Cellular architecture is maintained by a complex array of three major protein systems: microtubules, intermediate filaments and actin/microfilaments. Each of these three cytoskeletal systems assembles into separate networks within cells. Taken together, these three networks are comprised of proteins which represent the major architectural building blocks of both the cytoplasm and the nucleus (nucleoskeleton) of vertebrate cells. Associated with the cytoskeletal networks are a large variety of accessory proteins that serve to control their assembly, disassembly, dynamic properties, and ability to cross link to each other both homotypically and heterotypically. These three cytoskeletal systems play fundamental roles in cell and nuclear shape; cell locomotion and cell division; signal transduction; and cell/cell and cell substrate adhesion. They also provide cells with their mechanical properties. Because of their essential roles in many cellular functions, it is critically important to understand the changes that take place in these cytoskeletal systems during the normal process of cellular aging. At the present time, remarkably little is known about the role of the cytoskeleton in the normal aging process, even though it is well established that there are numerous changes in cytoskeletal systems that have become the hallmarks of age-related disorders.
Clues as to the relevance of the cytoskeleton and nucleoskeleton in normal aging come from human diseases which show the age-dependent onset of clinical problems. Intriguingly, these frequently involve mutations in contractile proteins and the nuclear form of intermediate filaments, the nuclear lamins. The conditions of patients bearing these mutations worsen with age, leading to cardiac hypertrophy and heart failure or sudden death from arrhythmias. The recent demonstration that the premature aging disease of children, Hutchinson Gilford Progeria Syndrome, is caused by mutations in nuclear lamin A has led to studies that strongly suggest that this nucleoskeletal protein is involved in the changes in epigenetic regulation, DNA repair and senescence that accompany normal cell aging. Other studies have shown that a mutation in the actin isoform located in the stereocilia that extend from the apical surface of the hair cells of the cochlea results in an autosomal dominant form of deafness. This may relate to the type of hearing loss that accompanies normal aging and also involves changes in the actin cytoskeleton.
Cell death as a result of aging is believed to occur through an apoptotic pathway. Several studies suggest that the actin cytoskeleton can regulate the release of reactive oxygen species from mitochondria, thereby playing an important role in the initiation of cell death. Other studies show that stabilizing f-actin with the drug jasplakinolide stimulates a cell-death pathway, while de-stabilizing the f-actin network by overexpressing the regulatory protein gelsolin that inhibits apoptosis. There is also growing evidence that intermediate filaments modulate the motility and function of mitochondria, in addition to anchoring them in certain regions of the cell. In addition, microtubules are known to be the major tracks upon which mitochondria move to their positions within cells. So, it is quite likely that studies of cytoskeletal/mitochondrial interactions will shed important new light on the normal cell aging process.
Considering the importance of the cytoskeleton in cell function and the severe lack of understanding of how the different components of the cytoskeleton system are affected by the aging process, NIA has identified areas of research interests, but the areas of interest for this FOA are not limited to the ones listed below:
- Develop a basic understanding of microtubule morphology and dynamics at the cellular and molecular levels in aging tissues. For example, it is important to understand whether the microtubule cytoskeleton is over- or under-stabilized during aging in adult stem cells, in progenitor cells, or in terminally differentiated cells.
- Determine if there is polymorphism of genes in the microtubule system, and if this is correlated with aging and disease.
- Determine to what extent a damaged microtubule cytoskeleton affects transcriptional regulation in differentiated tissues. Changes in nuclear architecture and gene expression have been shown to accompany the aging process. Since the nuclear envelope is connected to the microtubule cytoskeleton via various linker proteins, a change in microtubule organization and stability during aging could influence nuclear architecture. Studies should be carried out to determine whether perturbing the microtubule cytoskeleton in specific cell types could cause changes in nuclear organization and gene expression.
- Determine if changes in the microtubule cytoskeleton affect the accuracy and efficiency of cell division in adult stem cells. An important aspect of aging is the declining ability of an organism to replenish the worn or damaged tissues with new cells. It would be important to determine how the aging microtubule cytoskeleton might contribute to this decline.
- Determine the changes in the mechanical properties of cytoskeletal intermediate filaments (IF) in normally aging cells. Since there is an emerging notion that older cells are mechanically stiffer, it is certainly important to study the roles of IF as potentially causative factors in altering both the mechanical properties of the aging cell and its responses to external forces such as shear stress and stretch.
- Define the changes in the nucleoskeletal intermediate filament systems in aging cells: the nuclear lamins. It will be of great interest to determine whether changes in the nuclear lamins as a function of aging are involved in processes related to normal senescence such as alterations in DNA repair mechanisms, changes in nuclear transport and other essential nuclear functions.
- Cause-effect relationships: If the cytoskeleton is defective, and cell function is defective, how can we test whether the changes in the cytoskeleton cause the defects in cell function? Pharmacological perturbation of signaling pathways that regulate the cytoskeleton might be informative for aging questions since this direction could have the potential for therapeutic interventions.
- Gene dosage effects: It may also be of interest to look at gene dosage effects for genes involved in regulating the cytoskeleton and its associated proteins along with the signaling pathways that regulate it. Model organisms may be a good way to move forward in this area.
- Aging and actin signaling pathways. Examining pathways both upstream and downstream of the actin cytoskeleton itself might be an especially productive area for aging research. These include the mTOR pathway which is already widely implicated in aging; the role of phosphoinositides as central regulators of actin; and ROS pathways that have been shown to regulate actin in yeast and in vertebrate cells.
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