A natural extracellular factor that induces Hsp72, inhibits apoptosis, andrestores stress resistance in aged human cells

Experiments with cultured cells showed that most cellular stress resistance components are specialized for certain types of damage. For example, super oxide dismutase protects from oxidative damage; DNA repair enzymes guard ag ainst mutagens and other DNA-damaging agents. On the other hand, the major inducible heat shock protein Hsp72 protects cells from a large variety of s tresses and thus represents a generalized repair/stress resistance componen t. Hsp72 not only refolds damaged proteins but also interferes with program med cell death signaling pathways, thus providing cells with time to repair the damage, hence its universality as a stress protector. In the present s tudy we demonstrate the occurrence in murine and human ascites fluids (AF) of a natural nontoxic extracellular factor (ascites Hsp72-inducing factor, AHIF) capable of activating Hsp72 expression in different types of cells vi a a pathway distinct from the heat shock response pathway. AHIF is unique i n that it is the first physiological factor capable of inducing synthesis o f Hsp72 not only in young cells but, remarkably, also in aged human cells t hat largely have lost the ability to express Hsp72 in response to stresses, a manifestation at the cellular level of a progressive impairment in the a bility to adapt to environmental changes which characterizes aging. Pretrea tment of aged human cells with AF triggers Hsp72 expression at levels seen in young stressed cells and protects cells from a variety of otherwise leth al stressful treatments such as heat shock, TNF, UV irradiation, etoposide, and menadione. Activation of Hsp72 expression is essential for antiapoptot ic action of AHIF because specific inhibition of Hsp72 expression by antise nse RNA abolishes the cytoprotective effect of AF. In view of an important link between stress resistance and longevity in different organisms, the ab ilities of AHIF make it a unique candidate for the role of a systemic regul ator of the aging process. While a cell-autonomous stress response diminish es with aging, aged cells retain the ability to respond to an extracellular factor which induces the expression of Hsp72. This finding opens up exciti ng possibilities for using AF factor to restore stress resistance to old ce lls and organisms and the possibility of interfering with the aging process . The ability to induce stress resistance in young cells and to restore it in aged cells could serve as a basis for developing effective antiapoptotic therapies. (C) 1999 Academic Press.