A new key to the aging process?
Integrin-dependent kinase
LifeSciencesToday based on materials from Sanford-Burnham Medical Research Institute:
Integrin-linked kinase – a new key to the aging process?Two articles just published in the journal Aging Cell help to understand the molecular basis of aging and its impact on the development of heart disease, cancer and other age-related diseases (Kumsta et al., Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1; Nishimura et al., A dual role for integrin-linked kinase and beta1-integrin in modulating cardiac aging).
The authors of these articles are scientists of the Sanford–Burnham Medical Research Institute, collaborating within the framework of the Development, Aging, and Regeneration Program.
Malene Hansen, PhD, associate professor at the Webb Center for Neuroscience, Aging, and Stem Cell Research (Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research), and her group completed a study showing that a decrease in the level of integrin-dependent kinase (integrin-linked kinase, ILK) increases the lifespan of C. elegans by increasing the level of heat shock proteins (HSP), which protect the cell from stress caused by environmental exposure.
C. elegans is a microscopic short–lived roundworm, widely used by scientists as a model genetic system to study the fundamentals of many biological processes, including aging. Over the past few decades, it has become quite obvious that the information obtained by studying one organism, even as simple as a worm, can be very important for understanding the functions of cells of other organisms, including humans.
The signal protein integrin-dependent kinase plays a crucial role in many biological processes, including cell migration, their survival and proliferation. It has long been known that an increased level of ILK expression contributes to the formation of tumors. A study on C. elegans showed that ILK "informs" neurons about a stressful state using heat shock factor-1 (HSF-1), a protein that regulates the activity of HSPs. In a cell under stress caused by temperature changes, infection, inflammation or starvation, cellular proteins unfold, forming non-functional conformations that tend to form large toxic aggregates. Heat shock proteins (chaperones) act as "escorts" that can prevent these harmful interactions to the cell and thereby help it cope with stress.
"Our results show that due to a decrease in the level of integrin-dependent kinase, HSF-1-mediated protective response to stress increases, which leads to an increase in healthy life expectancy. Interestingly, we knew about the age-related increase in ILK levels in cell lines derived from mouse hearts. Thus, the mechanism we have established corresponds to what we know about the molecular profile of aging cells," Dr. Hansen comments on his work. "These studies are important because they provide information about how integrin-dependent kinase promotes aging at the molecular level. Having understood this process, we will know what to look for when things go awry with age-related pathologies such as cancer and cardiomyopathy."
Professor Rolf Bodmer, PhD, director of the program "Development, Aging, Regeneration", leads a group of researchers focusing on the molecular mechanisms of organ formation and the genetic basis of the development of the heart and its performance. A researcher in his laboratory, Karen Ocorr, PhD, led a group whose goal was to get to the "heart" of ILK's effect on aging by studying the heart muscle directly. If a decrease in the levels of integrin-dependent kinase can increase the lifespan of drosophila, as it happens in C. elegans, this will confirm that the effects of ILK are evolutionarily preserved in different species, and will make it more likely that this mechanism is similar in humans.
Dr. Okorr used the Drosophila model system, in which the levels of ILK and integrin beta-1 can be gradually suppressed. This means that scientists can fine-tune the rise and fall of these proteins to test response thresholds. Integrin beta-1 is the binding partner of ILK, a member of the integrin family of proteins that help cells communicate with each other and transmit information.
Wild-type drosophila heart (left); in the heart of a drosophila with ILK knockdown
there are "gaps" between the cells. (Photo: sanfordburnham.org )
Drosophila is the simplest model system with a heart, and its development and functional characteristics are extremely similar to those of humans. Like in humans, the heart of this fly can contract independently, without direct connection with nerves, and its function is to deliver nutrients and hormones in the blood to the cells of the body. Since the drosophila heart is not responsible for oxygen delivery (flies have a different system for this), scientists can use this model to study a heart with impaired functions, which is impossible on humans.
It is important to note that Dr. Okorr has developed a number of subtle tools for assessing the parameters of the functionality of the drosophila heart, such as the frequency of contractions, contractility, as well as arrhythmias.
"We have indeed established that, as in C. elegans, a decrease in ILK levels increases the lifespan of fruit flies. Experiments on insects with a moderate decrease in the levels of integrin-dependent kinase and integrin beta-1, in which we evaluated some of the parameters of the heart's performance, including its rigidity, and the frequency of arrhythmias, which increases with age in humans, showed an improvement in heart function in old insects," Dr. Okorr comments on the results of the study.
"Our results, showing that manipulation of ILK and integrin expression has a similar effect of increasing life expectancy in both C. elegans and Drosophila, convincingly prove that this mechanism is evolutionarily preserved in different species. If this is the case, we will eventually be able to decipher the cellular and molecular foundations of human aging, which will provide targets for the development of drugs for the treatment of age-related diseases such as heart disease and cancer," concludes Professor Bodmer.
Portal "Eternal youth" http://vechnayamolodost.ru15.01.2014