What If We Could ‘Cure’ Aging?
The U of M's Institute on the Biology of Aging and Metabolism is discovering groundbreaking new pathways that could help our bodies work better, longer.
It’s the middle of September and Church Street is abuzz with the energy of young people discovering their way in the world. Students with backpacks chat as they climb the steps to Lind Hall while bikers glide toward University Avenue. A skateboarder takes a jump off the steps on the plaza above the Church Street Garage.
On the south side of Washington Avenue, the researchers in The Institute on the Biology of Aging and Metabolism (iBAM), located upstairs in Nils Hasselmo Hall, are busy at work. Inside, two women in white coats are loading slabs of dry ice into a minus-80-degree freezer used to store tissue from research mice. Elsewhere, in a separate tissue culture room, research technicians are growing human cells in petri dishes.
iBAM, which is engaged in many features of aging research, has six faculty members, each of whom has their own lab. Together they employ more than 100 undergraduate and graduate students, as well as postdoctoral fellows, research technicians, and research assistant professors. Biochemist and physician Laura Niedernhofer, M.D., and molecular biologist Paul Robbins oversee the labs. Partners in life as well as work, they came to the U of M from Scripps Research in 2018 to help establish the University as a leader in the emerging field of geroscience, which, according to the National Institutes of Health, seeks “to understand the genetic, molecular, and cellular mechanisms that make aging a major risk factor and driver of common chronic conditions and diseases of older people.”
Internationally recognized experts in the quest to slow and even prevent the debilitating diseases of old age—including cancer, diabetes, heart disease, and dementia—Niedernhofer and Robbins hope to eventually treat old age itself.
Their work feels increasingly urgent. In April 2023, the CDC said the average American life expectancy is now 76.4 years, up from 69.84 in 1960. Today, the United States is entering what’s popularly referred to as a “silver tsunami,” where aging individuals begin to far outnumber younger ones. Minnesota alone now has more people 65 and older than it does school-aged children. And that trend is accelerating, according to the Aging in Minnesota Fact Sheet 2022, a document compiled for the state legislature by Project REACH (Rural Experts Advancing Community Health), a U of M initiative to support the state’s rural seniors.
These overarching trends also stretch into the future. From 2030 to 2050, the state’s 85+ population will triple. Greater Minnesota will feel the brunt of this demographic shift even more than our urban centers.
Other countries—including Singapore, the United Kingdom, and Japan—have recently announced public health initiatives to increase their populations’ “health spans,” or the years people enjoy good health before dying. Unfortunately, a recent New York Times opinion piece by the former New York City health commissioner states that ordinary Americans can only expect to enjoy one birthday in good health after they reach 65.
The social and economic costs of these demographic shifts are daunting. The Congressional Budget Office projects that spending on long-term services and support for the 65+ population will more than double from 1.3 percent of gross domestic product in 2010 to 3 percent in 2050.
“We are in an unprecedented point in human history where the number of individuals who are over the age of 65 is doubling and sometimes tripling,” says Niedernhofer. “On top of that, it’s the first time in human history where the number of old people is outnumbering the number of youth. That has huge social and societal and budgetary and health care implications. The frightening part is that 75 percent of people between the ages of 65 and 69 will have at least one disease, while 50 percent will have two, and 25 percent will have three. So, if you cure one, you’re [still] not making them better.”
That’s the significant challenge iBAM hopes to address.
Laura Niedernhofer and Paul Robbins came to the University of Minnesota in 2018. But they actually began their collaboration at the University of Pittsburgh School of Medicine, where they worked in microbiology and molecular genetics. In 2012, they moved to Scripps Research in Jupiter, Florida, specifically because the institute had a department of metabolism and aging.
When that department disbanded, both were eager to continue their research in the area. The U of M’s Medical School, with the support of the state legislature, had made Biology of Aging one of its four focuses of “Medical Discovery Teams,” to advance research in areas that are critical to the wellbeing of our state and the world. (The other three areas are Addiction, Optical Imaging & Brain Science, and a Rural & American Indian Health Disparities.) That investment made the U of M an appealing next step for Niedernhofer and Robbins. “It turned out to be the perfect opportunity for us,” says Niedernhofer.
The theory driving geroscience, still a nascent field with no formal path of study from the FDA, is that if you can develop therapeutics—in essence, drugs—to treat aging itself, you will also slow or even stop the diseases associated with it. “You can extend lifespan by curing each age-related disease,” says Robbins. “But you won’t extend or increase the number of people who are healthy because of the comorbidities [related maladies associated with each illness].”
According to Robbins, historically scientific research has been funded by targeting individual diseases. That means one person may be working on diabetes but not necessarily talking to people working on cancer research or orthopedists about bone health. Patients take a different pill for each disease, even though sometimes those medications don’t work well together. Geroscience instead focuses on the root cause of many of these diseases.
"The goal isn’t to get people to live to 150, but to increase our health span. “What we want is for people to be healthy, healthy, healthy, and then have a stroke on the golf course when they are 100,” says Robbins. “Something is going to kill you. [We’re] just trying to keep people ... healthier for a longer time.”
Part of iBAM’s research studies include natural products that you can buy at GNC and drugs that are already FDA approved for other conditions. That’s a major advantage, both in terms of time and money.
“New drug discovery is a time-consuming and costly journey. It typically takes around a decade and costs billions of dollars to get a new drug from the lab bench to the pharmacy shelf,” says Lei Zhang, a research assistant professor in the Robbins Lab. “To get FDA approval, every drug must go through extensive testing to ensure a drug’s efficacy, safety, pharmacokinetics, and potential side effects. Drug repurposing is like a shortcut on this long journey. Instead of starting from scratch, it aims to find new therapeutic applications for already approved drugs.”
Zhang cites aspirin as a successful example of drug repurposing. First sold as a painkiller, it was later used as an antiplatelet aggregation drug to prevent cardiovascular issues and is also used as an anti-inflammatory. Another drug, called Sildenafil, was initially developed to treat high blood pressure, but it was later repurposed by Pfizer to treat erectile dysfunction and is now known as Viagra.
“Since these drugs have already been tested extensively, we have a ton of data about their safety and how they work in the body,” Zhang says. “So, instead of starting from scratch, we can focus on how effective they are for a new condition. ... And, there’s a reduced risk. These drugs have already been deemed safe in earlier trials, so they’re less likely to hit a roadblock later on.”
The DNA connection
Niedernhofer initially became interested in geroscience through her work in DNA damage and repair, since that damage is a potent driver of aging. (She also previously studied pediatric genetic diseases.) Robbins started his career in cancer research. As he expanded to other diseases, he noticed that the molecular changes driving age-related diseases were the same. When he heard about the concept of geroscience, he says he bought into it “hook, line, and sinker. I had turned 50 and I was thinking, ‘Everything I’m studying, all the same pathways are affected. I should be thinking about this regarding aging.’”
The iBam team is involved in numerous research projects, including approximately two dozen funded grants. Three active clinical studies are taking place at the University in geroscience, and 16 more are in the planning stages.
Niedernhofer’s work centers on what are called senescent cells, which are cells that linger in the body as we age. These cells are damaged or stressed or just old; they are still alive, but have stopped dividing. That’s a problem because senescent cells increase inflammation, which in turn increases the risk of developing an age-related disease. “They are the bad apples in a bushel of healthy apples that cause the rest of them to rot,” explains Robbins. While a body with a robust immune system can flush out these cells, an aging body doesn’t do that as efficiently or effectively. The hypothesis—which has been proven in mice and other model organisms and is now being tested in clinical trials in humans—is that if we can find drugs that clear these cells, we will live healthier lives.
Neidernhofer’s lab focuses primarily on preclinical studies of the diseases of old age and is famous for developing a mouse that ages six times faster than normal. That’s a critical research milestone when it comes to developing drugs that could be used for humans, because the mice model what happens as cells age. Her lab also studies centenarians, identifying the pathways and genes that enable those long-lived individuals to be largely disease free. That helps determine which drugs could target those same pathways in people who aren’t aging well.
“To me, the biology of aging is standing the test of time,” Neidernhofer says. “There’s no doubt about it. We know what [aging] is. Now we just have to figure out how to drug it.”
That’s where the Robbins Lab, which focuses on drug development, comes in. Working together with colleagues at the Mayo Clinic, Niedernhofer and Robbins have codiscovered a class of drugs called senotherapeutics. There are two types of senotherapeutics: Senolytics are designed to clear senescent cells from the body; senomorphics modify the cells themselves.
The work at iBAM is interdisciplinary and includes anyone from biomedical engineers to computer scientists. That cohort includes Josh Bartz (at far right, above), a third-year Ph.D. student working in the field of bioinformatics and computational biology, which applies the tools of computation to capture and interpret biological data. Working in the lab of iBAM Professor Xiao Dong, Bartz explores various hypotheses to connect DNA damage as a cause of aging to the greater observable traits or phenotypes of aging. He says that even though he himself is still young, he feels a powerful connection to the work he is doing. “My parents are getting older. I’m close with them and it’s tough to see sometimes. Aging is a graceful process, but also one that can be very painful for many people. While I don’t think there’ll probably ever be a good way to die, there are certainly good ways to age. And that’s a big idea I believe in: trying to figure out why we age so that we can make a better way to age, one that’s less painful for most people.”
“We’ve identified a number of compounds, natural products, repurposed compounds, and even developed some novel compounds that will kill certain types or maybe most types of senescent cells,” says Robbins, who adds these senolytics have been shown to work in mice. The majority of these natural supplements and drugs, including the type 2 diabetes drug Metformin, are already FDA-approved to treat specific diseases—they just haven’t been approved for geroscience. Most of the drugs that show promise to be effective senolytics are off patent or soon to be off patent, which will also make them more affordable and accessible to the general public.
“These are very inexpensive approaches and extremely attractive because they could be broadly applied and sent to developing countries,” says Niedernhofer. That’s a prospect that particularly motivates Rahagir Salakeen, a second-year doctoral student who works in the Niedernhofer Lab on the impact of cellular senescence on liver damage. “I grew up in Dhaka, Bangladesh, in a household that had frequent runs to the hospital because my parents and grandparents were battling metabolic diseases, including cardiac disease and type 2 diabetes,” he says.
“Most developing countries are experiencing the shift from very young to very old populations. And I don’t think a lot of these countries, including my own, are prepared for this,” he says. The work isn’t about “billionaires who want to live hundreds of years. It’s about the quality of life for mass populations and keeping them out of hospitals as long as possible.”
Energizing an entire profession
In addition to discovering the fundamental mechanisms that regulate the aging process, developing drugs to target those mechanisms, and conducting clinical trials for those drugs, iBAM is also committed to educating the next generation of researchers on aging.
“Laura has really been very encouraging to female scientists to succeed, to pursue their passion for science and basic science research,” says Linshan Shang, a research assistant professor at the Neidernhofer Lab. Shang is part of an NIH-funded consortium to identify biomarkers of senescent cells and create a detailed map of cellular senescence across the lifespan and physiological states.
“The opportunities ... at iBAM are fantastic,” agrees Anna Carey, a fourth-year doctoral student in pharmacology working in the lab of iBAM Assistant Professor Christina Camell. There she studies how immune cells in fat tissue change during aging, and how that promotes dysfunction in a person’s lipid metabolism. “Lipolysis is actually really important during infection and is key for promoting a proper inflammatory response,” Carey says. “And if that’s disregulated, if we see this metabolic dysfunction that accompanies a really inflammatory response, what’s the link there? Can we target that to provide a healthier outcome for older individuals during infection?”
It’s questions like those that drive the work at iBAM. Niedernhofer estimates that the scientific community will know if senolytics work in two to five years. And she envisions a huge benefit to the greater good if they are approved. “With the health care system that we have right now, the estimate is [that] somewhere between $32 and $75 trillion will be saved in keeping the baby boomers healthy. All that money could be spent on climate change or something else, but it will be spent on health care if we don’t do something.”
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