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). 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. 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. 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. My laboratory is focused on the molecular basis of mammalian aging and age-related diseases and in particular the role that mitochondrial metabolism and oxidative stress plays in these processes. In this regard we have focused on three predominant pathways during this last year. The first area of emphasis is to explore the biology of mammalian sirtuins. This is a family of NAD-dependent deacetylases first implicated in aging of lower organisms. The founding member of this family is the yeast Sir2 gene, first described as a regulator of transcriptional silencing and later as a modulator of life span. In mammals, seven sirtuin family members (SIRT1-7) exist. We have predominantly concentrated on the biology of SIRT1, the closest mammalian homologue of the yeast Sir2 gene. We have shown that in mice, SIRT1 expression is induced upon starvation via a pathway involving the Foxo3a transcription factor and p53 (Nemoto et al., 2004). We have further demonstrated a role for SIRT1 in regulating mitochondrial flux. This process we believe involves the generation of new mitochondria through PGC-1-dependent biogenesis (Nemoto et al., 2005) as well as the clearance of old mitochondria through autophagy (Lee et al., 2008). We have also explored the biology of mitochondrial SIRT3, demonstrating a role for this protein in overall ATP homeostasis and in particular, in regulating the acetylation of the electron transport chain (Ahn et al., PNAS, 2008). Ongoing efforts are related to exploring the biology of SIRT2 using various in vitro and in vivo approaches. We have recently reviewed our progress and the work of others in this field (Finkel et al., Nature 2009).
A second aim of the laboratory is to understand the role of stem cells in aging. Our interest in this area was sparked by our previous clinical observations regarding a decline in endothelial cell progenitor number and function in patients with impaired vascular function (Hill et al., 2003). We were interested in understanding the potential biological connections between aging and stem cell dysfunction. Our major new finding with regard to this aim involved a mouse model of accelerated aging known as the klotho mouse. This animal model lacks the gene encoding klotho that encodes for a circulating protein. We demonstrated that klotho mice have widespread stem and progenitor cell dysfunction and that klotho can serve as a circulating Wnt inhibitor (Liu et al., 2007). This result suggests a novel potential role for Wnt signaling in mammalian aging. While we continue to pursue these observations, we have also explored other models of stem cell dysfunction including the bmi1 deficient mouse. This animal is characterized by a post-natal defect in hematopoietic and neural stem cell self renewal. We have recently demonstrated that tissues within the bmi1-/- mice are characterized by a rise in intracellular reactive oxygen species (ROS) and that this oxidative stress can activate the DNA damage response (DDR) pathway. Genetic ablation of the DDR by Chk2 deletion can extend the life span of the bmi1-/- mice (Liu et al, Nature 2009). We are currently extending these observations to try and understand the role of mitochondrial dysfunction in the normal aging pattern and biology of hematopoietic stem cells. These results have also encouraged us to look more carefully at the underlying cellular response to DNA damage and genomic instability and the role of these alterations in aging. A preliminary set of such observations was published this year (Cao et al., Mol Cell 2009). Finally we have pursued the connection between mTOR activity and mitochondrial metabolism. The mTOR pathway serves as a nodal point for energy homeostasis and has been implicated in mediating the beneficial effects of caloric restriction and overall lifespan for a variety of simple organisms. We have demonstrated that this pathway is also implicated in mammalian mitochondrial metabolism (Schieke et al., 2006). Additional studies have pursued this connection with regard to the cell cycle and stem cell function(Schieke et al., Cell Cycle, 2008;Schieke et al., JBC, 2008). Ongoing efforts are in characterizing mouse models that have altered mTOR activity. Furthermore, given that the mTOR pathway is an important nutrient regulator of autophagy we have sought to further characterize this (e.g. authophagy) process. These results have suggested a role for protein acetylation in the regulation of autophagy (Lee and Finkel, JBC 2009). Ongoing efforts are pursuing the interconnection between autophagy and nutrient sensing through both TOR-dependent and independent pathways.
| Meschiari, Cesar A; Ero, Osasere Kelvin; Pan, Haihui et al. (2017) The impact of aging on cardiac extracellular matrix. Geroscience 39:7-18 |
| Yan, Ye; Finkel, Toren (2017) Autophagy as a regulator of cardiovascular redox homeostasis. Free Radic Biol Med 109:108-113 |
| Marmisolle, Inés; Martínez, Jennyfer; Liu, Jie et al. (2017) Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation. Arch Biochem Biophys 613:12-22 |
| Sun, Nuo; Malide, Daniela; Liu, Jie et al. (2017) A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat Protoc 12:1576-1587 |
| Pan, Haihui; Yan, Ye; Liu, Chengyu et al. (2017) The role of ZKSCAN3 in the transcriptional regulation of autophagy. Autophagy 13:1235-1238 |
| Budinger, G R Scott; Kohanski, Ronald A; Gan, Weiniu et al. (2017) The Intersection of Aging Biology and the Pathobiology of Lung Diseases: A Joint NHLBI/NIA Workshop. J Gerontol A Biol Sci Med Sci 72:1492-1500 |
| Pan, Haihui; Finkel, Toren (2017) Key proteins and pathways that regulate lifespan. J Biol Chem 292:6452-6460 |
| Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222 |
| Torisu, Kumiko; Singh, Krishna K; Torisu, Takehiro et al. (2016) Intact endothelial autophagy is required to maintain vascular lipid homeostasis. Aging Cell 15:187-91 |
| Sun, Nuo; Youle, Richard J; Finkel, Toren (2016) The Mitochondrial Basis of Aging. Mol Cell 61:654-666 |
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