Integrin-linked kinase – a new key to the aging process?

By Susan Gammon, Ph.D.
January 13, 2014
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When you think of aging do you think of gray hair and wrinkles? Many people do. But in Sanford-Burnham’s Development, Aging, and Regeneration Program, two collaborating research groups led by Malene Hansen and Rolf Bodmer have more serious aging issues on their mind. In back-to-back papers in Aging Cell, their research is helping to uncover the molecular basis of aging and its impact on heart disease, cancer, and other age-related diseases.

Malene Hansen, Ph.D., associate professor in the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, and her research team have completed a study showing that depleting integrin-linked kinase (ILK) extends the longevity of C. elegans by increasing the level of heat-shock proteins (HSPs)—the proteins that protect cells against environmental stress.

C. elegans is a microscopic and short-lived nematode—a roundworm—commonly used as a model genetic system by scientists to understand the fundamental basis of many biological processes, including that of aging. Over the past several decades, it has become increasingly clear that knowledge from one organism, even one so simple as a worm, can provide important information about cellular functions in other organisms, including humans.

ILK is a signaling protein that plays critical roles in many biological processes, including cell migration, survival, and proliferation, and has long been known to promote tumor formation when up-regulated. The C. elegans study found that ILK uses heat shock factor-1 (HSF-1)—a protein that regulates HSP activity—to tell neurons that the cell is undergoing “stress.” When cells experience stress such as changes in temperature, infection, inflammation, and/or starvation, cellular proteins “unfold” and form non-functional conformations that are prone to forming large and harmful aggregates. HSPs act as “chaperones” that can prevent inappropriate interactions and can thus help the cell to cope with the stress.

“Our results show that by reducing ILK levels, there is an increase in the HSF-1-mediated protective response to stress that leads to an extended, healthy lifespan. Interestingly, we knew that ILK levels increase with age in cell lines derived from mouse hearts, so the mechanism we uncovered fits with what we understand about the molecular profile of aging cells,” said Hansen. “These studies are important because they provide insight on how ILK contributes to the aging process on a molecular level. Understanding the process helps us know what to look for when things go awry in age-related pathologies such as cancer and cardiomyopathies.”

Across the hall, Rolf Bodmer, Ph.D., professor in Sanford-Burnham’s NCI-Designated Cancer Center and director of the Development, Aging, and Regeneration Program, leads a team of researchers focused on the molecular mechanisms of organ formation and the genetic basis of heart development and performance. Karen Ocorr, Ph.D., a research assistant professor in Bodmer’s group led a team aimed to get to the “heart” of ILK’s effects on aging by looking directly at cardiac muscle. If reduced ILK had the ability to extend life in Drosophila as it does in C. elegans, it would provide support that the effects were conserved among species, and confidence that the mechanism may be similar in humans.

Ocorr’s team used a model Drosophila system where ILK and beta-1 integrin levels could be incrementally “knocked down”—meaning they could finely tune increasing and decreasing levels to test response thresholds. Beta-1 integrin is a binding partner for ILK and is a component of the integrin family of proteins that help cells connect to each other and pass information.

Drosophila is the simplest model system with a heart, and the developmental and functional characteristics are remarkably similar to humans. Like humans, their hearts can beat on their own, without a direct connection to nerves, and serve the purpose of delivering nutrients and hormones in the blood to the body’s cells. Because the heart is not responsible for delivering oxygen in the fly (there is another system that does that), it is possible to study malfunctioning hearts that normally would kill a human.

Importantly, Ocorr has developed a number of sophisticated tools to measure heart functions such as heart rate, contractility, and arrhythmias in Drosophila.

“Indeed we found, as in C. elegans, that reduced levels of ILK extended the lifespan of Drosophila, and when we measured a number of heart-performance parameters, including the heart “stiffness,” and incidence of arrhythmias, which increase with age in humans, in animals with moderate reduction in ILK and beta-1 integrin, those animals had improved heart function at older ages,” said Ocorr.

Hansen and Bodmer emphasized that their research groups contributed valuable data to each other’s studies to illustrate an evolutionary conserved mechanism for the longevity function of ILK.“Our results, showing that manipulation of ILK and integrin expression produce similar life-extension benefits in both C. elegans and Drosophila, strongly suggest that the mechanism is conserved across species. If so, we may ultimately be able to decipher the cellular and molecular basis of human aging that will provide targets for drug development to treat age-related diseases, such as heart disease and cancer.” said Bodmer.

Caroline Kumsta, Ph.D., is a postdoctoral fellow in Hansen’s lab and was first author on the C. elegans paper. Mayuko Nishimura, Ph.D., is a postdoctoral fellow in Bodmer’s lab and was first author on the Drosophila paper.

Direct links to the papers are at:

http://onlinelibrary.wiley.com/doi/10.1111/acel.12189/abstract
http://onlinelibrary.wiley.com/doi/10.1111/acel.12193/abstract

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Susan Gammon, Ph.D.

Susan is an Associate Director of Communications at SBP.

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