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Department of Biological Science, University of Tulsa, Tulsa, OK 74104
4To whom correspondence should be addressed. E-mail: eun-han{at}utulsa.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • microarray • gene expression • dietary restriction
Because dietary restriction (DR) is the only experimental manipulation repeatedly shown to retard aging in mammals, studies of the biological mechanism behind prolonged life span have evoked great interest. Because DR has a profound effect on most tissues (1), it is plausible that the modulation of aging and senescence by DR occurs through cellular processes that have the potential to affect all cells in an organism. Gene expression, which is fundamental to all cells, is one such process. Changes in gene expression can markedly affect the physiologic state of an organism; furthermore, gene expression alters with age. Studies in the 1980s and 1990s indicate that DR alters the expression of a variety of genes; it is thought that these alterations underlie the increased survival and decreased pathology of DR animals. Yet, despite decades of research, the exact mechanisms continue to elude researchers.
With the sequencing of the genome(s) and the advent of high-density array technology, gene expression arrays such as cDNA or oligonucleotide microarrays have emerged as a powerful tool with which to measure genome-wide gene expression in cells and tissues. In comparison with more traditional methods of analysis, microarrays have been compared to "turning on a light after trying to discern the details of one’s surroundings with a torch" (2). Gene expression arrays have been used to measure gene expression profiles across multiple species from yeast to humans, and across many treatment conditions from cancer to starvation. Because gene expression arrays allow rapid screening and quantification of differences in large groups of functionally related genes, this technology is well-suited to the systematic study of the complex, multigenetic process induced by DR.
An observation that is particularly critical to the study of altered gene expression is that change in levels of mRNA transcripts parallels changes in the levels of the proteins they encode. For example, increases in mRNA transcripts for superoxide dismutase, catalase, and glutathione peroxidase parallel an increase in their activities (3,4). Similarly, decreases in mRNA transcripts for T-kininogen (5), senescence marker protein (6), and calcitonin gene-related peptide (7) are correlated with decreases in the levels of their associated proteins. Another observation of note is that the effect of DR on gene expression varies from gene to gene (8), i.e., DR can lead to no change, an increase, or a decrease in gene expression levels. Therefore, it was concluded that the effect of DR on transcription is not due to an overall alteration in the general transcriptional apparatus of the cell.
Given the above, we reviewed the effect of DR on gene expression in vertebrate and invertebrate animals using published data generated by microarray approaches since 1999. There were 24 such articles covering 22 unique studies (Table 1). We requested from the authors, and in most cases received, lists of genes with significantly altered transcription levels between treatment groups (see supplemental Table 1 for a list of genes cited in at least 2 studies). We also compiled an inventory of molecular functions and biological processes as derived by the authors (Table 2). It is hoped that this synopsis will provide a better understanding of the pattern of gene expression unique to DR and thus bring to light the specific antiaging mechanisms behind DR.
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The most commonly reported functional categories across the 15 mouse studies were metabolism (e.g., carbohydrate, lipid, protein, amino acid), stress response (e.g., heat shock, oxidative), immune response, energy metabolism, and regulation of transcription (Table 2). The effect of DR on these biological processes may give rise to the resultant extended life span seen in mice. In fact, one of the more popular hypotheses is that DR is one means of manipulating systems involved in energy sensing, regulation and metabolism; as such, it induces an evolutionarily conserved stress response, thus enhancing stress resistance (33–37). The consistency across the mouse studies of reporting these particular functional groups supports this hypothesis.
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Although there was no consensus of functional categories across the 3 rat studies, some combination of 2 commonly cited metabolism, stress response, energy metabolism and cell growth (Table 2). As with mice, these findings support a theory of enhanced stress resistance as the underlying mechanism for prolongevity resulting from DR.
In addition, the study of Jervis and Robaire (26) showed that DR attenuated or reversed age-related changes throughout the epididymis, especially genes associated with protein synthesis and mitochondrial function. Similarly, in the study by Chen (25) with the anterior pituitary, long-term DR prevented 8 of 28 age-related alterations. It has been postulated that age-related changes in gene expression associated with immune response, oxidative stress, and energy metabolism are counteracted by DR (38), and these studies appear to support that idea. Chen (25) astutely pointed out, however, that although DR appears to slow down the aging process, the effect of DR is rather limited because <30% of the age-related alterations in gene expression were prevented. DR definitely attenuates and/or retards many aging phenomena and extends life span. However, a large fraction of genes that change with age are not altered by DR and, vice versa, a relative large number of genes that do not change with age are altered by DR.
Other vertebrate organisms. Our review of the literature includes a study using pigs and one using rhesus monkeys. Costa et al. (27) reported the changes in gene expression induced by the restriction of dietary energy and protein in young porcine (male Duroc-based pigs) skeletal muscles (longissimus dorsi and psoas muscles). Genes involved in the turnover of protein, glycogen, and lipid, and genes for glycolysis, oxidative phosphorylation, and ATP synthesis had higher expression levels in both muscles after DR. The expression of several ribosomal protein genes involved in translation and genes for the growth modulation or differentiation were also significantly altered by DR. The overall profile of both muscles, which was one of metabolism, energy metabolism, apoptosis, and cell growth, is the same as that found in the studies involving rodents (Table 2).
The transcriptional profile of skeletal muscle (vastus lateralis) from DR rhesus monkeys (Macaca mulatta) was reported by Kayo et al. (28). DR resulted in an upregulation of structural and cytoskeletal genes and a reduction in the expression of genes involved in mitochondrial bioenergetics. The authors proposed that the reduced activity of the mitochondrial electron transport system suggested that DR monkeys may be in a hypometabolic state. In contrast to rodents, there was no evidence for the beneficial effects of adult onset DR on age-related gene expression in monkeys. Rather than conclude the extent to which DR modifies age-related gene expression may be species specific, these findings suggest that the significant differences between studies of DR redouble the challenge of building a unifying theory of aging.
Invertebrate organisms. Our review includes 2 studies involving microarray analysis of DR in invertebrate organisms, one involving yeast and the other flies. Lin et al. (29) established a model of DR in budding yeast Saccharomyces cerevisiae. Genomic-scale gene expression profiling of the yeast cells under DR revealed a switch of metabolism from fermentation to respiration, which mediated life extension. In essence, as is the case for vertebrate animals, DR affects metabolism and energy metabolism (Table 2). In contrast to vertebrates, however, the expression of most antioxidant genes was not increased by DR in yeast. Subsequently, the authors cautioned that the increase in antioxidant enzymes that occurs during DR in animals may be a result of increased respiration rather than a cause of prolongevity.
RNA transcript levels for the whole female Drosophila melanogaster genome during normal aging and DR were characterized by Pletcher et al. (30). Transcriptional levels of genes from a wide variety of biological functions and processes were affected by both age and diet. Specifically, as seen in other species, DR downregulated genes involved in cell growth, metabolism, signal transduction, and regulation of transcription (Table 2). These same functions showed significant age dependent changes and were ameliorated under DR, suggesting that particular molecular functions and biological processes associated with age-related changes in gene expression are counteracted by DR.
In conclusion, the comparison of all studies listed in Table 1 indicated there was no common gene altered by DR across the different species of animals. It seems that individual genes with altered expression by DR were constrained within species. However, because DR studies by microarray approach were rare in other species (pigs, monkeys, yeast, and flies) compared with mice and rats, the lack of data probably accounted for no matching genes. Apart from individual genes, when we analyzed the functions of the altered genes across all species, we found recurring themes shared among species (Table 2). For example, metabolism and cell growth were influenced in all species examined, energy metabolism was affected in mice, rats, pigs, monkeys, and yeast, and stress and immune response were influenced in mice, rats, and monkeys. We speculate that in the evolutionary process, individual genes can be affected by DR differently among species, but the overall physiologic influence by DR may be similar across species.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supplemental Table 1 is available with the online posting of this paper at www.nutrition.org.
3 Manuscript received 9 March 2005.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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