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Collaborating Laboratories 1. Oxidative Signalling, Osteoporosis & Aging Robert L. Jilka, XiaoDong Chen, Robert S. Weinstein, Stavros C. Manolagas Center for Osteoporosis and Metabolic Bone Diseases and Central Arkansas Veterans Healthcare System; University of Arkansas for Medical Sciences Funded by a Program Project Grant from NIA (S.C. Manolagas, P.I.) Background Activation of PPAR-gamma by rosiglitazone or oxidized lipids in vitro promotes the development of adipocytes, occurring at the expense of osteoblasts (Endocrinology 143:2376, 2002). Moreover, rosiglitazone-induced bone loss in mice is associated with increased marrow adiposity, decreased osteoblast number and bone formation rate, and increased osteoblast and osteocyte apoptosis (J Endo 183:203, 2004; Endocrinology 145:401,2004; ibid 146:1226, 2005). The levels of PPAR-gamma and Alox15 – a lipoxygenase that generates oxidized lipids – are inversely related to bone mass in mice (Science 303:229, 2004; J Clin Invest 113:846, 2004).Hypotheses & Aims We hypothesize that increased lipid oxidation as a function of age is an important contributing factor to involutional osteoporosis. To test this, we have collaborated an NIA Program Project Grant headed by Robert Shmookler Reis, and our mouse tibia samples have been analyzed by their Metabolic Assessment Core, under the direction of John J. Thaden. Together, we have obtained evidence in mice for age-dependent increase in PPAR-gamma activation by oxidized lipids derived from lipoxygenase Alox15, an increase that is apparently functionally coupled to the pathogenesis of age-related bone loss. Three products of Alox15 activity, 9-HODE, 13-HODE, and 12-HETE, were significantly increased at 25 months of age relative to 8 or 16 months, as a fraction of total polyunsaturated fatty acids. Isoprostanes are also increased at 25 months, whereas 5 other HETEs, including 4 produced by Alox-15-independent pathways, are not significantly elevated with age. Since mRNAs for Alox15 as well as PPAR-gamma are elevated in mouse calvarial cells with age, we propose that these are functionally related aging processes. Significance We propose that the age-dependent increase in ROS leads to an increase in Alox15, and to PPAR-gamma activation by oxidized lipids. Age-related bone loss may be due in part to increased adipogenesis, at the expense of osteoblastogenesis, and increased apoptosis of osteoblast progenitors. This understanding may lead to new modes of intervention to offset the senescent decline in bone mass and strength.Results of Collaboration Data SlidesTeam Robert L. Jilka, Ph.D., Project Leader XiaoDong Chen, Ph.D., Robert S. Weinstein, M.D. Stavros C. Manolagas, M.D., Ph.D., P.I. of Program Project --------------------------------2. Neuronal Oxidative Damage during Aging Jason Chang, Steve Barger, Harry Brown, Tarun Garg Dept. of Neurobiology & Developmental Sciences University of Arkansas for Medical Sciences Background The centrality of the nervous system to longevity has become evident in two invertebrate models. Overexpression of human superoxide dismutase (SOD1) in Drosophila melanogaster motor neurons greatly extends its life span, suggesting that neuronal resistance to oxidative stress is the key to extension of life in these flies. In the nematode C. elegans, worms bearing a mutation that extends lifespan can be restored to normal lifespan by expression of a normal (unmutated) copy of that gene, just in motorneurons, whereas expression targeted to other tissues was much less effective. Thus, in worms as in flies, it looks as though the nervous system is all that matters for lifespan! The relationship between life span and neuronal resistance to oxidative stress in mammals, however, has not been studied.Hypotheses & Aims The retina (as anexperimentally accessible compartment of the CNS)undergoes age-dependent degeneration in humans and other mammals. We propose that this degeneration is a result of oxidative damage, and impaired defenses against that damage during aging. We are therefore testing the response of retinal pigmented epithelial cells to oxidative stresses, as a function of age and (in later studies) as a function of longevity. Significance We hope through these studies to learn about the fundamental mechanisms of aging, and to develop prophylactic and therapeutic measures to prevent and cure retinal degeneration in the elderly.Team Jason Chang, Ph.D., Project Leader Steve Barger, Ph.D., Investigator Harry Brown, O.D., M.D. Tarun Garg, Ph.D, Research Associate
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