Can Anti-Aging Interventions Delay Dementia?

An estimated one in 10 adults over the age of 65 in the U.S. has some form of dementia. Illustrations by Becky Sehenuk Waite

Why do we age, why do some of us stay healthy longer than others, and what can we do about it? In an age rife with multi-step skincare regimens, cryotherapies, and intravenous vitamin therapies, these questions intrigue the general public and researchers alike. 

Anti-aging remedies are often shrouded in dishonest gimmicks and sometimes even macabre treatments. But LSA Professor Ursula Jakob has a science-centric vision for the fight against aging that we all face. Her dream? To be able to extend the healthy years of human life by building biological resistance against the many diseases that we face as we get older. 

“What Doesn’t Kill You Makes You Stronger”

The upbeat Kelly Clarkson song lyric and popular affirmation appears to have some truth to it, based on what Jakob has learned. Jakob, the Patricia S. Yaeger Collegiate Professor in the Department of Molecular, Cellular, and Developmental Biology, studies aging in the short-lived roundworm C. elegans. The commonalities between roundworms and humans at the molecular level make the worms valuable tools for the discovery of anti-aging regimens relevant to human health. Instead of waiting years to see whether the anti-aging intervention works, researchers using this model organism can have answers within a few weeks. 

Jakob and her team made the exciting discovery that some of the longer-lived organisms within the population naturally experienced an oxidative stress event very early in life. Then, when the researchers exposed the entire population of worms to oxidative stress in early life, the animals lived a healthier and longer life.

Prof. Ursula Jakob, pictured here with MCDB doctoral student Akash Rai, hopes her research eventually leads to the development of medications and behavioral changes that extend healthy lifespan in humans. Photo by Leisa Thompson/Michigan Photography

These findings were particularly exciting, Jakob says, as other studies have indicated that interventions that slow the decline in aging physiology extend lifespan by delaying the onset of many chronic diseases. This includes cancer and potentially even neurodegenerative conditions such as Alzheimer’s disease. Jakob’s research supported this idea by showing that worms that produced more oxidative stress early in their development lived longer and were more resistant against the toxicity of proteins associated with Alzheimer’s. 

The idea that stress can actually make us healthier may seem counterintuitive. However, triggering mild oxidative stress, such as during moderate exercise in the gym or on the tennis court, is different from experiencing persistent oxidative stress conditions that are associated with chronic inflammation and become worse as we age.

“Oxidative stress is a cellular and molecular process that stems from an overproduction of oxidants and free radicals in the body. It can damage us in higher doses but can trigger a long-term beneficial response when experienced at the right time and at the right amount,” Jakob explains. This effect is referred to as hormesis. 

The results are intriguing—yet how would this work at the molecular and cellular level? Jakob and her team have now shown that these oxidative stress events alter the epigenetic make-up of the cell. In other words, they lead to persistent changes in the types and levels of cellular macromolecules without causing permanent genetic changes or mutations.

Jakob’s lab is currently focused on identifying the crucial players and processes that are responsible for these beneficial cellular long-term changes. “We are very enthusiastic about this research, and where it will lead us—who knows, maybe simply increasing the amount of olive oil in our diet will do the trick,” says Jakob.

Long-Lasting Resilience

Jakob’s work, published together with her former postdoctoral fellow Daphne Bazopoulou and current research lab specialist Bryndon Oleson, builds on the foundational knowledge produced by U-M’s robust anti-aging research community—particularly the work of Michigan Medicine researcher Richard A. Miller, professor of pathology and director of the Paul F. Glenn Center for Aging Research. 

Miller and his team have found that newborn mice can live 15 percent longer if they receive less milk in the first three weeks of life. The same group also found that the drug rapamycin can extend lifespan by up to 26 percent in mice, and delay the development of cancer, kidney disease, and age-dependent changes in the heart, liver, and tendons.
 

With plans to test her ideas in mice, Jakob hopes her findings on transient stress, hormesis, and epigenetic state will eventually lead to the development of medications and behavioral changes that extend healthy lifespan in humans, and thus reduce the burden of age-related diseases. 

“An estimated one in 10 adults over the age of 65 in the U.S. has some form of dementia,” Jakob says. “Finding such interventions could be a game-changer in the field of neurodegenerative diseases and potentially other age-associated diseases.”

Jakob points out that the major risk factor for many other diseases—including cancer, diabetes, and heart disease—is age, and “the socioeconomic burden of these diseases on both the afflicted person and their loved ones is immense,” Jakob says. She advocates that “instead of trying to target these diseases individually, we should be targeting the overall process of aging with the goal to produce long-lasting protection against all of these diseases at the same time. 

“Our main impetus is to find interventions that promote healthy aging and increase lifespan. What more could we want?” 

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