Human diploid fibroblasts eventually lose the capacity to replicate in culture and enter a viable but nonproliferative state of senescence. Recently, it has been demonstrated that retroviral-mediated gene transfer into primary fibroblasts of an activated ras gene (V12ras) rapidly accelerates development of the senescent phenotype. Using this in vitro system, we have sought to define the mediators of Ras-induced senescence. We demonstrate that expression of V12Ras results in an increase in intracellular and in particular, mitochondrial reactive oxygen species. The ability of V12Ras to induce growth arrest and senescence is shown to be partially inhibited by coexpression of an activated rac1 gene. A more dramatic rescue of V12Ras-expressing cells is demonstrated when the cells are placed in a low oxygen environment, a condition in which reactive oxygen species production is inhibited. In addition, in a 1% oxygen environment, Ras is unable to trigger an increase in the level of the cyclin-dependent kinase inhibitor p21 or to activate the senescent program. Under normoxic (20% O 2 ) conditions, the V12Ras senescent phenotype is demonstrated to be unaffected by scavengers of superoxide but rescued by scavengers of hydrogen peroxide. These results suggest that in normal diploid cells, Ras proteins regulate oxidant production and that a rise in intracellular H 2 O 2 represents a critical signal mediating replicative senescence.

Conventionally, "elderly" has been defined as a chronological age of 65 years old or older, while those from 65 through 74 years old are referred to as "early elderly" and those over 75 years old as "late elderly." However, the evidence on which this definition is based is unknown. We have attempted to review the definition of elderly by analyzing data from long-term longitudinal epidemiological studies, and clinical and pathological studies that have been accumulated at the Tokyo Metropolitan Geriatric Hospital and the Tokyo Metropolitan Institute of Gerontology. Our recommendation might be a starting point in developing a strategy for a successful society by reviewing the definition of elderly based on comprehensive evidence in all aspects of social, cultural and medical sciences.

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Primary infection with varicella-zoster virus (VZV) causes the characteristic syndrome of varicella, or chickenpox. Experiments in severe combined immunodeficiency mice with human skin grafts (SCIDhu mice) indicate that VZV infection of T cells can mediate transfer of infectious virus to skin. VZV-infected T cells reached epithelial sites of replication within 24 h after entering the circulation. Memory CD4+ T cells were the predominant population recovered from skin in SCIDhu mice given uninfected or infected mononuclear cells, suggesting that immune surveillance by memory T cells may facilitate VZV transfer. The increased susceptibility of memory T cells to VZV infection may further enhance their role in VZV pathogenesis. During VZV skin infection, viral gene products down-regulated interferon-α to permit focal replication, whereas adjacent epidermal cells mounted a potent interferon-α response against cell–cell spread. Interleukin-1α, although activated in VZV-infected cells, did not trigger expression of endothelial adhesion molecules, thereby avoiding early recruitment of inflammatory cells. The prolonged varicella incubation period appears to represent the time required for VZV to overcome antiviral responses of epidermal cells and generate vesicles at the skin surface. Modulation of VZV replication by cutaneous innate immunity may avoid an incapacitating infection of the host that would limit opportunities for VZV transmission.

Coronary collateral vessels reduce damage to ischemic myocardium after coronary obstruction. Factors that stimulate collateral formation are expected to have ameliorating effects on myocardial infarction. In a canine experimental myocardial infarct model, intracoronary injection of basic fibroblast growth factor (bFGF) improved cardiac systolic function and reduced infarct size. Treatment with bFGF increased the number of arterioles and capillaries in the infarct. Thus, the angiogenic action of bFGF might lead to a reduction in infarct size. The application of bFGF might bring about a therapeutic modality for the salvage of infarcted myocardium.