Introducing Professor Nikki Holbrook, Stress Signaling and Aging Section Editor

Dear Colleagues

It is my pleasure to introduce Nikki Holbrook as founding editor of the newest dedicated section in Cell Stress & Chaperones, “Stress Signaling and Aging.” Nikki served as Chief of the Laboratory of Cellular and Molecular Biology at the National Institute on Aging from 1997–2001 and is currently Professor of Internal Medicine in the Section of Geriatrics, Yale University School of Medicine. She is also a Fellow of the Gerontological Society of America.

Nikki is a founding member of the Cell Stress & Chaperones Editorial Board, where she has contributed extensively as a reviewer and monitoring editor. In addition, she has published work from her laboratory in our journal, including the first study showing that aspirin enhances the hyperthermic responses of rats resulting in increased expression of Hsp70 in vivo (Fawcett et al 1997). In collaboration with James Stevens and coworkers (Halleck et al 1997) Nikki also published on stress signaling, demonstrating that the genes encoding both the endoplasmic reticulum chaperone Grp78 and the growth arrest–deoxyribonucleic acid (DNA) damage protein Gadd153 are responsive to reductive stress and share steps in their upstream signaling pathways.

Nikki's group was among the first to demonstrate changes in the heat shock response as a function of mammalian aging (Fargnoli et al 1990) and to link age-related changes in the activation of heat shock proteins in the intact host to hormonal axes important in mediating responses to physiological or behavioral (or both) stress (Blake et al 1991; Udelsman et al 1993). More recently, she has turned her attention to an investigation of the response to oxidant injury and the role of growth factor signaling molecules in mediating the activation of pathways important for cell survival. Of particular interest in this regard are the extracellular signal–regulated kinase (ERK) mitogen-activated protein kinase pathway, the PI3-kinase–Akt pathway, and activation of phospholipase C–γ1, all of which support survival of mammalian cells after oxidant injury (Guyton et al 1996; Wang et al 2000, 2001). Using hepatocytes derived from rats, Nikki and her colleagues have demonstrated an age-related reduction in hydrogen peroxide–induced activation of the ERK and Akt prosurvival signaling pathways and have provided additional evidence that the attenuation of these stress responses contributes to lower survival of aged cells (Liu et al 1996; Ikeyama et al 2002). Current studies are focused on better understanding the basis for the age-related decline in stress responsiveness so that strategies can be devised to up-regulate these homeostatic responses and to improve stress tolerance in the elderly. Other studies have demonstrated a role for c-Jun N-terminal kinase (JNK) in regulating tumor cell growth and a function for c-Jun in protecting cells against DNA damage (Potapova et al 2000a, b, Potapova 2001).

A number of significant studies involving stress signaling or aging (or both) have been published in Cell Stress & Chaperones. Actually, they are too numerous to include all of them in this brief letter, so a sampling is provided with the hope that interested readers will search out others in either the print or on-line version of Cell Stress & Chaperones. Our first article on aging, authored by Locke and Tanguay (1996), showed that hearts of aged rats were impaired in their ability to produce cytoprotective heat shock proteins, a possible contributing factor to the increased susceptibility of aged hearts to stress. In contrast, both Hsf activation and Hsp70 accumulation are similar in aged and adult rat skeletal muscles (Locke 2000). Ectopic expression of Hsp70 in aged IMR90 cells in culture suppresses the activation of JNK by heat shock and protects from heat-induced apoptosis (Volloch et al 1998). It was shown in the same study that aged cells have a reduced ability to induce endogenous Hsp70, which can be restored by treating them with a protease inhibitor. Under these conditions, JNK activation is suppressed, and apoptosis is reduced.

Smith and coworkers (Nair et al 1996) showed that a common assembly pathway, involving multiple accessory proteins and Hsp90 used for the progesterone receptor, extends to different classes of transcription factors as well as protein kinases and the aryl hydrocarbon receptor. Furthermore, geldanamycin, an inhibitor of Hsp90, blocks kinase-mediated signaling events during T-lymphocyte activation (Schnaider et al 2000). Gaestel and coworkers (Schultz et al 1997) provided evidence that p38RK and MAPKAP kinase 2 are part of a signal transduction pathway leading to Hsp27 phosphorylation in HL-60 cells but that this phosphorylation event is not needed for HL-60 cell differentiation.

A number of papers have added to our understanding of induced cytoprotection (thermotolerance), links between the stress response and apoptotic pathways, and blocking of signal transduction pathways. For example, Hsp70 is involved in the cytoprotection of macrophages infected with Salmonella choleraesuis against cell death induced by tumor necrosis factor–α (Nishimura et al 1997). Hsp70 can protect Rat-1 cells in culture against heat-induced apoptosis by increasing the rate of inactivation of JNK (Volloch et al 2000). Heat shock may inhibit proinflammatory responses in lung cells by activating the promoter for I-κBα, thus keeping NF-κB inactive (Wong et al 1999). In rats a heat pretreatment reduces sepsis-induced apoptosis, which is likely, in part, because of the inhibition of inflammation (Chen et al 2000). Hsp27 is also a player in cytoprotection, and it is known to protect the mitochondria of thermotolerant cells against apoptotic stimuli (Samali et al 2001).

Roles of heat shock proteins in extracellular environments were heralded by several papers, including a report on the surface localization of Hsp70 on certain tumor cells with a possible role in NK-mediated antitumor responses (Botzler et al 1998) and a report that U-937 promonocytic cells can take up Hsp70 by endocytosis (Guzhova et al 1998). Another molecular chaperone Hsp60 and antibodies against it were found in the peripheral circulation of normal humans (Pockley et al 1999). In contrast, antibodies against stress-inducible Hsp70, but not Hsp60, were detected in sera from patients with acute heat-induced illness (Wu et al 2001), and it was shown that exercise increases the levels of Hsp70 detectable in human serum (Walsh et al 2001). Extracellular and plasma Hsp70 have the potential to activate the human complement system, another arm of innate immunity that can produce additional proinflammatory mediators (Prohászka et al 2002). These extracellular heat shock proteins and their antibodies have the potential to signal through cell surface receptors and to block signaling, respectively, between cells, tissues, and organs in ways that we are just beginning to appreciate. The proceedings of an international symposium on heat shock proteins in biology and medicine were published as the November 2000 issue. It contains articles by Asea, Calderwood, Srivastava, and others showing extracellular activities of heat shock proteins as “chaperokines” and mediators of both innate and adaptive immune responses.

Clearly, the time is ripe for a dedicated section on stress signaling and aging. To introduce Professor Holbrook as section editor and to emphasize the continuing commitment of our journal to this research area, we have collected in this issue timely reviews on some of the most exciting aspects of stress signaling and aging. They are marked appropriately, we think, by the Chinese symbol for longevity (shou).