2007 ANNUAL SCIENTIFIC MEETING 87 Why might a single gene exert an anti-aging function in such a broad range of organisms? An important insight came from the discovery that the SIR2 gene product was a protein with a novel biochemical activity - NAD-dependent deacetylase (9, 10). This deacetylase activity allows SIR2 to remove acetyl tags from lysine residues along other proteins in cells, including key regulatory proteins. Thus, SIR2 can affect many important pathways in cells. The NAD requirement of SIR2 inextricably links it to metabolism, for which NAD and the reduced NADH are critical conduits. For this reason, it was proposed that sirtuins mediate the known effects of metabolism and diet on aging, i.e. sirtuins may trigger the salutary effects of CR ( 11 ). Where does the hypothesis that sirtuins mediate CR stand? In yeast, ample evidence has been provided that effects of moderate CR require SIR2 (12, 13) and, in a certain strain, the SIR2 related sirtuins, HSTl and HST2 (14). In fruit flies, the effects of dietary restriction have been shown to require the fruit flies' SIR2 gene (15). In mice, at least one of the effects of CR, increased physical activity, has been shown to require the mammalian SIR2 gene, SIR.Tl (16). Further, SIRTl levels are controlled by nitric oxide, a small molecule the synthesis of which is induced by CR and which is required for the resulting physiological effects of this dietary regimen (17). Indeed, SIRTl protein levels are increased in many tissues by CR (18), consistent with its candidacy as a CR mediator. Moreover, SIRTl has been shown to deacetylate many key transcriptional factors and cofactors in the nucleus on mammalian cells. These include factors that mediate two of the most important effects of CR, altered metebolism and stress resistance. In the case of stress resistence, SIRTl targets include p53 (19, 20), FOXO (21, 22), and Ku-Bax (23)- all involved in the cellular response to oxidative and other stresses. In the case of metabolism, SIRTl regulates fat storage in white adipocytes (24), insulin secretion in beta cells (25, 26), and metabolism in muscle and liver (27). SIRTl and its homologous sirtuins offer a new strategy to approach diseases of aging, including diabetes and cardiovascular disease. 1) Weind.ruch, R. & Walford, R.L.:Charles C. Thomas, Springfield, Illinois, 1988 2) Guarente, L.: Nature, 444, 868-874, 2006 3) Fernandes, G., Yunis, E.J. & Good, R. A.: Nature, 263, 504-507,1976 4) Zhu, H., Gou, Q. & Mattson, M.P.:Brain Res., 842, 224-229, 1999 5) Kaeberlein, M., Mc Vey, M. & Guarente, L.: Genes Dev., 13, 2570-2580, 1999 6) Sinclair, D. A. & Guarente, L.:Cell, 91, 1033-1042, 1997 7) Tissenbaum, H.A. & Guarente, L.: Nature, 410, 227-230, 2001 8) Berdichevsky, A., Viswanathan, M., Horvitz, R. & Guarente, L.: Cell, 16, 1165-1178, 2006 9) Imai, S., Armstrong, C.M., Kaeberlein, M. & Guarente, L.: Nature, 403, 795-800, 2000 10) Landry, J. et al.:Proc Natl Acad. Sci. USA, 97, 5807-5811, 2000 11) Guarente, L.: Genes Dev., 14, 1021-1026, 2000 12) Lin, S.J., Defossez, P.A. & Guarente, L: Science, 289, 2126-2128, 2000 13) Lin, S.J. et al.: Nature, 418, 344-348, 2002 14) Lamming, D.W. et al.: Science, 309, 1861-1864, 2005 15) Rogina, B. & Helfand, S.L.:Proc. Natl Acad. Sci. USA, 101, 15998-16003, 2004 16) Chen, D., Steele, A.D., Lindquist, S. & Guarente, L.:Science, 310, 1641, 2005 17) Nisoli, E. et al.: Science, 310,314-317, 2005 18) Cohen, H.Y. et al.: Science, 305, 390-392, 2004 19) Luo, J. et al.: Cell, 107, 137-148, 2001 20) Vaziri, H. et al.: Cell, 107, 149-159, 2001 21) Motta, M.C. et al.: Cell, 116, 551-563, 2004 22) Brunet, A. et al.: Science, 303, 2011-2015, 2004 23) Cohen, H, Y. et al.: Mol. Cell, 13, 627-638, 2004 24) Picard, F. et al.: Nature, 429, 771-776, 2004 25) Bordone, L. et al.: PLoS Biol., 4, e31, 2005 26) Moynihan, K. A. et al.: Cell Metab., 2, 105-117, 2005 27) Rodgers, J.T. et al.: Nature, 434, 113-118, 2005

88 JOURNAL OF COSMETIC SCIENCE THE IMMUNE SYSTEM: A BRIDGE BETWEEN HEALTH AND DISEASE Howard B. Fleit, Ph.D. Department of Pathology, Stony Brook University School of Medicine The immune system has evolved to provide protection against invasion by disease producing microorganisms. The human immune system is comprised of two distinct pathways that cooperate with one another on a cellular and molecular basis. These two pathways are the innate and the adaptive components of immunity. The innate pathway consists of cells and molecules that provide the body's first line of defense against infectious microorganisms. The adaptive pathway of the immune system consists of specialized cells called lymphocytes (B cells and T cells). Adaptive immune responses are more specific and develop greater activity upon subsequent exposure to the pathogen. Cells from both arms of the immune system utilize membrane receptors to recognize distinct components associated with microorganisms. Innate Immunity Epithelial cells and their products provide the first line of defense in innate immunity protecting the host from invasion of microbes from the external environment. However, if a microbe enters the tissues or circulation they initially encounter cellular components of innate immunity. A prominent group of innate immune cells are phagocytes. Mononuclear phagocytes include monocytes that circulate in the blood and macrophages that are found in virtually every organ. Polymorphonuclear leukocytes consist predominantly of neutrophils that circulate in the blood along with a small number of eosinophils and basophils. Other cells that participate in innate immunity include dendritic cells found in various lymphoid organs, Langerhans cells found in the skin and natural killer cells (NK cells) found in the blood. A family of plasma proteins called the complement system also plays a critical role in the early interaction of the host with invading pathogens. In addition to its role in providing the initial defense against infections, the innate immune responses enhance the subsequent adaptive immune responses against the infectious microorganism. Cells of the innate immune system recognize structures that are shared by classes of microbial organisms. These structures are broadly classified as Pathogen associated molecular patterns (PAMPS). Receptors have evolved on phagocytic cells of the innate immune system to recognize these P AMPS and are called Pattern Recognition Receptors (PRR.). Adaptive Immunity Cells of the adaptive immune pathway, lymphocytes, express receptors that recognize diverse molecules produced by microbes as well as noninfectious molecules. These molecules are referred to as antigens and the receptors on B cells and T cells that recognize and bind antigens are called B cell antigen receptors and T cell antigen receptors. These specific antigen receptors trigger effector functions that are designed to eliminate the invading pathogen. Thus binding of antigen to the B cell antigen receptor results in the production of antibodies that function to eliminate microorganisms from extracellular locations whereas activated T cells eliminate microbes that are living inside cells. The adaptive immune pathway is characterized by diversity, specificity and memory. Diversity is provided by millions of different lymphocytes each expressing a unique antigen receptor. These receptors arise during development of these lymphocytes in a random manner and are available to respond to an antigen when an individual encounters that specific molecule. Specificity refers to the concept that each antigen receptor recognizes a precise component of the antigen molecule called an epitope. When a lymphocyte binds an antigen via its antigen receptor the receptor transduces an activating signal into the cell. This signal instructs the cell to replicate and one of the progeny cells differentiates into an effector cell while the other produces a clone of itself which is referred to as a memory cell. Each time the cell with the specific receptor for that antigen encounters the epitope it expands the pool of memory cells for that antigen and increases the speed and magnitude of the immune response. This is the mechanism by which vaccine development occurs. The specificity and diversity of the lymphocyte receptors results in a clonal distribution of receptors for antigen such that the total population of lymphocytes consists of many different clones. Two classes of T lymphocytes exist. One class is referred to as cytolytic T cells and recognize foreign antigenic epitopes presented to it by a surface protein on host cells. This protein is called the Major Histocompatibility Class 1 protein and presents antigenic epitopes from pathogens that infect a cell. Cytolytic T cells play a prominent role in host defense against virally infected host cells. A second class of T cells is called helper T cells and they recognize foreign antigenic epitopes presented by Major Histocompatibility Class 2 protein. These molecules present antigenic peptides that 'professional antigen