Reference conditions An involvement of the molecular chaperones in the definition of species longevity can be assumed from the observed influences of genotypes, levels of Hsp expression, and mutational defects. Thus, a modifier of life span linked to chromosome 4 has been identified as a haplotype marker within the microsomal transfer protein complex comprising the chaperone protein disulfide isomerase (PDI). An influence of genotype can be supposed also from the observation that for Hsp70 the TT polymorphic variant was observed to be significantly increased within a healthy aged Irish population, while conversely the TC genotype was significantly decreased. Also correlations have been observed between a polymorphism in the Hsp70-A1 gene promoter and low self-rated health in aged Danish twins (Singh et al., 2004) as well as impaired longevity in women (Altomare et al., 2003).
A relationship between the level of chaperone expression and the longevity of species can be assumed from the observation that the constitutional expression of Hsp70 in human pancreatic islets is about five times higher than in the islets of mice or rats. Also, the basal level of expression of Hsp70 in the human brain has been observed to be about 50 fold higher than in rat brain. Modifications of chaperone expression caused by hormonal factors may also influence life span. Thus, in humans, the estrogen-induced higher levels of expression of Hsp72 and Hsp90 alpha might contribute to the difference in longevity between genders. Concerning the circulating levels of chaperones, regression analysis has revealed a progressive decline with age in the serum levels of Hsp60 and Hsp70, probably a consequence of the age-related reduced ability to respond to stress (Krall, 2005).
Possibly, the level of expression or the stress response of selected chaperones could be used for the estimation of a biological age index (Krall and Saxtrup, 2000).
That not only the protein chaperones but also the DNA chaperones are probably important modifiers of longevity can be assumed from the consequences of inborn errors of the RecQ protein/DNA-chaperones. Thus, various mutations in these proteins shorten life span as observed in the mosaic progeric syndromes of Werner, Blooms, and Rothmund-Thomson (Krall, 2004).
The increasing awareness of the possible significance of the functional decline of the molecular chaperones for age-related disorders has initiated the development of a mathematical model to explore the chaperone system and its possible implications in aging (Proctor et al, 2005).
Experimental procedures influencing the life span of species
An increase in the level of expression of the molecular chaperones is a common denominator for the experimental procedures so far known to cause an increase of life span in species.
Transgenic modulation of chaperone expression. Transgenic overexpression of chaperones has been shown to extend the life span of a number of experimental organisms as e.g., for Hsp104 in yeast (Shama et al., 1998), Hsp16 in C. elegans, Hsp70 in Drosophila (Tatar et al., 1997), hsp26 and hsp27 in Drosophila (Krall, 2005). Heat shock proteins normally decrease in expression as a function of age, as judged from individual cases to whole-genome transcriptional profiles in C. elegans (Lund et al., 2002).
Overexpression of the transcription factor HSF-1 that controls stress-inducible gene expression and protein folding homeostasis, extends life span in C. elegans daf-2-insulin/IGF-1 receptor mutants (Hsu et al., 2003), as down-regulation of HSF-1 shortens life span of the mutants. Down-regulation of the individual molecular chaperones decreased longevity of the mutants to a lesser extent and did not affect life span in wild-type animals, probably due to the redundancy of chaperone function (Morley and Marimoto, 2004).
The Ames mouse model of longevity also showed an up-regulation of a heat shock protein, suggesting a contribution of a chaperone to extended life in a hormone model (low levels of human growth hormone releasing hormone) (Dozmorov et al., 2001).
Hormesis. Intermittent mild heat stress (hormesis) increases the level of expression of the molecular chaperones and has been observed to give rise to life span extension in Drosophila (Hercus, 2003) and in yeast (Shama et al., 1998). For the possible benefits of exposure to stress in humans, we need to consider that chaperone expression and function might not be the same in all individuals. This reflects the levels of genetic variation in the human population that are expressed as heritable phenotypic variation during periods of environmental change. This phenotypic variation results in differential modulation of chaperone and target function in response to stress. The availability of free chaperones correlated with the type and degree of stress confers the organism a level of protection that ultimately regulates survival fitness (Rutherford, 2003). Thus, exposure to stress in itself might not be beneficial if the response of the organism towards stress is deficient or inappropriate. A competitive edge might be found in organisms whereby stress can induce a good protective response of properly working molecular chaperones that can help achieve improved life conditions at an advanced age without risk for chaperone overload (Soti et al., 2005).
The extraordinary capacity of centenarians to achieve exceptional old age is due to some extent to their ability to counter the increased cellular stress normally associated with aging. Hsp70 protein induction by heat is reduced in the cells of most aged humans but not in centenarians. This effect is likely due to potent HSF-1 activity. As a matter of fact, HSF-1 has auxiliary factors that contribute to its activation, and could be involved in the age-associated attenuation in the response to stress (Shamovsky and Gershon, 2004). Another study reported that low circulating serum levels of Hsp70 in centenarians could well correlate with the absence of a disease state, since damage to tissues or organs as observed in cardiovascular disease or autoimmune diseases would result in high serum levels of Hsp70 (Krall, 2005).
Caloric restriction. The best experimental intervention so far, which can extend life span in rodents and in multiple invertebrate species and reliably retard aging and age-related degenerative diseases, is dietary caloric restriction (CR). Gene and protein expression profiles are profoundly altered as a consequence of dietary CR. In particular, several molecular chaperones are induced to protect cells from stress, by preserving not only protein structures but also general cellular structure, increasing the levels of GSH, inhibiting apoptotic death, and maintaining a pool of vital proteins (Li et al., 2004). Life-span studies due to CR in nonhuman primates have not yet been completed, but recent data indicate the beneficial effects of CR on a number of physiological markers. The effects of CR on human metabolism are various, but the specific mechanism(s) that lead to its positive effect on life span are not completely understood, but they might coincide with other well-described mechanisms known to regulate life span. Possibly the observed increase in the expression of Hsp70 caused by CR contributes to the positive effect on life span (Ingram et al., 2004).
Interference with histone acetylation. The recently discovered histone deacetylase (HDAC) inhibitors (i.e., tricostatin A and phenylbutyrate) can induce the expression of heat shock proteins hsp22 and hsp70, resulting in extended life span in Drosophila. In particular, hsp22, a mitochondrial chaperone, has been linked to decreased survival when absent. Life extension has also been shown in cells exposed to polyphenolic compounds capable of activating the sirtuins (family of NAD+ dependent deacetylases) in a manner comparable to CR (Lamming et al., 2004). Evidence that sirtuin activators might slow down aging by inducing chaperone function has not yet been presented. However, it is likely that organisms in nature responding to signals such as the ones elicited by sirtuin activators might prepare in advance to a deteriorating environment. Such stress-signaling molecules might enhance chaperone function prior to forthcoming insults (Lamming et al, 2004). Sirtl, the mammalian analog of yeast Sir2, recently has been shown directly to modify chromatin and silence transcription (Vaquero et al., 2004). The question is open whether Sirtl, in addition to silencing transcription, also influences the aging of mammals by suppression of recombination and genomic instability (Lombard et al., 2005) in possible association with histone chaperones (Prado et al., 2004). Thus, the positive effect of the sirtuins on life span might depend less on gene-silencing than on genomic stabilization—a scenario obviating the apparent contradiction that deacetylases as well as deacetylase inhibitors contribute to longevity (Kroll, 2005).
Chemical chaperones. Future intervention studies are aimed at inducing the heat shock response with chemical mimicry, that is, with synthetic compounds—chemical chaperones or nonspecific agents—that could imitate the effect of environmental stressors without the damaging effects they might carry (Castro-Fernandez et al., 2005), and in clinical studies follow up the up-regulation of the heat shock response (e.g., by epigenetic derepression or specific reactivation of Hsf-1). Also, the functional promiscuity of the molecular chaperones opens for the possibility of an increase in chaperone capacity by transfection with individual chaperones (Kroll, 2005).
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