Of Mice, Men, and the Fountain of Youth

A Harvard scientist is using mice to discover the secrets of longevity and her findings may help humans live longer and better.

Words and Photos By Daniel Merino

It is the end of November and outside the Harvard T. H. Chan School of Public Health, the cold of a Boston winter is in the air. Sarah Mitchell doesn’t seem to notice. She is wearing a flowery white tank top while carrying a tray of blood-filled vials up from the basement. “I was up at 7 am collecting poo, so I’m sorry if I smell,” she says with a New Zealand twang as we walk down a hallway lined with shelves of half-full water bottles and coffee cups not allowed into the laboratories beyond.

“I’m collaborating on a project where we are looking at the microbiome of healthy aging in mice,” she says, explaining the “poo” collecting from earlier. But the little vials of mouse blood are for something else. “I am spinning blood for one of my longevity studies,” she says, placing the clinking vessels into a centrifuge. “Maybe we can find a circulatory signal of healthy aging. Blood is easy to get a sample of, taking a muscle biopsy fucking hurts.”

Originally from New Zealand, Sarah Mitchell earned a Ph.D. from the University of Sydney before transferring to the National Insitute of Aging in Baltimore to research fasting and longevity. During the government hiring freeze in 2017, she was “stolen” by Jay Mitchell and moved to Harvard where she now works as a Research Associate in his lab.

Sarah Mitchell’s research is part of a group of scientists examining how caloric restriction (CR) and intermittent fasting improve health and longevity. They have found that when, and how much you eat has huge effects on how the body reacts to injury, surgery, disease, and even aging. “The first published reports on CR and its health benefits were in 1913,” she says. “We have come a long way since then but we still have a long way to go.”

In a paper published September 2018, Sarah Mitchell compared two different diets and three feeding regimes to tease out the relative importance of diet, fasting, and CR in mice. “We found that the composition of diet doesn’t really matter in terms of lifespan. Diet composition dictates what you die of,” she says. “[CR or fasting] can’t cure you of something, you have to die eventually, but it pushes back the time that you get these things.”

Sarah Mitchell follows a fasting mimicking diet herself. “I do it two days a week, 16-hour fasts,” she says, but not because she wants to live forever. “I am about healthspan, for people to live healthy then just drop dead.” She was quick to say that more research needs to be done before she would recommend a fasting mimicking diet, but she and other scientists are doing that exact research.

In Jay Mitchell’s lab at Harvard (no relation), she is part of a team trying to translate her mouse model discoveries into clinical results in humans. “We are trying to figure out how the phenomenon known as calorie restriction works on a molecular level,” says Jay Mitchell.

The hope is that once the mechanisms are understood, doctors could recommend specific diets for specific needs. ”If you are about to undergo a planned trauma like surgery, then you want to control certain parts of your diet,” says Dr. Charles Ozaki, the John A. Mannick Professor of Surgery at Brigham and Women’s Hospital. In collaboration with the Mitchell lab, Ozaki is running a small pilot study to see if CR in the days leading up to vascular surgery improves outcomes. It does so in mice, but “one never really knows how rodent data will translate to the complexity of the human situation, thus our rationale to continue early human studies,” says Ozaki.

There have been human studies, like those of Dr. Valtar Longo, that have shown good translatability between the mouse findings and humans when it comes to the mechanisms of fasting. “We are discovering which pathways lead to metabolic molecular damage,” says Dr. Luigi Fontana, of the University of Sydney. “The idea is that if you block the upstream causes of these things you can live longer and live healthier.”

But while scientists can do short-term studies in humans, there is just no way to control one person’s diet for 80 years, much less a large study group, in order to study longevity. That is where the mouse model, Sarah Mitchell’s specialty, comes in.  

“She is truly an expert at conducting nutritional studies in animals,” says Dr. Michael Bonkowski of the Sinclair Lab at Harvard Medical School. “Sarah’s work is beginning to unravel that it is not just the composition of diet, but also the timing of consumption that has an important role in longevity.” There is a lot going on in the field today, and Sarah Mitchell does not shy away from the task. “She’ll take on 6 or 7 studies, not just one,” says Bonkowski, and that means a lot of mice.

As Sarah Mitchell swipes her keycard and steps into the “mouse room”, she warns that it might smell a little. Inside are a dozen or so tall stacks of stainless steel shelves on which sit plastic and metal enclosures containing three to five grey, brown, and black mice. She starts pulling down enclosures to examine the mice in them and the cards that describe their particular diets. She moves swiftly, like an old audiophile flipping through boxes of vinyl at a record shop.

“There is a lot of groundwork you have to put in on just a hope and a prayer,” she says, referencing the long hours and daily tedium of caring for her mice. But her determination and hope are often rewarded. “The oldest mouse I’ve ever had lived to 3 years 9 months,” she says. The average lifespan of a mouse in captivity is 2 years. “When I opened it up and looked at its organs, it looked just like a young mouse. It had just… crapped out.” That mouse, named Lucy, was part of a study comparing longevity between 20% CR and 40% CR mice. Lucy was a 20% CR female, and “was the oldest, maybe ever, for a non-genetically modified mouse,” Sarah Mitchell says proudly.

She points out a grey mouse with a noticeable hunchback. The way it moves is off, it seems frail and timid compared to the other mice in the enclosure. Sarah Mitchell explains that this mouse was genetically modified to have Cockayne syndrome, a rare neurodegenerative disorder that causes extreme premature aging. Depending on how the disease manifests, the life expectancy in humans can be fewer than 10 years.

“I’ve actually met one of the patients who have it,” she says. “Making regular, ‘wildtype’ people live longer is great, but helping people like this, who dont even have a regular lifespan, to live longer and better is really important.”

If the mice are anything to go by, her work may do both.