia, where the governments recently advised women to delay getting pregnant until the summer when the outbreak is predicted to wane.

The chart below shows the sharp increase in microcephaly cases in Brazil

Zika


— Amy Roeder

To see the original article, please click here.

Targeting fat-tissue hormone may lead to type 2 diabetes treatment

cell_gokhan-feature-470x313A new study by researchers from Harvard T.H. Chan School of Public Health and colleagues describes the pre-clinical development of a therapeutic that could potentially be used to treat type 2 diabetes, fatty liver disease, and other metabolic diseases. The researchers developed an antibody that improves glucose regulation and reduces fatty liver in obese mice by targeting a hormone in adipose (fat) tissue called aP2 (also known as FABP4).

The study was published online December 23, 2015 in Science Translational Medicine.

“The importance of this study is two-fold: first, demonstrating the importance of aP2 as a critical hormone in abnormal glucose metabolism, and secondly, showing that aP2 can be effectively targeted to treat diabetes and potentially other immunometabolic diseases,” said Gökhan S. Hotamisligil, J.S. Simmons Professor of Genetics and Metabolism and chair of the Department of Genetics and Complex Diseases and the Sabri Ülker Center at Harvard Chan School.

The work is the product of a collaboration on immunometabolism between the biopharmaceutical company UCB and a team of researchers led by Hotamisligil and lead author M. Furkan Burak, a former Hotamisligil lab member and currently a resident in internal medicine at Mount Auburn Hospital, Cambridge, MA. Coordinated by Harvard’s Office of Technology Development (OTD), the collaboration successfully twins UCB’s world-class expertise in monoclonal antibody discovery with Hotamisligil’s insight and experience in aP2 biology.

The increase in adipose tissue characteristic of obesity has long been linked to increased risk for metabolic diseases such as type 2 diabetes and cardiovascular disease. Recently, it has become clear that the tissue itself plays an active role in metabolic disease, in part by releasing hormones which act in distant sites such as the liver, muscle, and brain that affect systemic metabolism. Work from the Hotamisligil lab previously identified the protein aP2 as a critical hormone mediating communication between adipose tissue and liver. Since aP2 levels are significantly increased in humans with obesity, diabetes, and atherosclerosis, and mutations that reduce aP2 result in significantly reduced risk of diabetes, dyslipidemia, and heart disease, strategies to modify aP2 function carry promise as new lines of therapeutic entities against these common and debilitating chronic diseases.

In the new study, Burak and colleagues describe the development and evaluation of novel monoclonal antibodies targeting aP2. The team found that one of these antibodies effectively improved glucose regulation in two independent models of obesity. Additionally, beneficial reductions in liver fat were observed.

These monoclonal antibodies have the potential to be transformative first-in-class therapeutics to fight obesity-related metabolic and immunometabolic disease, say the authors. This work is still at the preclinical stage and will require extensive evaluation for safety and effectiveness before being considered for use in humans.

Other Harvard Chan School authors included Karen Inouye, Ariel White, Alexandra Lee, Gurol Tuncman, Ediz Calay, Motohiro Sekiya, Amir Tirosh, and Kosei Eguchi.

The study was supported by a sponsored research agreement to Hotamisligil, and Harvard OTD has licensed the technology described in this study to UCB.

“Development of a therapeutic monoclonal antibody that targets secreted fatty acid binding protein aP2 to treat type 2 diabetes,” M. Furkan Burak, Karen E. Inouye, Ariel White, Alexandra Lee, Gurol Tuncman, Ediz S. Calay, Motohiro Sekiya, Amir Tirosh, Kosei Eguchi, Gabriel Birrane, Daniel Lightwood, Louise Howells, Geofrey Odede, Hanna Hailu, Shauna West, Rachel Garlish, Helen Neale, Carl Doyle, Adrian Moore, Gökhan S. Hotamisligil, Science Translational Medicine, online December 23, 2015.

For more information:
Kathryn Claiborn
claiborn@hsph.harvard.edu
617-432-3061

To see the original article please click here.

In pursuit of an elusive foe

Sarah-Fortune-lab-2The bacteria that cause tuberculosis are experts at survival, allowing the disease to persist even when faced with the immune system and drugs. Harvard T.H. Chan School of Public Health’s Sarah Fortune is on a mission to figure out why.

Of all the health problems that dominate our thoughts and anxieties, tuberculosis (TB) probably ranks low on the list. But as infectious diseases go, it is a major global threat. Tuberculosis is among the top 15 causes of death worldwide, and it is estimated that a third of the world’s population is carrying the culprit bacterium, Mycobacterium tuberculosis (Mtb).

“Those global numbers reflect a lot of complexity, some of which is the co-epidemic with HIV/AIDS, which has just been catastrophic,” explains Sarah Fortune, Professor of Immunology and Infectious Diseases at the Harvard Chan School and a leader in TB research. “But that explanation is also too simplistic, and neglects the fact that TB just does not conform to our understanding of infection and cure in the way that many other infectious diseases do.”

Sarah Fortune lab-2

Members of the Fortune lab, from left: Thibault Barbier, Alex Sakatos, Sarah Fortune, and Jacob Fohtung.

Fortune heads up a group that is exploring the complexities of TB. In a bustling laboratory on the eighth floor of the Chan School’s Building 1, her team of 14 graduate students and postdoctoral fellows works across the spectrum of modern science. The group wields the latest imaging equipment to visualize microbes; employs advanced genomic methods, such as high-throughput DNA sequencing, to trace individual bacterial cells using their genetic material; and uses powerful informatics to wade through an ever-increasing amount of data.

A microbial black sheep

With most infectious diseases, there are two opposing outcomes: A person gets infected and eventually recovers, ridding the body of the pathogen and developing immunity to future infection. Or, the infection proves too challenging to overcome — with or without treatment — and the person succumbs.

Yet in TB, the relationship between microbe and man is much more complicated. People become infected and their immune system kicks into high gear. Yet these natural defenses, while designed for microbial annihilation, also inadvertently lead to the propagation of disease. Despite the body’s well-honed ability to kill millions and millions of bacteria, invariably a few are left standing — which means that those who are infected with Mtb remain infected.

“You have this giant pool of people who are carrying the organism and are at risk of developing active disease — getting sick — and transmitting it to others,” says Fortune. That pool significantly hinders efforts to control TB for two reasons. Currently, it is difficult to identify those who have latent disease. It is also difficult to predict which patients with latent disease will go on to develop an active infection, posing risks not only for individual patients but also for those around them who can contract the disease. In addition to these clinical challenges, there are equally significant challenges in the laboratory. “A lot of our fundamental understanding of TB comes out of studies of the 19th and early 20th century, and frankly, a lot of our assumptions about what the disease looks like are wrong. And we are only beginning to understand that now,” she acknowledges.

TB hits home

Fortune understands well the devastation that can be wrought by TB. As a medical student at Columbia University in the early 1990s, she found herself at the epicenter of a major outbreak of multi-drug resistant TB (MDR-TB) that spread across New York City and poured into the region’s hospitals — infecting and even killing several healthcare workers. The severity of that outbreak was on par with what is often now seen in parts of the developing world. “The reality of global TB was playing out right in front of our eyes, right in our own neighborhood,” she recalls.

Sarah Fortune-portraitWithin that crucible, Fortune’s future professional path was forged. Coinciding with the MDR-TB crisis in New York, the country was also grappling with the emergence and explosion of HIV, the virus that causes AIDS. As she pondered a direction for her research career, Fortune noticed a surge of interest in HIV, but relatively few laboratories dedicated to TB. “It struck me that more people needed to work on TB, so that was what I was going to do.”

Now, some two decades later, her Chan School laboratory is harnessing state-of-the-art tools and uniting scientists from various disciplines to tackle TB. One of the keys to controlling the disease on a global scale, she believes, lies in understanding why Mtb is such a good survivor, both in the face of the immune response and in the face of drugs, which also fail to fully quash the bacteria. Her team focuses on these two facets of the disease by exploring a singular question: What is it about the Mtb population that allows a few cells to survive?

Bacteria as individuals

The prevailing idea is that, as a group, Mtb cells are not homogeneous. While most cells in a population are susceptible to killing by the immune system or by drugs, there are a few specialized “survivors” that constitute the group’s contingency plan — the “go to” cells when the going gets tough, as it does when the immune system flares or when drugs flow. Fortune believes that these rare, specialized cells are why TB treatments are so protracted — a 6-month course of antibiotics is needed to treat the disease — and also why it has been so difficult to develop an effective TB vaccine.

To strike at the heart of these problems, Fortune’s laboratory seeks to understand how the TB contingency cells form in the first place. Biologically speaking, there are a few possibilities. The cells could vary genetically, through changes to their DNA. They could also differ as a result of variations in their epigenome, a chemical code embedded within DNA that determines when and where certain genes get switched on or off. And finally, they could be programmed through molecular differences set in motion by a key group of regulators called transcription factors.

This notion of bacterial individuality signifies a stark departure from the picture of Mtb that was commonly held as recently as a decade ago. Imagine a caveman, Fortune says: “I’m going to hunker down, I’m not going to do very much, and that is how I am going to survive.” The idea made some sense at the time because Mtb is coated with an unusually tough outer shell made of wax — a kind of molecular bomb shelter that can protect against the threat of the immune system and drugs.

But Fortune and her team are learning that these presumed do-nothing microbes are in fact much more sophisticated than once thought, and that some of the bacteria adopt unique roles. Unlike most cohabitating bacteria, which each perform the same functions for individual gain, Mtb can adopt distinct roles in service of the entire group — making them more like a colony of bees than a colony of bacteria.

A lesson in geometry

Fortune’s team has made significant strides in the past few years in figuring out how Mtb variability arises, particularly as it relates to the response to drugs. This work not only has major clinical implications — understanding why some bacteria are susceptible to drugs and others are not could improve patient care — but it also relies on a time-tested approach in the laboratory: growing Mtb in the presence (or absence) of different drugs. While these studies may be conceptually straightforward, what they are revealing is striking. Fortune and her colleagues have discovered that differences in drug response stem from the way in which the bacteria reproduce.

Mtb is rod-shaped and looks rather like a miniature cucumber. Most bacteria of this shape grow simply by elongating — like a slinky that gets stretched from both ends and then snipped in the middle — to give rise to two, virtually identical “daughter” cells. But Mtb takes a different approach. The mother cell grows asymmetrically, by extruding one if its cucumber-like ends, and then divides at its center. That leaves one daughter cell with mostly new contents (corresponding to growing end) and the other with the lion’s share of the old stuff.

This dichotomy between old and new turns out to have important biological implications, resulting in physiological differences between what can get in and out of the cells, and how fast they grow — processes that are exquisitely sensitive to antibiotics. For example, the Mtb daughter that inherits the brand new cell wall is more susceptible to certain types of antibiotics than her hand-me-down clad sister.

“It’s a very simple geometric solution that creates a huge amount of variation in the individual cells in a population,” says Fortune. This elegant approach is not unique to TB — mammalian cells, particularly stem cells and cancer cells, also use asymmetric division to generate cellular diversity.

A solvable problem

Now, Fortune is moving on from studies of drug resistance to address the thorny question of how variability in Mtb growth enables the bacterium to survive the human immune response. Two critical elements are making this work possible: technology and collaboration.

To study bacterial individuality, researchers need to study individuals — that is, single cells. Thanks to advances in genomics and single-cell technologies, it is now feasible to mark each bacterium with a unique bar code and then follow the fate of each cell. Fortune and her colleagues are leveraging these capabilities to study Mtb infection in animal models. Such in vivo studies are incredibly complicated — “more complex by orders and orders of magnitude,” says Fortune — than their previous work.

Although these studies are challenging, the potential payoff is huge: The findings promise to open a window on the biological factors that allow a select few Mtb cells to dodge the immune system. During Mtb infection, the bacteria take up residence inside immune cells called macrophages, typically the first line of defense against microbial invaders. While most macrophages can kill their unwelcome guests, some cannot. The question is, why? Does the fault lie with the macrophage or with the bacterium? Or is it the bacterium-macrophage combination? With the ability to capture and analyze single cells, both bacterial and immune cells, Fortune is now exploring these very questions.

The outcomes will not only inform our biological understanding of TB, but could also propel the development of a vaccine — a holy grail of modern TB research. “All of the epidemiological models suggest that the way the global TB epidemic is going to be stopped is through an effective vaccine,” explains Fortune.

While there is a long-standing vaccine against TB, known as bacille Calmette-Guerin or BCG, its impact on disease spread is minimal. The most commonly administered vaccine worldwide, BCG mainly protects babies and young children from a form of TB that affects the central nervous system (known as TB meningitis) — but it is not effective against pulmonary TB, the transmissible form of the disease. Unfortunately, innovation in this area has not yet met with success. The results of a large clinical trial of a new TB vaccine, published in early 2013, proved deeply disappointing, showing no greater protection from TB than that offered by BCG. It was the first new candidate TB vaccine in 90 years.

Despite these and other challenges, Fortune remains undeterred — and optimistic. She acknowledges that the recent missteps in TB vaccine development only underscore how much we have yet to learn about TB and its culprit bacteria before a potent vaccine can be engineered.

While gaining that knowledge is a formidable challenge, it is not insurmountable. “We have the ability to conquer TB. It is a biologically solvable problem,” she says.

Nicole Davis

photos: Emily Cuccarese

To see the original article please click here.

Sarah Merritt Fortune promoted to Tenured Professor

Sarah_Fortune-copy1BPH faculty member, Sarah Merritt Fortune, has been promoted to Professor of Immunology and Infectious Diseases in the Department of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health.

Spanning the field from molecules to populations, Dr. Fortune’s research has focused on Mycobacterium tuberculosis (Mtb) using novel genetic tools and new technologies to study the related biological problems. Rather than focusing on a single approach, her research has touched on a variety of sub-fields, and, in each case, she has made a substantial impact often changing thinking in each area. Using a combination of single cell, genetic, and genomic approaches, Dr. Fortune seeks to understand why there is successful immune clearance within infected individuals and why, in some cases, sterilization is incomplete.

Dr. Fortune strives to build a broad understanding of the global epidemic of tuberculosis (TB) and foster multidisciplinary discussion of solutions. She is the Director of the TB Research Program at the Ragon Institute of MGH, MIT, and Harvard, Co-Director of the Harvard University Center for AIDS Research (CFAR) Developmental Core, and Associate Member of the Broad Institute. Dr. Fortune is the Co-Director of the National HIV-TB Working Group for the Centers for AIDS Research and is the Co-organizer of the 2016 Keystone Symposium, TB and Associated Co-morbidities. She is a member of the Gates Foundation TB Vaccine Portfolio Management Working Group and its Collaboration for TB Vaccine Discovery. Dr. Fortune is also the Associate Editor for Science Advances, an open access journal for high quality and important research articles from American Association for the Advancement of Science (AAAS) publishing.

In 1996, Dr. Fortune completed her MD at the Columbia University College of Physicians & Surgeons followed by an internship and residency in Internal Medicine at Brigham and Women’s Hospital. In 2001 she pursued a clinical fellowship in the Division of Infectious Diseases at Brigham and Women’s Hospital and Massachusetts General Hospital. Dr. Fortune completed a postdoctoral research fellowship in the Department of Immunology and Infectious Diseases at the School in 2006, and that same year she joined the faculty as Assistant Professor in the Department of Immunology and Infectious Diseases. In 2012 she was promoted to Melvin J. and Geraldine L. Glimcher Associate Professor of Biological Sciences. Dr. Fortune was honored by the School’s Committee on the Concerns of Women Faculty in 2013 with the Alice B. Hamilton Award, which recognizes the path-breaking achievements of a promising young woman investigator in public health.

Congratulations Dr. Fortune!

Chemicals linked with severe respiratory disease found in common e-cigarette flavors

Ecigs-655x436-2-470x313Diacetyl, a flavoring chemical linked to cases of severe respiratory disease, was found in more than 75% of flavored electronic cigarettes and refill liquids tested by researchers at Harvard T.H. Chan School of Public Health. Two other potentially harmful related compounds were also found in many of the tested flavors, which included varieties with potential appeal to young people such as Cotton Candy, Fruit Squirts, and Cupcake.

The study will be published online December 8, 2015 in Environmental Health Perspectives and will be available here after the embargo lifts: http://ehp.niehs.nih.gov/15-10185.

The Occupational Safety and Health Administration and the flavoring industry have warned workers about diacetyl because of the association between inhaling this chemical and the debilitating respiratory disease bronchiolitis obliterans, colloquially termed “Popcorn Lung” because it first appeared in workers who inhaled artificial butter flavor in microwave popcorn processing facilities.

“Recognition of the hazards associated with inhaling flavoring chemicals started with ‘Popcorn Lung’ over a decade ago. However, diacetyl and other related flavoring chemicals are used in many other flavors beyond butter-flavored popcorn, including fruit flavors, alcohol flavors, and, we learned in our study, candy flavored e-cigarettes,” said lead author Joseph Allen, assistant professor of exposure assessment science.

There are currently more than 7,000 varieties of flavored e-cigarettes and e-juice (liquid containing nicotine that is used in refillable devices) on the market. Although the popularity and use of e-cigarettes continues to increase, there is a lack of data on their potential health effects. E-cigarettes are not currently regulated, but the U.S. Food and Drug Administration (FDA) has issued a proposed rule to include e-cigarettes under its authority to regulate certain tobacco and nicotine-containing products.

Allen and colleagues tested 51 types of flavored e-cigarettes and liquids sold by leading brands for the presence of diacetyl, acetoin, and 2,3-pentanedione, two related flavoring compounds that are listed as “high priority,” i.e. they may pose a respiratory hazard in the workplace, by the Flavor and Extract Manufacturers Association. Each e-cigarette was inserted into a sealed chamber attached to a lab-built device that drew air through the e-cigarette for eight seconds at a time with a resting period of 15 or 30 second between each draw. The air stream was then analyzed.

At least one of the three chemicals was detected in 47 of the 51 flavors tested. Diacetyl was detected above the laboratory limit of detection in 39 of the flavors tested. Acetoin and 2,3-pentanedione were detected in 46 and 23 and of the flavors, respectively.

“Since most of the health concerns about e-cigarettes have focused on nicotine, there is still much we do not know about e-cigarettes. In addition to containing varying levels of the addictive substance nicotine, they also contain other cancer-causing chemicals, such as formaldehyde, and as our study shows, flavoring chemicals that can cause lung damage,” said study co-author David Christiani, Elkan Blout Professor of Environmental Genetics.

Other Harvard Chan School authors included, Skye Flanigan, Mallory LeBlanc, Jose Vallarino, Piers MacNaughton, and James Stewart.

This study was supported by NIH/NIEHS Center Grant P30ES000002.

“Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3-Pentanedione, and Acetoin in a Sample of 51 1 Products, Including Fruit-, Candy-, and Cocktail-Flavored E-Cigarettes,” Joseph G. Allen, Skye S. Flanigan, Mallory LeBlanc, Jose Vallarino, Piers MacNaughton, James H. Stewart, David C. Christiani, Environmental Health Perspectives, December 8, 2015, doi: 10.1289/ehp.1510185

 

Symposium gathers experts on oxidative stress and mitochondria

JBL_Yuan-Little-Hunter-470x290

JBL Center Director Zhi-Min Yuan, Professor Emeritus John B. Little, Acting Dean David Hunter

Cutting-edge work on molecular mechanisms involved in the cellular response to stress was the focus at the 18th annual John B. Little Symposium, held October 23-24, 2015 at Harvard T.H. Chan School of Public Health.

The symposium is hosted each year by the John B. Little (JBL) Center for Radiation Sciences. Both the symposium and the center are named for John B. Little, James Steven Simmons Professor of Radiobiology Emeritus, one of the first scholars to characterize problems in public health associated with radiation exposure.

Attendees packed the School’s Snyder auditorium to hear experts in the field discuss topics related to oxidative stress, which is caused by high levels of chemically reactive molecules containing oxygen (called reactive oxygen species, or ROS). Oxidative stress can cause damage to DNA, protein, and lipids, leading to myriad pathologies such as type 2 diabetes, Alzheimer’s disease, atherosclerosis, and cancer. Some speakers focused on mitochondria, the cell components that convert food and oxygen into energy and power metabolic activities. Mitochondria also generate ROS, and may overproduce it if their function is deregulated.

Work in this area provides important evidence toward advancing the JBL Center’s research mission in radiation sciences, said Director Zhi-Min Yuan, professor of radiobiology. One of the ways that oxidative stress is induced is through ionizing radiation from environmental sources or medical procedures such as CT scans. Elucidating this process will help researchers understand mechanisms underlying the cellular response to ionizing radiation and how the biological system adapts, he said.

Tobias Walther

Tobias Walther, professor of genetics and complex diseases

Tobias Walther, professor of genetics and complex diseases

In his opening remarks, Acting Dean David Hunter observed that some attendees may be wondering why this event was being held at a school of public health. A quarter of the School’s faculty identifies as laboratory scientists, Hunter said, and the School has “a deep commitment to analyzing problems from the cell level to the community level.”

Hunter and other speakers acknowledged the support that the Morningside Foundation, established by the family of the late T. H. Chan, has provided to the JBL Center and the symposium. The foundation also supported the establishment in 2012 of the Morningside Professorship in Radiobiology, in honor of Little. Gerald Chan, SM ’75, SD ’79, director of the foundation, was a student of Little’s.

Presenting during the symposium’s opening session, Tobias Walther, professor of genetics and complex diseases, discussed new advances in understanding the complex biology of lipid droplets—organelles that store energy for cells and interact with mitochondria. Walther’s research partner Robert Farese, professor of genetics and complex diseases, moderated the session, which also included Amy Wagers of Harvard Medical School. She described her lab’s work identifying a protein that seems to reverse age-related muscle mass decline in mice. Read more about Walther and Farese’s work.

Harvard Chan School faculty members Bernardo Lemos, assistant professor of environmental epigenetics, and James Mitchell, associate professor of genetics and complex diseases, also led sessions.

— Amy Roeder

Photos: Emily Cuccarese

To see the original article, please click here.

Dissecting the power of a historic malaria vaccine

Mosquito_cross-release-470x290An international team unravels the genetic basis for the protective effects of the RTS,S malaria vaccine — the first candidate vaccine to win approval by European health officials.

 

Last month, the public health community marked one of the most significant biomedical milestones in the fight against malaria in nearly half a century: European regulators authorized the world’s most advanced malaria vaccine candidate — more than three decades in the making — and paved the way for subsequent review by the World Health Organization. Now, as this historic vaccine, known as RTS,S/AS01 (RTS,S), prepares for its next major step, critical new insights into how it fends off malaria are coming to light.

In a technological tour de force, an international research team has harnessed sophisticated molecular tools and analysis methods to probe the underlying biology of RTS,S, helping to explain how it protects against a disease that kills roughly half a million people each year, mostly infants and young children in Africa. The work, led by the Harvard T. H. Chan School of Public Health, the Broad Institute, the Fred Hutchinson Cancer Research Center, the University of Washington, and other leading institutions, was published online October 21, 2015 in the The New England Journal of Medicine. Read the article.

“Through this broad, multinational collaboration, we have brought the power of genomic tools to bear on a disease that poses one of the most significant threats to global public health,” said senior author Dyann Wirth, the Richard Pearson Strong Professor of Infectious Diseases and chair of the Department of Immunology and Infectious Diseases at the Harvard T. H. Chan School of Public Health. Wirth led the NEJM study together with Peter Gilbert of the Fred Hutchinson Cancer Research Center.

Malaria is caused by the Plasmodium parasite, a single-celled organism that is transmitted to humans by mosquitoes. The disease is prevalent in tropical and sub-tropical areas, especially countries in sub-Saharan Africa, and jeopardizes the health of more than half of the world’s population. Efforts to control and hopefully eradicate this global health threat require multiple defensive measures, including effective anti-malaria drugs, insecticide-treated bed nets and other efforts aimed at insect vector control. Another key component is a robust vaccine, which can provide long-term protection against the disease.

Recognizing this need, scientists at GlaxoSmithKline (GSK) embarked on the design of RTS,S in the late 1980’s. Following its early development, GSK and PATH, an international non-profit focused on global health innovation, launched a public-private partnership to further develop the vaccine. Roughly four years ago, as RTS,S progressed through clinical testing, the data revealed a sobering reality: The vaccine was effective in young children, but its protection was not absolute — it offered only partial protection against malaria, and that protection waned over time.

Wirth and her colleagues set out to understand the basis of this partial efficacy. They knew the vaccine was engineered to target a specific protein that sits on the surface of the parasite, called CS (short for circumsporozoite), and that CS was highly variable among parasites. They wondered if the effectiveness of RTS,S might vary according to the genetic makeup of CS, similar to the way the seasonal flu vaccine works. For example, some flu vaccines are better at fighting disease because they are more closely matched to the genes of the influenza viruses that predominate in a given year. (Unlike the flu vaccine, however, the composition of RTS,S is stable, and does not shift from year to year.)

To explore this question, the team harnessed advanced genomic technologies and statistical methods to understand how genetic variation in CS influences the vaccine’s ability to ward off malaria in young children. The work, made possible by a scientific collaboration spanning more than 15 countries and over 25 institutions, was conducted as part of a phase 3 trial of RTS,S/AS01 that ran from 2009 to 2013. The trial included 11 study sites in Africa and involved over 15,000 children.

The research team was given special access, through a collaboration with the vaccine division of the healthcare company GlaxoSmithKline, to blood samples from over 5,000 trial participants. By isolating and sequencing parasite DNA from these samples (which include samples from both vaccinated and unvaccinated children), the team was able to determine whether certain versions (or “alleles”) of CS are linked with better vaccine protection. Earlier efforts, which involved fewer patient samples and cruder methods, failed to detect such an association.

“This uniquely valuable data set posed some challenges to data analysis. The statistical team extended methods previously developed for HIV to provide interpretable answers about differential vaccine efficacy by malaria genetics,” said Peter Gilbert, director of the statistical center for the HIV Vaccine Trials Network at the Fred Hutchinson Cancer Research Center.

Through their deep survey of genetic variability in CS, the researchers made a crucial discovery: The vaccine is significantly more effective at preventing malaria in children infected with parasites that match the vaccine’s version of CS (so-called “matched” alleles) than in those who harbor mismatched parasite alleles. In the case of matched alleles, vaccine efficacy is 50% (measured over one year); with mismatched alleles, it is 33%. (The same effect was not noted in infants.) Moreover, Wirth and her colleagues found that the vaccine was most effective shortly after the final dose.

“This is the first study that was big enough and used a methodology that was sufficiently sensitive to detect this phenomenon. Now that we know that it exists, it contributes to our understanding of how RTS,S confers protection and informs future vaccine development efforts,” said Dan Neafsey, associate director of the Genomic Center for Infectious Diseases at the Broad Institute and co-first author of the NEJM paper.

The researchers’ findings also uncover fundamental aspects of the anti-malaria immunity conferred by RTS,S. These include a non-specific component that offers protection regardless of the parasite strain and a second, strain-specific component that provides additional protection if there is an identical match between the parasite’s CS and the one used in the vaccine.

“Expanding scientific knowledge and innovation is of paramount importance in global efforts to control malaria,” said Pedro Alonso, Director of the WHO Global Malaria Program. “The results of this new genomic study will give us a better understanding of how the RTS,S malaria vaccine works and how it might be improved. This, in turn, could have long-term implications for future vaccine development.”

While the NEJM study offers important insights into the RTS,S vaccine and suggests a path forward for its deployment, it also offers a model for tackling other major infectious diseases that involve highly variable vaccine targets. The approach is already being applied in HIV vaccine trials, and Wirth and her colleagues plan to apply it to future malaria vaccine trials.

Moreover, the work underscores how a full and comprehensive catalogue of the genetic diversity of key pathogens could inform the design of robust, effective vaccines. Indeed, the development of RTS,S began more than thirty years ago — when the scientific tools for probing microbial genomes where just in their infancy. Now the biomedical arsenal has advanced considerably, transformed by the growth of modern, genome-scale tools.

“The tools and methods needed to fully characterize the genomes of major pathogens are now well within our grasp,” said Wirth. “We have an unprecedented opportunity — and an obligation — to apply them in novel ways that will benefit public health across the globe.”

— Nicole Davis

To see the original article, please click here.

Brendan Manning, Xihong Lin receive prestigious NCI awards

Brendan-Manning_Xihong-Lin_518x320-470x290Two faculty members from Harvard T.H. Chan School of Public Health—Xihong Lin and Brendan Manning—will receive prestigious National Cancer Institute Outstanding Investigator Awards (OIA). These multimillion-dollar seven-year awards, providing extended funding stability, are aimed at giving promising and productive investigators enough time and money to continue or embark on projects of unusual potential in cancer research—and to take greater risks in their work.

Lin, Henry Pickering Walcott Professor of Biostatistics and chair of the Department of Biostatistics, is globally recognized for her leadership and expertise in statistical genetics and genomics. She will receive $6.6 million to develop and apply innovative statistical and computational methods for analyzing massive genetic and genomic data in cancer epidemiology and clinical science. This work will aid in the development of cutting-edge methods for discovering genetic and environmental factors of cancer; provide a better understanding of cancer progression; and inform new approaches to studying cancer progression and new treatment strategies.

“I am very much flattered by this enabling award,” said Lin. “The award gives me plenty of flexibility and freedom to explore cutting-edge data science research in cancer.”

Manning, professor of genetics and complex diseases, has led seminal research over the past decade that has shaped understanding of the mechanisms and potential therapeutic targets for the treatment of human diseases, with a core focus on genetic tumor syndromes and sporadic cancers. His highly innovative approach integrates biochemistry, cell biology, genetics, genomics, proteomics, metabolomics, bioinformatics, and animal models. He will receive $5.3 million for efforts to define the wiring and functions of a signaling network—the PI3K-mTOR network—that is aberrantly regulated at a high frequency across a wide spectrum of human cancers. Manning will examine the critical role of this network in influencing the sensitivity and resistance of tumors to targeted cancer therapies and in tumor cell metabolism.

“I am honored to receive this award on behalf of the members of my laboratory, both past and present, who made the foundational discoveries on which our future research is grounded,” said Manning. “This seven-year grant, its substantial resources and the freedom of its structure will allow us to explore some of the most difficult, but critically important, aspects of tumor biology.”

— Karen Feldscher

photo: Emily Cuccarese

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The Aging Game

Aging_boarddetailB462x326A Special Report by Amy Gutman, Boston-based writer,
and Madeline Drexler, editor, Harvard Public Health

To see the original article, please click here.

 

 

The Gray Wave. The Silver Tsunami. The Agequake.

Aging societies have been on the horizon for decades, not just in the United States but also around the world. The driving forces are well-established: falling fertility rates (by far, the most important factor), longer life expectancy, and the maturing of large cohorts such as the baby boomers in the U.S.

But what demographers once thought would be the passage of a single large generation—like the postwar boomers—through the age brackets is now predicted to be a permanent fixture of many developed societies. Age distributions in many countries once formed a pyramid—with billions of young people filling out the bottom and dwindling numbers of older survivors at the apex. Soon, however, this distribution may more nearly resemble a square, with roughly equal numbers of people in each age group.

Imagining what this “new normal” will mean for developed and developing societies alike raises profound questions. How will societies age successfully? Will most people live longer lives but be sicker for more years than in prior generations?

How should work be organized when a society has more people over 65 than under 5? As people live longer, when will they want or need to retire because of cognitive or physical aging? Will growing economies slow or even reverse their trajectories as older cohorts leave the workforce?

What can people do to increase the number of years of healthy, joyful senior living? Will people in their 80s, 90s, or older need as much help with aspects of daily living in the future as they did 20 years ago, or will they be more self-sufficient longer? Will “dying with dignity” be possible in a culture driven by technologically advanced health systems and nursing homes focused more on protecting the frail elderly than on empowering them?

This issue of Harvard Public Health examines how individuals and societies will navigate the previously uncharted waters of rapidly aging societies. Among the experts interviewed are faculty from the Harvard T. H. Chan School of Public Health, in fields ranging from social epidemiology to health policy to biochemistry. Here are their thoughts on what lies ahead.

1. What Is “Successful Aging”?

The MacArthur Foundation Research Network on an Aging Society has defined successful aging by three criteria: avoidance of disease and disability; maintenance of high cognitive and physical function; and engagement with life.

By these standards, the U.S. has generally done well. As life expectancy has improved overall (though some sections of the country have seen declines), more older people have managed to stay healthy or disability-free. This scenario—higher life expectancy and lower incidence of disease and disability—has led to what public health researchers call a “compression of morbidity”: more years spent in good health and fewer lived in poor health.

In the future, will people enjoy a “compression of morbidity”—living both longer lives and fewer years in poor health? Or will those extra years be spent paying the price of unhealthy lifestyles—in poor health due to heart disease, diabetes, and other chronic conditions?

But according to Lisa Berkman, Thomas D. Cabot Professor of Public Policy and of Epidemiology at the Harvard T.H. Chan School of Public Health and director of the Harvard Center for Population and Development Studies, this promising trend may have stalled in recent years. “There is evidence from national studies that people who are now in their 30s and 40s may actually be in worse shape than people that age were a generation ago—an increase in diabetes, obesity, and other chronic conditions,” she says.

“This virtuous cycle, where people are living not only longer but healthier, may not continue.” Moreover, says Berkman, there are substantial social and economic gaps in healthy life expectancy, with those who are poorer or who have less education facing much worse outcomes. And racial and ethnic disparities in healthy aging reflect a historical legacy of disadvantage.

WILL AGING SLOW THE ECONOMY?

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Emily Cuccarese / Harvard Chan

 

An older population with chronic diseases bodes ill not only for public health but also for the economy. “Nations with swiftly aging populations may find themselves with a growing disease burden on their hands: nearly one-quarter of the world’s burden of disease is attributable to illness in adults aged sixty and over,” notes an article in the Spring 2015 issue of Daedalus written by David Bloom, Clarence James Gamble Professor of Economics and Demography in the Harvard Chan Department of Global Health and PopulationDavid Canning, Richard Saltonstall Professor of Population Sciences and professor of economics and international health; and research assistant Alyssa Lubet. “In turn, the majority (nearly 70 percent) of the older-adult disease burden is due to noncommunicable diseases (NCDs) such as heart disease, cancer, chronic respiratory disease, musculoskeletal conditions, and mental disorders such as Alzheimer’s and dementia.”

As a result, population aging may slow economic growth, strain existing pension and health care systems, and weigh down younger generations. “One dire prediction,” the authors warn, “is that population aging will slow or perhaps even reverse the engines of national economic growth.”

ORGANIZING WORK REQUIRES NEW ASSUMPTIONS

“Until now, everybody had been looking at what makes individuals age successfully. But nobody asked: How do societies age successfully?” observes Berkman. “What happens to a country when there are more people over 65 than there are under 5? The fundamental issues are not how are we going to pay for Social Security or Medicare, although those are not trivial issues. The deeper issues are how should work be organized? What will happen to people with disabilities? How do different life trajectories lead to different health outcomes? In dealing with these issues, you can’t reorganize a little bit—you have to reorganize dramatically. To do this well, you have to rethink a lot of assumptions as a society.”

DOES AGE NO LONGER MATTER?

One of the fundamental assumptions that may change is that all older people need help. In economics, the oft-cited Old Age Dependency Ratio—or ratio of individuals ages 65 and older (presumably “dependent”) to those ages 18–65 (in the labor force)—bears this out. But in 2014, Dana Goldman of the University of Southern California and colleagues published in the Journal of Gerontology a study of older Americans that contradicts this model. The researchers found that among individuals ages 85 and older, 28 percent had excellent or very good self-reported health and 56 percent reported no health-based limitations in work or housework. As the study’s authors ask, “When does age no longer matter?”

THIS IS NO DEMOGRAPHIC GLITCH

“Originally, we thought the aging society would look like the boa constrictor in The Little Prince,” says Harvard Chan’s Lisa Berkman. “The boa constrictor swallows an animal, and you see the animal move all the way through the snake. But that’s not how this demographic shift is going to happen. The structure will probably be with us forever.”

At the beginning of the 20th century, the distribution of the U.S. population looked like a pyramid. Only 4.1 percent of the population was age 65 and older; today, that figure is 14 percent, and the classic pyramid is morphing.

By 2050, the senior cohort will rise to more than 20 percent, and the age structure in the U.S. and all other developed nations will have at least as many people alive at older ages as at younger ages. The global number of people ages 100 and older will likely more than double by 2030, with projections of nearly 3.4 million by 2050. “Never before in history have countries had their population age to this extent and as rapidly,” adds David Bloom, Clarence James Gamble Professor of Economics and Demography in the Harvard Chan Department of Global Health and Population. “These are uncharted waters.”

2. Sowing Healthy Habits

Don’t smoke. Exercise regularly. Eat a healthy diet filled with plenty of fruits and vegetables, replace saturated fats with plant oils, and limit sugar-sweetened beverages. Drink moderate amounts of alcohol.

Those are the pillars of healthy aging, according to Walter Willett, Fredrick John Stare Professor of Epidemiology and Nutrition and chair of the Department of Nutrition at the Harvard Chan School. And a mountain of public health research backs up his advice—including the Nurses’ Health Study (NHS), established in 1976 by the Harvard Chan School’s Frank Speizer, now professor of environmental science, with funding from the National Institutes of Health.

This ongoing investigation, which began with some 121,000 middle-aged women, “shows the flip side of the coin,” explains Willett—revealing not only the conditions that elevate the risk for disease but also those that help prevent potentially fatal conditions, from breast cancer and atherosclerosis to diabetes and dementia.

The Nurses’ Health Study defines healthy aging as survival past age 70 without any major chronic diseases or major impairments in memory, mental health, or physical abilities. In 2011, all of the women in the original NHS were 65 or older. Here are the study’s key findings about their healthy aging:

BODY MASS INDEX (BMI)

Of the women who survived until at least age 70, those who had a higher BMI at midlife were less likely to survive to a healthy old age. Obese women (with BMI of 30 or greater) had an 80 percent lower chance of healthy survival compared with their leaner counterparts (with BMI between 18.5 and 22.9). And the more weight a woman gained from age 18 until midlife, the lower her chance for healthy survival after age 70.

PHYSICAL ACTIVITY

Higher physical activity levels at midlife predicted healthier survival. Better yet, the chance of healthy aging markedly improved even at modest activity levels: Women who jogged or cycled about five hours per week almost doubled their chance of healthy aging. Two or more hours per week of brisk walking also upped the chances of a healthy old age. Perhaps most encouraging: Regardless of whether a woman was lean or over-weight, being physically active increased her odds of optimal health.

flavonoidsMEDITERRANEAN DIET AND TELOMERES

The Mediterranean diet appeared to increase telomere length, a key biomarker of aging. Likened to the plastic tips on the ends of shoelaces, telomeres are stretches of DNA at the ends of chromosomes that protect genetic data. Shorter telomeres are associated with decreased life expectancy and increased rates of age-related chronic diseases.

FLAVONOIDS AT MIDLIFE

A midlife diet rich in flavonoids improved the odds of healthy aging. Bioactive compounds in plant foods, flavonoids have been linked to lower risks of fatal or nonfatal cardiovascular disease, hypertension, stroke, cancer, diabetes, and neurodegenerative diseases. High-flavonoid foods include oranges, berries, onions, and apples.

cognitionVITAMIN D AND COGNITION

Among women ages 60 to 70, lower levels of vitamin D in the blood of were associated with significantly worse cognitive function—such as memorization of words and numbers. The finding bolsters the theory that vitamin D, which is critically important for bone and muscle health and the prevention of falls, may also play a role in brain function.

3. Rethinking Work

When Social Security was established in 1935, most other government benefits kicked in at age 65. To put that in context, life expectancy for American men at the time was only about 60 years. Today, however, according to the Social Security Administration, men who retire at age 65 can expect to live for an additional 19 years; women, an additional 21 years. Should retirement therefore be postponed?

In general, being employed is positively associated with health, says Lisa Berkman. Partly that’s because healthy people are more likely to be able to work. But employment itself also appears to bring both physical and mental health benefits. Having a job boosts social engagement, keeps up intellectual and interpersonal skills, and staves off the time when one must draw on savings and pensions. “One of the good parts of working longer is the maintenance of cognitive functioning,” says Berkman. “In societies where retirement age is early, such as France and Italy, cognition falls more as people age.”

That fact argues for delayed retirement. But not everyone is able or willing to stay in the workforce, in part because people hold onto their health or lose it at vastly different rates—and government policies must acknowledge this heterogeneity. According to Berkman, certain segments of the population—such as people whose health has been worn down by physically arduous jobs—need the option to take an early path to retirement. And as David Bloom notes, people who are more educated and who earn more tend to live longer—which raises questions of fairness in retirement policies. “If some people will have much longer lives and some people will have just modestly longer lives, but you raise the retirement age for everybody, there’s an ethical issue,” he said in a recent interview.

BENEFITS OF VOLUNTEERING

Perhaps the most convincing argument for encouraging people to keep busy and engaged after 65—whether or not in the formal workforce—is a raft of research showing that senior volunteering has been tied to reduced risk of hypertension, improved self-reported health and well-being, delayed physical disability, enhanced cognition, and lower risk of death. And research shows that while members of lower socioeconomic groups are less likely to volunteer, they will reap disproportionately greater benefits.

“One of the good things about eternally volunteering is that it embeds people in social networks,” explains Berkman. “They are engaged, they work with others, they collaborate with people of all ages. They’re not receiving support, they’re giving support—and giving support turns out to be really important. One of the best things we can do is to keep people naturally embedded in communities that are cohesive and enduring.”

Employment can yield both physical and mental health benefits as one ages – a potent argument for raising the retirement age. But for those whose jobs have worn them down physically or emotionally, the discussion about raising the retirement age raises important ethical and practical issues.

In the U.S., the most robustly studied volunteer program is Experience Corps, which invites volunteers ages 55 and older into public elementary schools several times a week (for at least 12 hours total) to tutor children at risk of reading failure. A 2010 study in Social Science & Medicine by S.I. Hong of the National University of Singapore and Nancy Morrow-Howell of Washington University compared changes in health outcomes over two years between Experience Corps volunteers and a matched sample of older adults who were not engaged in high-commitment volunteering. The study found that the Experience Corps group reported fewer depressive symptoms and fewer functional constraints in such activities as walking, running, or climbing stairs, while the comparison group showed an increase in these measures.

REMOVING THE COBWEBS

A 2009 study in the Journal of Gerontology by Michelle Carlson of the Mailman School of Public Health at Columbia University and colleagues explored in finer detail the cognitive gains among Experience Corps volunteers. This small study involved African-American women in Baltimore. All were all low-income and low-education and therefore faced a statistically greater risk for cognitive impairment. The researchers used fMRI scans, which measure blood flow, to trace the biological underpinnings of brain plasticity. After their stints as volunteers, the women demonstrated increases in activity in several key areas of the brain, compared with those in the control group. They also had better scores in standard tests of visual function and concentration. As one woman said of her time at Experience Corps, “It removed the cobwebs from my brain.”

“[T]hese activities are generative in giving meaning and purpose to one’s life … which may make them more rewarding and personally enriching than highly stimulating activities performed alone,” the researchers wrote. “As a result, individuals may place more value on these activities beyond their immediate personal benefit and may sustain interest longer.”

Just as compelling, the program’s dividends were truly multigenerational, reaching far beyond the volunteers themselves. Compared with students in the control schools, the kindergarten-to-third-grade students in the Experience Corps schools had improved standardized reading scores and markedly fewer referrals for behavioral problems.

THE “LUMP OF LABOR” FALLACY

Some say that older people who feel healthy and prefer to stay in the workforce should be encouraged to do so. Others argue that the senior cohort will steal jobs from younger people.

But according to Harvard Chan’s Lisa Berkman, the latter assumption is plain wrong. Indeed, its wrongness has a catchy name in the economics literature: the “lump-of-labor fallacy.” Writing in Daedalus in 2015, Berkman and her co- authors explain: “For many years, common sense suggested that the number of jobs in the economy is finite, and that a new population entering the labor force would therefore push other workers out. This so-called lump-of-labor fallacy has been invoked at moments in history when women’s labor-force participation increased, because it was thought that they would take ‘good jobs’ away from men. Immigrants to the United States continue to be accused of stealing jobs from other, native lower-wage workers. Likewise, many older people who wish to continue working today are accused of taking jobs from younger workers, creating intergenerational conflict.

“The lump-of-labor fallacy is one of the most dangerous myths in economics. … This is shown most clearly in the United States, where the sharp increase in female labor force participation not only did not cause mass unemployment for men, but actually correlated with a rise in male employment rates. More specifically, recent findings from cross-national comparisons show that higher employment of older individuals is actually positively correlated with higher employment of the young; that is, countries with a high prevalence of early retirement tend to have higher unemployment rates and lower employment of the young.”

As Berkman says, “If older people are working, they’re earning, they’re spending. They don’t draw on Social Security as much. They contribute productively. Overall, that’s good for growth.”

4. Breakthroughs in Biology

Imagine old age without heart disease, cancer, or dementia. Imagine a long life of physical and mental vigor, capped by a brief period of decline before death. Imagine being able to achieve this ideal through a pill or simple changes in diet.

That’s exactly what Harvard Chan School scientists in the Department of Genetics and Complex Diseases are imagining in their quest to understand the biology of senescence and the secrets of what has come to be known as “healthy aging.”

JUNKING THE “RUST” METAPHOR

Until recently, bodily decline was considered to be the inevitable outcome of tiny corrosive hits to the system: genetic, cellular, metabolic, environmental, stress-induced. The reigning metaphor was the body as rusting car, with each failing part the final stage of a distinct chain of biological events.

Today, however, researchers suspect there is a fundamental cause behind all these seemingly separate breakdowns. “As humans grow older, they don’t get just one aging-related disorder—they suffer a spectrum of disorders,” says associate professor James “Jay” Mitchell. “The new thinking is that these disorders are mechanistically linked to the aging process itself—whatever that process is.”

According to assistant professor William Mair, the key questions in this new paradigm are: “Why are we more likely to get diseases when we’re old than when we’re young? And how can we shift that risk of frailty?”

CLUES IN THE LAB

The idea that aging is driven by a biological mainspring is buttressed by epidemiological studies of centenarians. These resilient human survivors of 100-plus years tend to die

not from cardiovascular disease or malignancies or neurodegeneration, but rather from the complications of overall deterioration and the body’s inability to maintain homeostasis and rebound from injury or infection. Centenarians usually succumb swiftly at the end—to a broken hip, say, or a short bout of pneumonia. Put another way, they enjoy a longer “health span.”

Can centenarians’ hardy biology be replicated? Mitchell and Mair believe it can.

Animal research has proven that dietary restriction—whether cutting total calories, reducing specific dietary constituents such as proteins, or placing animals on various fasting regimens—extends life span and decreases age-related debility. So dramatic is this biological benefit, Mitchell describes its inverse—today’s human epidemic of obesity-related metabolic disorders—as a wave of “premature aging.”

Elaborating on these findings, Mitchell has shown that lowering quantities of certain amino acids in the diet causes mice to increase cellular production of the gas hydrogen sulfide, which in turn protects the animals against tissue damage after minor surgery. He has also found that increased production of the gas extends life span in worms, flies, and yeast—along the same biological pathways conserved in Homo sapiens.

Research in the lab suggests that dietary restriction— cutting calories or reducing certain items in the diet—extends lifespan and decreases age-related debility. In that context, today’s human epidemic of obesity-related diseases could be seen as a wave of “premature aging.”

Mair, meanwhile, has demonstrated that nematode worms that express an active form of a protein called AMPK—a kind of molecular fuel gauge—were likewise long-lived, despite eating normally. The implication is that tweaking cellular mechanisms in the nervous system that sense energy generated by nutrients could confer the same propensity for healthy aging as do low-calorie diets, without the need to alter food intake.

WHAT’S NEXT?

Both Mitchell and Mair foresee a day when their kind of basic research finds its way into human clinical medicine.

Mitchell predicts that doctors may someday prescribe certain kinds of fasts before surgery or chemotherapy to boost the body’s resilience and improve outcomes. Mair hopes to find molecular targets that could pave the way to therapeutic drugs; if taken in old age—when one was about to encounter risk factors for certain diseases or suffer early symptoms—the medications could prevent the afflictions or at least reduce their spread or severity.

The goal, the scientists agree, is not a fountain of youth but rather golden years that are relatively robust and independent. As Mitchell sees it, “Aging is a public health problem—and basic biology is the answer.”

INVESTMENT IN DELAYED-AGING RESEARCH COULD HAVE LARGE PAYOFF

Aging is a primary risk factor for numerous deadly and debilitating conditions, but research to date has largely focused on treating the conditions commonly linked to aging today—such as cancer and heart disease—rather than on addressing the biological processes at the root of aging.

Slowing the biological aging process—what scientists call “delayed aging”—may offer substantial health and economic returns. A 2013 study in Health Affairs estimated that delayed aging could increase healthy, nondisabled life expectancy in the U.S. by an additional 2.2 years. Researchers calculated the economic value of this gain to be $7.1 trillion over 50 years, using a standard formula in which a healthy year of life is valued at $100,000.

5. Connecting With Others

Screen Shot 2015-09-03 at 2.10.31 PMGood advice on lifestyle and successful aging is one thing— following it is another. “Many investments have to be made throughout the life course, in terms of health habits like exercise and diet,” says Ichiro Kawachi, John L. Loeb and Frances Lehman Loeb Professor of Social Epidemiology and chair of the Department of Social and Behavioral Sciences at the Harvard Chan School. “But I’m also interested in what you can do once you do reach old age and you haven’t made those investments. Can you still make a difference?”

Kawachi’s answer: a resounding “yes.”

“One of the most important things that you can do individually, if you retire, is to maintain social connections,” he says. “Connecting with other people is as important as diet and exercise. It’s not too late, even at age 60, to overcome some of the health problems you may have encountered earlier in life.

“When you socialize and converse with friends, you’re exercising all your facilities and improving blood flow to the brain, which helps maintain cognitive function,” says Kawachi. “There’s exchange of information of different kinds, such as learning about the latest health tips or getting advice. And you receive affirmative messages and emotional support.”

Socializing with friends after retirement is as important as diet and exercise. It improves blood flow to the brain, maintains cognitive function, promotes the exchange of useful information, and elicits emotional support.

SURPRISES FROM JAPAN’S “SPORTS CLUBS”

Japan’s population is aging at the fastest pace of anywhere in the world. The proportion of its population over the age of 60 is projected to rise to an astounding 42 percent by 2050. To minimize the impact of this trend on health care costs, Japan’s government has focused on preventing long-term care as much as possible—using social participation approaches.

One of Kawachi’s intriguing studies, published in PLOS One in 2012, looked at the effect of membership in Japan’s “sports clubs”— organizations that offer mini-golf, walking clubs, lawn tennis, croquet, and other activities shared with friends. He divided his subjects, who were 65 and older, into four groups: those who were physically active and belonged to a sports club; those who were physically active but exercised alone; those who were not physically active but still belonged to a sports club (doing administrative or other work); and those who were not physically active and did not belong to a sports club.

As predicted, people who actively exercised and belonged to sports clubs enjoyed the best health. But those who belonged to sports clubs and didn’t exercise came in a very close second—their functional disability rate was virtually the same as the avid sports club exercisers. Those who exercised alone actually fared worse than the sports club sedentarians. And the stay-at-home couch potatoes, not surprisingly, came in last.

“In other words, the exercise didn’t add to the benefits of participating,” says Kawachi. “It was the belonging that prevented disability.”

IKIGAI: A LIFE WORTH LIVING

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BLEND IMAGES / Veer.com

 

In a 12-year study of more than 30,000 men and women published in 2009 in the Journal of Psychosomatic Research, a Japanese team of researchers explored the effect of Japan’s powerful—but, to Westerners, perhaps ineffable—concept of ikigai, which the Japanese believe to be an important factor for achieving health and a fulfilling life. Ikigai is variously defined as something to live for, the joy and goal of living, a life worth living, or “the reason to get out of bed.” It includes not only pleasure and happiness but also meaning and self-realization. As a baseline measure at the beginning of the study, the researchers simply asked participants: “Do you have ikigai in your life?”

In Japan, people who said they had ikigai—pleasure and happiness, a life of meaning—12 years later had lower risk of death from all causes.

A dozen years later, the middle- aged and elderly men and women who answered “yes” had less risk of death from all causes, including external causes such as injury. Death from stroke and coronary heart disease was also lower among men and women with ikigai than among those without it.

6. Preserving Purpose

In 1991, a family practice physician named Bill Thomas conducted a radical experiment: He brought life to a place where death had prevailed.

A PARAKEET OR A PLANT

The medical director of Chase Memorial Nursing Home in the upstate New York town of New Berlin, Thomas was struck by the sterility and despair that pervaded every room. So he issued an almost unfathomable order: to move 106 additional residents into the facility, pretty much all in one day. The newcomers included two dogs, four cats, and 100 parakeets. They were soon followed by a colony of rabbits, a flock of laying hens, and hundreds of indoor plants. Each of the nursing home’s human residents was soon taking care of his or her own parakeet or plant.

ABOLISHING NURSING HOME PLAGUES

Thomas calls himself a “nursing home abolitionist.” He sees his mission as eradicating what he calls the three plagues in modern nursing homes: boredom, loneliness, and helplessness. And he is one of Atul Gawande’s heroes. In his new book Being Mortal: Medicine and What Matters in the End, Gawande, a surgeon, professor in the Department of Health Policy and Management at the Harvard Chan School, and director of Ariadne Labs, explores the “medicalization of mortality”: the myopic focus on disease instead of goals when caring for patients at the end of life.

“When we don’t know what people’s priorities are, their care is often out of alignment with some of their most important goals,” Gawande said in a recent interview. “You really see it when you visit people who end up requiring residential care—assisted living or full-scale nursing homes. The facilities look more and more like hospitals. They’re built around nursing stations. The rules are focused on safety.”

On the one hand, it seems prudent to put safety first in nursing homes. But the upshot is that other goals of life may matter more to people, Gawande says. “People are forbidden from having a drink if they want to. Alzheimer’s patients on medically ordered puréed diets get caught sneaking cookies. You could have a roommate imposed upon you with no choice whatsoever. No regard for privacy. These are incredibly important concerns.”

Gawande’s prescription for this devastating mismatch of intent and results includes a list of clarifying questions that should be asked when a person has a serious or life-threatening illness, such as cancer, congestive heart failure, chronic obstructive pulmonary disease, or end-stage renal disease.

CONVERSATIONS IMPROVE OUTCOMES

“We measure the wrong things,” he says. “Less than a third of the time do people who arrive at the end of life have any conversation about what their goals and priorities are for the time they have left. When they have those conversations, they have markedly better outcomes, including reduced suffering, spending more time at home, and also living at least as long as they otherwise would—in many cases, longer. And better outcomes means that they’re less likely to get unwanted care. They have more peacefulness at the end of their lives.”

SEVEN QUESTIONS

Serious Illness Conversation Guide for Doctors and Patients

1. How much information about what is likely to be ahead with your illness would you like from me?

2. What is your understanding now of where you are with your illness?

3. If your health situation worsens, what are your most important goals?

4. What are your biggest fears and worries about the future with your health?

5. What abilities are so critical to your life that you can’t imagine living without them?

6. If you become sicker, how much are you willing to go through for the possibility of gaining more time?

7. How much does your family know about your priorities and wishes?

AUTONOMY, NOT JUST SAFETY

Gawande adds that Bill Thomas’ innovative experiment and similar interventions have demonstrated that people with the opportunity for purpose—even caring for a bird—at the end of life can bring meaning and joy to one’s final days, even for people with severe disabilities.

But to get there, society must overturn its conventional thinking about old age. “There are sometimes regulations that stand in the way, but most of the obstacles are cultural,” Gawande says. Medical care professionals frequently focus on giving patients the longest possible life, regardless of the quality. What a patient with a terminal disease may actually be looking for is “a few good days,” Gawande notes. As one nursing home administrator told him, “Safety is what we want for those we love; autonomy is what we want for ourselves.”