Biogerontology 1: 225–233, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands. 225 Review article Molecular chaperones and the aging process Csaba S˝ oti & P´ eter Csermely * Department of Medical Chemistry, Semmelweis University, P.O. Box 260, Budapest 8, H-1444, Hungary; * Author for correspondence (e-mail: csermely@puskin.sote.hu; fax: +36-1-266-6550) Received 14 February 2000; accepted 23 February 2000 Key words: aging, Alzheimer’s disease, chaperone, heat shock protein, immune response, longevity, neurodegen- erative diseases, protein folding, senescence, stress protein Abstract Molecular chaperones are abundant, well-conserved proteins responsible for the maintenance of the conformational homeostasis of cellular proteins and RNAs. Environmental stress is a proteotoxic insult to the cell, which leads to chaperone (heat shock protein, stress protein) induction. The protective role of chaperones is a key factor for cell survival and in repairing cellular damage. The present review summarizes our current knowledge about changes in chaperone expression and function in the aging process, as well as their possible involvement in the development of longevity and cellular senescence. We also overview their putative role in neurodegenerative diseases, such as in Alzheimer’s disease and the changes in immune and autoimmune response against various chaperones in aging. Abbreviations: Grp – glucose regulated protein; Hsc70 – the non-inducible (cognate) form of the 70 kDa heat shock protein; Hsp – heat shock protein Introduction: cellular roles of molecular chaperones Molecular chaperones bind to, and stabilize an other- wise unstable conformer of another protein or RNA and, by controlled binding and release, facilitate its correct fate in vivo: be it folding, oligomeric assembly, transport to a particular subcellular com- partment, or disposal by degradation. In the molecular level chaperones (1) protect against aggregation, (2) solubilize protein aggregates, (3) assist in protein folding/refolding by partial unfolding the intermediate structures in the folding process, (3) target ultimately damaged proteins to degradation and (5) sequester overloaded damaged proteins to larger aggregates. Chaperones are ubiquitous, highly conserved proteins, which probably played a major role in the evolu- tion of modern enzymes (Csermely 1997, 1999; Hartl 1996). Chaperones are vital for our cells during their whole lifetime. However, they are needed even more after environmental stress, that induces protein dam- age. Stress (especially its most studied archetype, heat shock) leads to the expression of most chaperones, which therefore are called heat-shock, or stress pro- teins. Lacking a settled view about their action in the molecular level, chaperones are still best classi- fied by their molecular weights. The major chaperone families are listed in Table 1. Besides the general chap- erones listed in Table 1, which have a rather large promiscuity in target-selection, there are also special- ized chaperones, such as Hsp47, the special chaperone of collagen. Chaperones usually do not increase the speed of protein folding, just inversely, by binding to folding intermediates, or by their repetitive pulling attempts extend the total folding time and simultan- eously increase the final yield of the native protein. Special steps of protein folding are accelerated by the so-called ‘folding catalysts’, such as peptidyl-prolyl isomerases (immunophilins), and protein disulfide iso- merases, which promote the cis-trans isomerization