Aging and longevity of differentiated cells in vitro That replicative senescence—the model of aging in vitro— probably is related to a chaperone deficit can be assumed from the increase in life span obtained by transfection with protein-chaperones, as well as from the attainment of cellular immortalization by heat shock procedures or transfection with RNA-chaperones (Kroll, 2004).
Aging and longevity of differentiated cells in vivo The great variability in the life span of differentiated cells in the organism shows a direct correlation to the constitutive expression of the molecular chaperones. Thus, compared with the short-lived epithelial cells, the basal expression of chaperones is relatively high in the long-lived post-mitotic cells as, for example, the neurons of the brain and the stromal cells of the eye lens. Thus, in the brain, the constitutive unstressed level of expression of Hsp70, Hsp90, and Hsp100 resembles that of heat-stressed somatic cells. In the stromal cells of the eye lens, the dominant chaperone is alpha-crystallin, which constitutes 40% of total cellular protein and assures the preservation of lifelong transparency of the lens in the absence of structural protein turnover. Chaperone dysfunction leads to protein aggregation, lens opacity and cataracts (Krall, 2005).
The inducibility of Hsp70 by heat shock is reduced to approximately 50% in old rat hepatocytes, suggesting that a reduced ability to express hsp70 in response to stress may be a common phenomenon underlying the aging process. This age-related decline in the Hsp70 stress response was reversed by caloric restriction (Heydari et al., 1996). There is a functional link between age-related decrements in Hsp70 expression and patho-physiological responses to heat stress leading to tissue injury and dysfunction (Kregel, 2002). Efficient removal of oxidized proteins depends on chaperone-mediated autophagy (see the section on lysosomal chaperones). This mechanism is severely impaired during aging demonstrated by the accumulation of oxidized proteins in old age (Kiffin et al., 2004).
Cells derived from older people show a very low heat response in terms of Hsp47 expression, and there is a gradual down-regulation of Hsp47 expression with age, regulated by transcriptional mechanisms. Hsp47 induction is markedly attenuated in high PDL cells, showing an age-related decrease in response to pro-collagen retention in the ER (Miyaishi et al., 1995). Polyphenol-rich Salix alba extracts can obviate this decrease in HSP47 expression (Nizard et al., 2004).
Damage to the ER organelle and its subsequent impaired functionality may be involved in the process of aging, judging by increased ER-chaperone expression, preferential oxidation of ER-resident proteins, and altered calcium homeostasis (van der Vlies et al., 2003).
Old cells show a greater sensitivity to ER stress than young cells, suggesting a link between stress resistance and longevity (Li and Holbrook, 2004).
Experimental procedures increasing the life span of differentiated cells
Experimental procedures increasing the level of expression of various chaperones have been shown to increase cellular life span and resistance against apoptosis. Thus, intermittent mild heat stress (hormesis) increases the level of various chaperones and improves cellular resistance against noxious agents. Further, an in vitro model of caloric restriction (CR) demonstrates an increase in Hsp70 expression and cellular resistance obtained by cell culture in CR-sera, possibly contributing to the effect of CR on cellular longevity. Also, the anti-apoptotic effect of nitric oxide is associated with an increase in the expression of Hsp70 as well as of the RNA-chaperone p68. The anti-apoptotic effect of nicotine could possibly relate to activation of the heat shock factor (Krall, 2005).
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