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ScienceWeek
AGING: CALORIC RESTRICTION AND LONGEVITY
The following points are made by J.W. Vaupel et al (Science 2003 301:1679):
1) Experiments in species as diverse as yeast, worms, flies, and rodents demonstrate that dietary restriction prolongs survival. Mair et al (1) have revealed that a lifetime of abstemiousness is not required to reduce one's risk of death -- at least in fruit flies. These researchers demonstrated that when flies fed a restricted diet are switched to a full diet, mortality soars to the level suffered by fully fed flies. Conversely, when the diet of fully fed Drosophila is restricted, mortality plunges within 2 days to the level enjoyed by flies that have experienced a lifelong restricted diet.
2) The alliterative title of the Mair et al. paper -- "Demography of Dietary Restriction and Death in Drosophila" -- gives due credit to demography as the source of their new discovery. Demographers have long realized that death rates provide age-specific information that cumulative survival curves cannot (2). Heeding this insight, Mair et al. analyzed the daily mortality of their fed and hungry flies. Demography offers a further lesson: Death of the frail alters the composition of a cohort, lowering subsequent mortality and possibly offsetting increases in mortality resulting from cumulative damage (3).
3) Replication and refinement of the Mair et al experiments, especially in rodents, the principal animal model of dietary-restriction studies, will be a research priority. Rodent and Drosophila dietary-restriction experiments differ in two key respects. First, rodents in these experiments cannot mate or produce offspring because they are maintained in solitary confinement or in same-sex cages. Mair et al allowed their flies to mate before separating them into containers holding approximately 100 females or 200 males. They did not report egg production, but it seems likely that fully-fed females lay many eggs whereas females on restricted diets lay few (4). Even in all male containers, fully-fed males may have engaged in behavior associated with attracting females (such as courtship songs composed of wing vibrations) to a greater extent than males on restricted diets. Hence, the Mair et al findings could be due to a switch in and out of costly reproductive activity, but evidence for this will require further study.
4) Second, in rodent experiments, diets are restricted by reducing food quantity (generally to 60% or ad libitum), whereas in Drosophila experiments, the effect is achieved by reducing food quality. In their study, Mair et al. cut the yeast and sugar content of the fly diet to about 43% of that in standard laboratory medium. Other work in Mediterranean fruit flies (medflies) (5) demonstrates that reductions in food quantity do not increase longevity, whereas reductions in food quality do. A key uncertainty is whether quantity- or quality-restricted diets or ad libitum diets mimic conditions in the wild.
References (abridged):
1. W. Mair, P. Goymer, S. D. Pletcher, L. Partridge, Science 301, 1731 (2003)
2. J. W. Vaupel et al., Science 280, 855 (1998)
3. J. W. Vaupel, A. I Yashin, Am. Stat. 393, 176 (1985)
4. T. P. Good, M. Tatar, J. Insect Physiol. 47, 1467 (2001)
5. J. R. Carey, Longevity: The Biology and Demography of Life Span (Princeton Univ. Press, Princeton, NJ, 2003)
Science http://www.sciencemag.org
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BIOLOGY OF AGING: CALORIC RESTRICTION AND GENE EXPRESSION
Most multicellular organisms exhibit a progressive and irreversible physiological decline that characterizes what is called "senescence" -- the aging process. The molecular basis of this process is unknown, but various mechanisms have been postulated, including: a) cumulative damage to DNA leading to genome instability; b) biochemical pathway alterations that lead to changes in *gene expression patterns; c) *telomere shortening in replicative cells; d) oxidative damage to critical macromolecules by reactive oxygen species; and e) nonenzymatic *glycation of proteins.
Experimental genetic manipulation of the aging process in multicellular organisms has been achieved in the fruit fly Drosophila through the overexpression of certain enzymes, and in the nematode worm C. elegans through alterations in the *insulin receptor pathway, and in both organisms through the experimental selection of stress-resistant mutants.
In mammals, however, the only intervention that appears to slow the intrinsic rate of aging is caloric restriction. Most studies of caloric restriction in mammals have involved laboratory rodents subjected to a long-term 25 to 50 percent reduction in caloric intake without essential nutrient deficiency, and the result in these rodents is a delayed onset of age-associated pathological and physiological changes and an extension of maximum lifespan. Various mechanisms have been postulated to explain this result, including increased DNA repair capacity, altered gene expression, depressed metabolic rate, and reduced oxidative stress.
The following points are made by C-K. Lee et al (Science 1999 285:1390):
1) The authors present a study to examine the molecular events associated with aging in mammals, with experiments involving analysis of the aging process in *skeletal muscle of mice. The authors report that the use of high-density *oligonucleotide arrays representing 6347 genes (5 to 10 percent of the mouse genome) revealed that aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes.
2) Most alterations were either completely or partially prevented by caloric restriction. *Transcriptional patterns of calorie-restricted animals suggest that caloric restriction retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage. The authors state: "The data presented here provide the first global assessment of the aging process in mammals at the molecular level and underscore the utility of large-scale parallel gene expression analysis in the study of complex biological phenomena."
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Notes:
gene expression patterns: This refers to the profile of genes in a genome that are actually operating (i.e., undergoing expression) at any point in time. In a mammal, for example, a liver cell is a liver cell because of a particular profile of expressed genes, and what that liver cell is doing at any point in time is determined by variations of that profile. It is the operating patterns (gene expression patterns) of the genome that are the paramount determinants of the behavior of cells.
telomere: Telomeres are defined ends of chromosomes that contain specific repeated DNA sequences. They are essential for normal chromosome replication, and since their length shortens a bit with each replication, they are believed to be involved in the aging of the cell.
glycation of proteins: "Glycation" is the post-translational (i.e., after protein synthesis) modification of a protein by the covalent attachment of a sugar residue, the modification resulting from a spontaneous amino-carbonyl reaction ("Maillard reaction"). Glycation of various proteins has recently been implicated in the etiology of various diseases such as the development of Alzheimer's-type pathologies (e.g., dementias).
insulin receptor pathway: Insulin is a polypeptide chemical messenger (hormone) comprising 51 amino acids in two chains linked by disulphide bridges. The insulin receptor is a specific membrane protein derived from an intracellular precursor and transported from specialized intracellular structures to the cell surface.
skeletal muscle: In general, the term "skeletal muscle" refers to striated muscle fibers (singly or in a collection) attached at one or both ends of a part of the body skeleton. "Striated muscle" is muscle usually associated with voluntary motion, the adjective "striated" arising from the microscopically visible cross striations which occur in the fibers as a result of regular overlapping of thick and thin muscle fiber filaments (myofilaments). In general, such fibers are specialized for rapid contraction and relaxation.
oligonucleotide arrays: The essential idea concerning the use of "arrays" in determining gene expression patterns involves the fact that for every gene (DNA sequence) undergoing expression there exists in the cytoplasm a specific RNA whose nucleotide sequence is a result of transcription of that gene (see next note on "transcriptional patterns"). There exists now a technique for profiling the large variety of RNAs that can be extracted from tissue, the technique depending on highly ordered arrays of large numbers of oligonucleotide probes (essentially pieces of DNA) in a parallel format, with specific DNA-RNA interactions producing localized fluorescences, and the array of fluorescences providing a profile of detectable RNAs. A determination of the profile of existing RNA sequences implies the profile of the DNA sequences (genes) that are being naturally expressed in the genome, and if one knows which genes are involved with which functions in that particular cell or organism, one has obtained a profile of -----existing functions. The use of such arrays of nucleotide probes (sometimes called micro-arrays or "chips") is now highly automated ("robotic"), and the technique can be used to determine the expression profile of thousands of genes in an ensemble of cells.
Transcriptional patterns: "Transcription" is the process by which genetic information in DNA is converted into RNA.
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