Washington People: Shin-ichiro Imai

Molecular biologist seeks the keys to healthy aging

Shin-ichiro Imai, MD, PhD, (second from left) leads a research team that investigates the processes of aging and longevity in mammals. From the left are Alessia Grozio, postdoctoral research associate; Imai; Kathryn Mills, research lab supervisor; and Sean Johnson, graduate research assistant. (Credit: Robert Boston)

As Shin-ichiro Imai grew up outside Tokyo, he heard his parents many times tell the story of his unlikely birth. According to Imai, doctors told his mother there was a high risk of losing the pregnancy because of a partially detached placenta. Imai’s mother went to great lengths to find a doctor willing to take a chance on the baby and provide her care.

“Again and again my parents told me this story,” Imai said. “It had a huge impact on me. When I was very young, I wanted to become a doctor. But the message that most ingrained itself in me was that even if there is a very small chance of success, I’m going to give it my best effort. That’s how I was born.”

Today, Imai, MD, PhD, is a professor of developmental biology and of medicine at Washington University School of Medicine in St. Louis. And though he does not treat patients, his research has shed light on the processes of aging and longevity, as he has sought to help people maintain better health into later years.

“I began research into aging early on and have been carrying the same interest for nearly 30 years,” Imai said. “The excellence of the science attracted me to Washington University. Our department has encouraged developmental biologists and aging researchers to work together in the same environment to cover the whole spectrum of growth from early development all the way to aging. Everyone is so collaborative and top-notch.”

Despite his precarious start, Imai was an active, outdoorsy child, bringing home all manner of small creatures.

“I collected insects, frogs, salamanders, snakes — well, only one snake,” he said with a laugh. “It escaped from the aquarium, and my mom stepped on it. So no more snakes. I had pet chipmunks and raised silkworms. I loved animals.”

Imai said his parents gave him many opportunities to learn. He took piano, calligraphy and martial arts lessons. He and his father, a high school history teacher, always had projects. Many of them were biology-related, such as growing sunflowers to document their heights and petal sizes. His mother, a high school English teacher, made sure Imai was exposed to the language early by playing tapes of stories and conversations for him.

The value of basic science

Imai remained committed to his early goal of becoming a medical doctor, attending Keio University in Tokyo. In his fourth year of the six-year medical program common in Japan, Imai took an interest in research.

“I knocked on the door of a professor who was running a research lab and asked him to let me have a project,” Imai said. “And the first project was to investigate how cells become immortal.”

Scientists have long been interested in the mechanisms that lead cells to continue dividing well past the time when they would be expected to stop. How cells develop immortality is thought to be important in cancer and aging.

“I thought there may be some kind of counting system in cells, and I wanted to understand it,” Imai said. “Mutations in that counting system seemed likely to contribute to cell immortalization.

“At that time, research was not an official part of the curriculum, so I actually began skipping classes to work on experiments,” he added, laughing. “I spent most of my time in the lab.”

Despite the intense research interest, Imai felt torn between pursuing a career treating patients and one dedicated to basic biomedical science. It was during a medical school lecture that his choice became clear.

“The professor talked about the importance of basic science,” Imai said. “His message was that one doctor can treat one patient at a time. But making some fundamental discovery in medicine can help thousands of patients at one time. This statement struck me, almost like a thunderbolt. It helped me make the final decision.”

Seeking cellular immortality

After completing his medical degree, Imai entered the university’s doctoral program and officially joined the lab where he had been volunteering so much time.

Determined to unlock the key to what allows cells to divide without limit, Imai told his labmates that he intended to do a complex set of experiments comparing the genes expressed by aging cells with those expressed by immortal cells. In theory, the genes that are turned on in one set of cells but are off in the other may be responsible for the switch from aging to immortality. Imai said the general response to his announcement was laughter.

“They told me, ‘You’re crazy. You just started. You don’t have that kind of skill,’” Imai remembered. “But I was stubborn, and I started working on it.”

The first attempt, Imai recalled, was a disaster. Today, relatively straightforward techniques exist to do such an experiment. But then, it was a painstaking process.

“It took almost two years to establish a system that let me compare the genes expressed before and after immortalization,” he said.

Imai identified several genes, and one in particular stood out because it was highly expressed in aging cells and almost totally shut down after immortalization. The gene manufactures a protein called collagenase. According to Imai, it was an underwhelming discovery.

“At the time, no one knew of any way the collagenase gene could be connected to cellular aging,” Imai said. “Initially, it was a disappointment.”

But in retrospect, Imai had stumbled upon an important result. Today, collagenase is known to be part of a group of protein factors involved in cellular senescence, the state in which cells have reached their division limits. Though this was unknown at the time, Imai saw the result as a clue to what might be going on in genes that leads to immortalization. His research led him to work with computer scientist Hiroaki Kitano, PhD, who would become a major figure in systems biology, the field of simulating complex biological events with computer models.

Together, Imai and Kitano proposed an explanation for how cells transition from aging to immortal states. In short, it involves the packaging of DNA. In young, healthy cells, certain genes are packaged away and silent. Gradually, this silencing is lost and these genes begin to be expressed, which drives the aging process. If these genes are silenced again, aging stops.

“My data and the computer simulations suggested this type of regulatory machinery,” Imai said. “But not much was known about possible components of this machinery in the late 1980s and early 1990s.”

One possibility was outlined in a paper by Leonard Guarente, PhD, at Massachusetts Institute of Technology (MIT) that appeared to identify the machinery that Imai said, in theory, must exist. The research implicated a class of proteins named SIR2. Since then, SIR2 and related molecules have come to be known as members of a protein family called sirtuins. SIR2 serves to silence certain genes. The group at MIT showed that the movement of SIR2 seemed to be the driving force of aging in yeast.

Imai met Guarente at a scientific meeting, shared his theories and was invited to join the lab at MIT as a postdoctoral scholar. And in 1999, they made an extremely important discovery about the nature of sirtuin biology, which appeared in Nature the following year.

Imai, Guarente and colleagues showed that the gene-silencing function of sirtuins, which promotes cellular longevity, is entirely dependent on energy levels in the cell.

“No one had ever heard of such a thing — a situation in which the amount of fuel in the cell directly controls how genes are expressed,” Imai said.

Productive aging

The fuel in this case is nicotinamide adenine dinucleotide (NAD), a molecule that serves as energy currency in cells and has been a familiar subject in biochemistry texts for decades. Imai and Guarente were the first to show that NAD also controls gene expression related to aging.

Without NAD, sirtuins can’t do their job. And when sirtuins stop working, genes that promote aging begin to be expressed. The study opened up tremendous new possibilities for examining the process of aging, including how the function of sirtuins relies on energy supplied by metabolism, which is shaped by diet and exercise.

Shin-ichiro Imai and his wife, Toshiko Imai, on a recent vacation to Chantilly, France. (Credit: Courtesy of S. Imai)

The work interested colleagues at Washington University, where Imai joined the faculty in 2001. Today, his research is focused on the functions of sirtuins and on how cells manufacture NAD, which ensures that sirtuins are properly fueled. He has expanded his work beyond individual cells and is interested in the organs and tissues that may play key roles in orchestrating aging throughout the body.

The work is ongoing, but Imai said he is seeing a comprehensive picture emerge. The mechanisms that control aging and longevity in the body appear to involve at least a three-way conversation between the brain, the muscles and the body’s fat stores.

With this in mind, one specific avenue of research Imai is pursing is the idea of boosting the body’s NAD. The chemical reactions that make NAD must first make a compound called NMN, which is derived from vitamin B3. Imai’s research, published in 2007, was the first to show that giving NMN to mice is beneficial in a number of age-associated diseases, such as type 2 diabetes.

In conjuction with the university’s Office of Technology Management, Imai has patented the use of NMN for the prevention and treatment of metabolic complications, including type 2 diabetes and other conditions associated with aging.

“We are working very hard to begin a phase 1 clinical trial evaluating the safety of NMN in people,” he said. “Many groups around the world are now studying NMN for its apparent anti-aging effects.”

“But simply extending people’s lifespans may not be a good idea in itself,” Imai added. “We are interested in encouraging productive aging — helping people stay as healthy and as productive as possible into their later years.”