The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16 INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16 INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16 INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16 INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.

The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16 INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16 INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16 INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16 INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.

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Background & Aims-Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C pathogenesis and treatment.

IntroductionThe hallmarks of AIDS are high levels of HIV-1 infection, depletion of CD4 ϩ T cells, and loss of immunity. The mechanism of HIV-1 immunopathogenesis is not clear because human patients are the only hosts that support high levels of HIV-1 replication and develop AIDS. Extensive studies have been performed in primate models with either low levels of HIV-1 replication (HIV-1 in chimps) or a different virus (simian immunodeficiency virus [SIV] or simian/human immunodeficiency virus [SHIV] in monkeys). 1-3 HIV-1 fails to infect murine cells due to blocks at multiple steps of the HIV life cycle. The mouse with a reconstituted human immune system would be an ideal small animal model for studying HIV-1 infection and pathogenesis. A number of human-mouse chimeric models have been developed, but with only limited success. The severe combined immunodeficient (SCID)-hu Thy/Liv mouse has an intact human thymus organ, thus allowing investigation of HIV-1 pathogenesis in a human lymphoid organ. [4][5][6] However, very low levels of human T cells are detected in the peripheral lymphoid organs or blood. The hu-peripheral blood lymphocyte (PBL)-SCID mouse supports transient and selective engraftment of xenoreactive human T cells. 7,8 Human CD34 ϩ cells transplanted into SCID or nonobese diabetic (NOD)/SCID mice lead to generation of mainly human myeloid and B cells in the mouse bone marrow, but inefficient generation of human T cells. 9,10 When CD34 ϩ human hematopoietic stem cells (HSCs)/hematopoietic stem progenitor cells (HSPCs) are injected directly into the liver of newborn Rag2-␥C double-knockout (DKO) mice, which lack T, B, and natural killer (NK) cells, the newborn liver environment of DKO mice supports efficient engraftment and development of a functional human immune system in central and peripheral lymphoid organs. 11,12 To demonstrate that the DKO-hu HSC mouse can support efficient HIV-1 infection with relevant immunopathogenesis, we show that CCR5 and CXCR4, the HIV-1 coreceptors, are both expressed on human T cells in central and peripheral lymphoid organs. DKO-hu HSC mice allow high plasma viremia with high levels of HIV-1 infection in lymphoid organs. Both CD4 ϩ CD45RO ϩ and CD4 ϩ CD45RO Ϫ T cells are productively infected in lymphoid organs. Human CD4 ϩ T cells are gradually depleted by HIV-1 in a dose-dependent manner. In addition, HIV-1 infection persists in infected DKO-hu HSC mice for at least 19 weeks, with recoverable infectious HIV-1 in lymphoid tissues. Materials and methods Construction of DKO-hu HSC mice with human CD34 ؉/؊ cells from cord blood or fetal liverHuman CD34 ϩ cells were isolated from cord blood (CB) or fetal liver (FL) tissues. FL CD34 ϩ (1 ϫ 10 6 ) or CB CD34 ϩ (1 ϫ 10 5 ) cells were injected intrahepatically into each newborn DKO mouse previously irradiated at 400 rad. 11 Human leukocytes (CD45 ϩ ) were analyzed for CD3, CD4, CD8, CD45RO, CD19, CCR5(2D7), and CXCR4(12G5) by fluorescenceactivated cell sorting (FACS). 13 HIV-1 infection and pathogenesis in DKO-hu HSC miceAt l...