By Sandy Marvinney
Decades of wear and tear — that’s the age-old explanation for common afflictions of aging: creaking joints, wrinkling skin, weakening muscles, slowing mental processes. Over millennia, people have sought methods to counter infirmities and boost longevity, mostly with uncertain effect.
Recent studies, however, show that aging is not caused only by wear and tear. Rather, it is also a fundamental biological process, influenced by specific functional pathways conserved across at least 600 million years of evolution. These discoveries could upend prevailing concepts of aging and longevity — and the diseases associated with aging, such as cancer, diabetes, heart disease and Alzheimer’s disease.
Researchers like UW Medicine’s Matt Kaeberlein, Ph.D., are at the forefront of this new science, the biology of aging. Their objective? To promote not just a long life, but lifelong well-being.
“Medical science is still so focused on finding treatments to cure diseases of aging after they manifest, that it overlooks the opportunity to intervene in the aging process before people are sick in order to delay disease onset,” Kaeberlein says. “The biology of aging has great potential to have a huge positive impact on human health.”
“The biology of aging has great potential to have a huge impact on human health.”
— Matt Kaeberlein, Ph.D.
Even without medical intervention, average life expectancy in developed countries has been increasing consistently over the past century, due largely to improvements in nutrition, sanitation and medical science. Kaeberlein, a UW associate professor in the Department of Pathology points out, however, that there is no evidence that the aging process itself has been slowed.
“The dramatic increase in Alzheimer’s disease and other chronic diseases of aging can be directly attributed to the fact that we have done a good job at making people live longer, on average, without affecting the rate of biological aging,” he says. “Maximum human lifespan is probably the same now as it was 2,000 years ago.”
Still, if more people live into their eighties and nineties — a demographic change already in motion in some societies — it will have an enormous impact on society. The question is: will people remain healthy at 85 or 95? Or will they still contract diseases associated with aging, like cancer, diabetes, Alzheimer’s disease? And how will this affect healthcare costs? These are the issues that concern Kaeberlein, who prefers to emphasize the concept of healthspan, rather than lifespan.
“Healthspan is the length of life spent free from severe age-related disease,” says Kaeberlein. “Our goal is to understand the basic biology of aging and what causes an organism to switch from youthful and healthy to aged and infirm. We want to extend a person’s healthspan.” He suspects that slowing the aging process and extending healthspan might add another 10 or 15 years to human life expectancy.
“If you want to extend lifespan, you almost always have to do something to affect the aging mechanism itself.”
— Matt Kaeberlein, Ph.D.
This paradigm-shifting approach — addressing the issues of aging and age-related disease in tandem — impresses Kaeberlein’s colleagues.
“Without hyperbole, Matt is one of the world’s leaders in unraveling the basic biology of aging,” says Thomas J. Montine, M.D., Ph.D., UW professor and chair of the Department of Pathology and the Nancy and Buster Alvord Endowed Chair in Neuropathology. Montine recruited Kaeberlein to join the Alzheimer’s Disease Research Center. “When the book on Alzheimer’s disease is finished, there has to be a chapter on why aging is essential to developing the disease.”
Kaeberlein is also inspiring an upcoming generation of medical scientists, like doctoral candidate Melana Yanos. “So many research scientists remain focused on a narrow area of inquiry,” Yanos says. “Matt thoroughly understands every single experiment in the lab, but he is always considering the bigger picture and a study’s value and potential impact.”
She especially appreciates the collaborative atmosphere in the lab. “Matt has an amazing ability to be available to every person on the lab team,” says Yanos. “He is a tremendous advocate…I don’t know how he does it, but his door is always open.”
“Matt…is always considering the bigger picture and a study’s value and potential impact.”
— Melana Yanos
Yanos is one of about 50 scientists and students in Kaeberlein’s laboratory. They’re working on more than 20 distinct projects to identify the genetic and environmental factors that modulate normal aging and longevity. It’s difficult to study these processes in humans. Our lives are long, involving a complex interplay of genetic and environmental factors. Just as important, scientists lack reliable biomarkers. Studies can only examine the relationships of specific factors on mortality, which may not be relevant to the basic mechanisms of normal aging.
For these reasons, short-lived yeast strains, worms and mice are the models of choice for conducting controlled experiments in most research labs, including Kaeberlein’s.
“When I was a postdoctoral fellow in genome sciences at the University of Washington, I started thinking about evolutionary conservation and whether any of the genes or mechanisms for aging I was studying in yeast were conserved across time and species,” Kaeberlein recalls. “I decided to test the idea in C. elegans, a nematode worm with about 1,000 cells. It’s about midway in the evolutionary chain between yeast and humans.” Worms have another advantage: unlike yeast, they show clear signs of aging.
“We tested many different gene mutations and gene knockdowns in both yeast and worms and asked what was similar. We were looking for lifespan extension rather than lifespan shortening,” says Kaeberlein. “It’s easy to break something to shorten an organism’s lifespan, but that doesn’t necessarily have anything to do with normal aging. If you want to extend lifespan, you almost always have to do something to affect the aging mechanism itself.”
One such mechanism is controlled by a substance, called mTOR, that regulates cell growth, metabolism and components of insulin signaling. It also controls the breakdown of damage that accumulates inside cells as they age. The mTOR pathway is a primary determinant of longevity in yeast, fruit flies and C. elegans, and it can be modulated by an FDA-approved immune-suppressant drug called rapamycin.
After initial studies showed that mTOR is important for aging in simple organisms, the next step was testing in mice. “There is now strong evidence that rapamycin inhibits mTOR in mice, that it affects multiple age-associated disease processes and significantly prolongs lifespan,” Kaeberlein says. Tumor-ridden mice given rapamycin, for instance, maintained cardiovascular health and lived longer than mice not treated with the drug.
“This pathway functions similarly in humans,” says Kaeberlein, “and we have good reason to believe that rapamycin or other mTOR inhibitors could have similar effects on human aging.”
The biology of aging is a small but rapidly growing area of biomedical investigation, gaining recognition in scientific and technology circles. Google has invested in aging-related biotechnology. China recently joined several European programs in developing top-level aging research programs.
UW Medicine is in a prime position to grow to even greater prominence in this new field; it is one of just five sites with a National Institutes of Health (NIH)-funded Nathan Shock Center of Excellence in the Basic Biology of Aging; Kaeberlein is the center’s co-director, and Peter S. Rabinovitch, M.D. ’79, Ph.D., Res. ’81, is the director. In addition, the NIH is funding doctoral- and postdoctoral-level aging research at the UW, and Kaeberlein is spearheading an effort to create a longevity institute at the University of Washington.
The benefits — for the planet’s rapidly aging “silver tsunami” and for the rest of us — could be profound. And it could come relatively soon.
“We have a lot of work ahead to bridge the research gap between mice and humans, but, for the first time in my career, I see a clear path toward reaching this goal,” says Kaeberlein. “With continued support, it’s possible that interventions could be available within a decade.”