Reactive Oxygen Species, Stem cells and Aging

Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

For many years it was generally believed that the production of reactive oxygen species (ROS) was an unwanted byproduct of aerobic metabolism and other cellular enzymatic processes and that ROS were uniformly deleterious in nature. We have spent the majority of our energies pursuing an alternative hypothesis; that production of ROS are tightly regulated, the targets of ROS are specific, and that oxidants contribute to disease progression, at least in part, through the redox-regulation of specific pathways (See Finkel and Holbrook, Nature, 408, 2000, 239-247; Finkel, T., Current Opinions Cell Biol., 15; 2003, 247-254; Balaban, Nemoto and Finkel, Cell 120, 2005, 483-497). [unreadable] [unreadable] Nearly ten years ago we observed that certain cells produce high levels of ROS when stimulated by peptide growth factors (Sundaresan et al, Science 1995, 270 296-299). The production of ROS was transient, peaking in the first few minutes following ligand stimulation and returning to baseline within 30 minutes after stimulation. Our initial observation was in vascular smooth muscle cells stimulated with the growth factor PDGF, but subsequently it has become clear that similar events transpire in a wide variety of different cell types stimulated by a host of different ligands. Interestingly we found that inhibiting this rise in ROS blocked the initial signaling events demonstrating an essential role in ROS generation for normal physiological signal transduction. [unreadable] We have also previously demonstrated that the source of the ligand stimulated ROS-generator in non-phagocytic cells shared certain molecular and biochemical similarities with the phagocytic NADPH oxidase. In particular, we were able to demonstrate a role for the small GTPase Rac1 in the regulation of the intracellular redox state. We have also shown with the help of our collaborators that the related GTPase Ras also plays an important role in redox regulation within cells. Interestingly, the ability of Ras proteins to induce transformation in the context of immortalized cell, or to induce senescence in the context of primary cells, appears dependent in some fashion on the ability of Ras proteins to induce a change in the level of ROS.[unreadable] [unreadable] These observations have been extended recently in our lab in an attempt to understand the molecular regulators of mitochondrial ROS production as well as mitochondrial oxygen consumption. We have recently been able to demonstrate a connection between several pathways that regulate lifespan and the production of mitochondrial function. These pathways include the NAD-dependent deacetylase SIRT1, the adapter molecule p66shc and the the mTOR pathway. These efforts have resulted in a series of recently published manuscripts including: Nemoto et al. 2006 J. Biol. Chem. 281, 10555-10560 and Schieke et al. 2006 J. Biol. Chem. 281, 27643-27652. We have also actively pursed the process of autophagy, a cellular adpatation to starvation. We have implicated the putative longevity gene Sirt1 in this process. This manuscript is currently undergoing peer review. [unreadable] [unreadable] We have also pursued the role of stem cells in aging and the role of oxidative stress in stem cell biology. Using a mouse model of accelerated aging called the klotho mouse, we were able to show that rapid aging in this model is associated with stem cell depletion (Liu et al., 2007 Science, 317, 803-806). We were than able to demonstrate that klotho can bind to a family of proteins called Wnt proteins known to regulate stem cell biology. This has led to the notion that Wnt proteins may play an important role in aging, a hypothesis we are actively pursuing. We are also actively pursuing the role of oxidants within stem cells. In particular we are interested in what signaling pathways oxidative stress induces and how activation of these pathways may limit stem cell function.