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The Science of Longevity

Posted by on Monday, May 16, 2022 in Features, Spring 2022 .

Photo by Erin O. Smith

When someone asks her age, Abrie Pillow says that she’s 10.

“I’m 82, but I put the eight and two together as a joke,” she laughs.

Pillow is energetic and busy, with gardening and other projects at home, church and community volunteer work, family gatherings and great grandchildren sleepovers. She and her husband, Joe Nickerson, 85, are aging well, she says.

She attributes her own longevity to always being mindful of what she eats, maintaining a healthy weight, staying physically and mentally active, and devoting her time and energy to others. She keeps her husband busy too.

“I haven’t convinced her yet that I’m retired,” Nickerson quips.

They also have genetics on their side. Pillow’s mother died last year at age 101; her father lived into his 70s. Nickerson’s parents lived to 90 and 95.

Pillow and Nickerson are doing what’s recommended for maintaining good health in general: eating healthy foods, exercising and staying socially engaged. The prescription is the same for living a long life.

To age well, “right now, environmentally, all we can control is our diet and our exercise,” says Laura Niedernhofer, MD’98, PhD’96, director of the Institute on the Biology of Aging and Metabolism at the University of Minnesota and an alumna of Vanderbilt University School of Medicine.

But medications that target aging to put off disease and extend our health span — the number of years we live in good health (not necessarily an extension of overall life span) — may be on the horizon. That’s the aim of investigators pursuing the “geroscience hypothesis,” the idea that aging itself is the greatest risk factor, by far, for most chronic diseases.

“Doesn’t it make sense to therapeutically target something about the biology of aging, instead of risk factors like blood pressure and cholesterol?” Niedernhofer asks. “We could be very impactful and reduce the risk of many diseases at the same time if we could target the biology of aging.”

The need is acute. The U.S. Census Bureau calls 2030 a “demographic turning point” when all baby boomers will be 65 or older, and by 2034, the Census Bureau projects that older adults will outnumber children for the first time in U.S. history. By 2060, nearly one in four Americans will be 65 or older, up from about one in six in 2020.

“Our society is going to change, and aging, as a broad field, needs input from people with every angle of expertise … from ethics to governance to policy to drug development and so on,” Niedernhofer says. “We need to go at this aggressively.”

 

Aging as a modifiable process

Defined simply, aging is a time-dependent decline in function — of a cell, a tissue, a whole organism.

For people, “aging starts when development ends, which means we start aging when we’re in our 20s,” says Laura Dugan, MD, who holds the Abram C. Shmerling, MD Chair in Alzheimer’s and Geriatric Medicine at Vanderbilt, cares for elderly patients and directs a neuroscience research laboratory focused on the aging brain. “Aging certainly increases disease risk, particularly for diseases of the brain. Biologically, aging may be starting earlier than we think.”

A hint that aging may be a regulated process, rather than simply “wear and tear” over time, came from the recognition of differences in aging among animals.

“There’s an incredible range in life span in the animal kingdom, ranging from small insects that live for a few days to whale and shark species that live 200-plus years,” says Kristopher Burkewitz, PhD, an aging researcher and assistant professor of Cell and Developmental Biology at Vanderbilt. “The aging process doesn’t occur at a fixed rate; it varies widely. This was a major clue that biological aging, not chronological aging but biological aging, might be modifiable.”

It’s also clear that the aging process varies widely between individuals of the same species. Centenarians who live to 100 and supercentenarians who live to 110 are being studied for insights into genetic, biological and lifestyle factors that increase longevity.

The oldest documented person was Jeanne Calment of France, who lived to the age of 122, Dugan says. “She was riding her bicycle at 119, which tells us the potential is there to see improved aging in humans, if we can figure it out.”

Even for the tiny nematode worm, C. elegans, variation in the aging process is the norm. The average worm lives about three weeks in the laboratory.

“In a genetically identical population where worms are all clones of each other, and they all live in exactly the same environment, a little petri dish, they vary in life span from two weeks to four weeks,” says Burkewitz, who uses C. elegans as a model system to explore mechanisms of aging. “Understanding the sources of this variability and how to predict it is one of the frontiers in the field.”

Studies in C. elegans laid the groundwork for the concept that genetic and biological signaling pathways control aging. In 1993, Cynthia Kenyon and colleagues at the University of California at San Francisco reported in the journal Nature that worms with mutations in a gene encoding an insulin receptor family member lived more than twice as long as wild-type worms.

“This discovery that a single gene could have such a strong impact on the aging process was really shocking and opened up this hope that we could do something to intervene in aging,” Burkewitz says.

Deregulated nutrient-sensing (insulin receptor signaling is one aspect) is one of nine “hallmarks of aging” — processes that characterize aging at the cellular level and are active areas of research.

“The hallmarks of aging are intertwined, and we don’t know which are going to be best for targeting aging. It may be a combination,” Niedernhofer notes.

 

The path to senolytics

Niedernhofer traces her interest in aging back to the first job she had in high school as a nurse’s assistant in a nursing home, where she became passionate about helping elderly individuals maintain dignity.

During college, she got curious about DNA damage and repair and worked for five years as a research assistant at Massachusetts Institute of Technology studying the impact of DNA damage on the structure of DNA.

In the Medical Scientist Training Program at VUSM, Niedernhofer continued probing DNA damage — from endogenous molecules generated by lipid oxidation in cells — in the laboratory of Lawrence Marnett, PhD. After completing her doctoral degrees, she opted to forgo a residency to continue her research with a postdoctoral fellowship at Erasmus Medical Centre in Rotterdam, Netherlands, where she studied DNA damage in mouse models.

Laura Niedernhofer, MD’98, PhD’96

It was there that her research interest in DNA damage and repair and her earlier passion for the elderly came together.

“I wanted to understand the health impact of DNA damage if you don’t repair it, and that just beautifully segued into aging. DNA damage is a hallmark of aging. What does the damage do? It causes cellular senescence (cells stop dividing but don’t die), and that drives aging,” Niedernhofer says. “It all kind of fell together.”

Niedernhofer and her colleagues developed mouse models with genetic defects in DNA repair mechanisms and showed that removing DNA repair mechanisms causes accelerated aging.

“It was absolutely crystal clear that mice that can’t repair DNA damage age fast,” she says.

Mutations that impact DNA repair have also been identified in people with progeroid syndromes — rare genetic disorders that cause clinical features of aging, such as hair loss, skin tightness, osteoporosis and cardiovascular diseases, at a young age. Mouse models of these syndromes are an important tool for aging research.

DNA damage that isn’t repaired — or other cellular stressors — triggers a signaling cascade that stops DNA replication and cell division and sets up a state of permanent arrest called senescence.

“The purpose of senescence is to prevent cancer; it’s a brilliant, evolutionarily conserved strategy,” Niedernhofer says.

But senescent cells, which “look like fried eggs,” change gene expression patterns and secrete pro-inflammatory and other destructive molecules. They need to be removed and are, in a process that happens readily in younger individuals, but slows with aging.

Scientists at the Mayo Clinic developed a mouse model with a drug-inducible “suicide” gene, that when activated, killed senescent cells. Their 2011 paper in Nature demonstrated that clearing senescent cells delayed the onset of age-related pathologies in a progeroid mouse model.

“These studies gave us confidence that senescent cells truly drive aging,” Niedernhofer says. “If we could clear them and improve health span with genetic tricks, then we could certainly do this with drugs.”

Niedernhofer and her colleagues screened drug libraries in DNA repair-deficient cells that senesce in culture; their Mayo Clinic colleagues used a bioinformatics approach. In 2015, they reported on a new class of drugs: senolytics, which selectively kill senescent cells. A combination of the cancer drug dasatinib and the natural plant product quercetin killed senescent cells and extended health span in progeroid mice. A single dose improved cardiovascular measures and exercise capacity in normal, aged mice.

 

Anti-aging drugs within the decade?

There are about 30 clinical trials currently testing senolytics, Niedernhofer says. A challenge, she notes, is that many of the drugs are natural products; her favorite is fisetin, which is abundant in strawberries.

The current trials of senolytics aim to show that the drugs reduce senescent cells, are safe, and perhaps offer some improvement in diseases like idiopathic pulmonary fibrosis, chronic kidney disease, osteoarthritis and even COVID infection. In the meantime, Niedernhofer and her colleagues are working to develop new senolytics that will interest pharmaceutical companies and fuel more research.

And senolytics are not alone. Multiple efforts are targeting other hallmarks of aging with resveratrol and related compounds, metabolites like NAD, and rapamycin.

But the current trials do not directly address the big questions of geroscience: Can drugs target aging itself? Can one drug delay disease onset or treat more than one disease at once?

Currently, the Food and Drug Administration does not consider old age, or frailty, a druggable target. The Targeting Aging with Metformin (TAME) trial will test whether individuals taking metformin, a commonly used diabetes drug, have delayed development or progression of age-related chronic diseases such as heart disease, cancer and neurodegenerative disease. Metformin appears to influence multiple hallmarks of aging and has been shown to delay aging in animal models. Once it is fully funded, the TAME trial plans to enroll 3,000 individuals ages 65-79 at 14 sites across the country.

“I think we will have an answer within this decade about whether this is really going to work,” Niedernhofer says. “And then it’s going to take a lot of fine-tuning.

“We’re also going to need biomarkers to determine which type of aging therapeutic someone needs. I think this will become a personalized medicine approach because we’re all different; we all age differently.”

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