Hormetic modulation of differentiation of normal human epidermal keratinocytes undergoing replicative senescence in vitro.

Normal human epidermal keratinocytes (NHEK) show both the Hayflick phenomenon of replicative senescence and differentiation in vitro, depending upon the culture conditions. Using this experimental model system, we have studied age-related changes in the ability of serially passaged NHEK to enter into differentiation in the presence of calcium, as measured by the levels of differentiation markers involucrin, p38 and Hsp27. The results obtained in these studies show that calcium-induced differentiation of NHEK becomes progressively delayed during cellular aging in vitro, which can be modulated by treatments such as mild heat stress, kinetin and curcumin. Whereas all these treatments on their own were able to increase the levels of various differentiation markers to varying extents, their effects were synergistic and rapid in the presence of calcium. Furthermore, all three modulators tested in the present study bring about their effects by inducing stress response pathways in terms of an increase in the levels of stress proteins Hsp90, Hsp70 and heme-oxygenase-1 (HO-1), which is indicative of stress-induced hormesis bringing about the biologically beneficial effects.