The yeast Saccharomyces cerevisiae, known popularly as bakers’ or brewers’ yeast, has been used extensively in aging research. Since 1990, it has emerged as an important model organism for the dissection of the biological aging process at the genetic and molecular levels. Its distant cousin, Schizosaccharomyces pombe, or fission yeast, was shown in 2000 to undergo a very similar aging process. This entry describes the research with S. cerevisiae, hereinafter called yeast, exclusively.
Yeast is a unicellular organism whose DNA is packaged into chromosomes that are localized in a subcellular structure called the nucleus. In addition to this organelle, yeast also possesses mitochondria, which are the power plants of the cell that generate the energy needed for cellular function. The mitochondrion also possesses its own DNA, but it is dependent on the nuclear genes for most of its biochemical functions. The yeast cell is very similar in structure and function to typical cells from higher organisms, including humans. It has been used widely to elucidate a variety of basic biological processes, because of the ease of experimentation. About 25 percent of human genes have yeast counterparts, and these human genes have frequently been shown to functionally replace the corresponding gene in the yeast cell.
Aging is not typically measured by time in yeast, but rather by the number of divisions an individual cell completes before it dies. An individual cell is easy to follow from birth to death because yeast divides asymmetrically by budding off new daughters. Unlike their mothers, the daughters start from scratch, having the potential for a full life span. Thus, individual cells are mortal, while the yeast population is immortal. The probability that a cell will continue dividing decreases exponentially as a function of the number of completed divisions. Thus, mortality rate increases exponentially with age. However, it plateaus at older ages in similarity to what has been observed in other species. Yeasts undergo a variety of changes as they age, and some of these are clearly detrimental. In view of this, it is reasonable to speak of an aging process. In practical terms, yeast life span is measured by observing individual cells periodically under a microscope and removing buds with a micro-manipulator.
As of 2000, twenty genes that determine yeast life span had been identified. This has been achieved in three ways. First, genes whose activity changes during the life span were isolated, followed by an examination of their causal role in yeast aging. Second, genes were tested for their function in longevity on the basis of hypotheses formulated regarding the aging process. Third, yeast mutants were selected on the basis of a phenotype (property) frequently associated with aging. The characterization of the isolated genes has provided a rich description of the aging process at the physiological level. The powerful tools of yeast genetics and cell biology have extended this description. Further analysis of the pathways and processes that were revealed by these genes has in some cases been refined to the biochemical and molecular levels. Methods for the preparation of age-synchronized yeast cells have facilitated biochemical and molecular studies.
There are many advantages to the study of aging in the yeast model system:
- The yeast cell is at the same time the yeast organism. Therefore, the study of yeast is pertinent to both cellular and organismal aging.
- Because yeast are microbes they divide very rapidly, in a short time generating much material for physiological, biochemical, and molecular analysis.
- Yeast mutants can be created and selected rapidly, again because it is a microbe producing many generations of progeny in a short time.
- Yeast life spans are short, and last as little as a few days.
- Methodologies for life span determination are in place. Several procedures for the bulk preparation of age-synchronized yeast cells are available.
- The basic phenomenology of yeast aging is well established.
- The yeast genome was the first to be completely sequenced. This has revolutionized yeast genetics. The priority of yeast in this field has resulted in rapid advances in the study of function at the whole genome level, providing a wide range of materials, tools, and concepts that are being applied to other organisms as well.
- Several yeast genetic databases are accessible online, which facilitates functional genome analyses. In addition, cross-referencing databases are online, allowing comparative genomic analyses.
- A large community of yeast researchers exists, and, consequently, there is a wealth of biological information and expertise that can be tapped.
Yeast also possesses certain disadvantages for aging research: (1) The role of cell-cell interactions and systemic mechanisms, such as endocrine function, in aging lies beyond the scope of yeast aging research; (2) the extent to which the results of studies in yeast can be extrapolated to an understanding of aging in humans has not as yet been demonstrated; and (3) the determination of yeast life spans and the preparation of age-synchronized yeast cells is tedious. The quantities of old yeast that can be obtained are relatively small.
Studies of yeast longevity have revealed the operation of four, broad physiological processes in yeast aging: metabolic control, stress resistance, gene dysregulation, and genetic stability. Interestingly, these processes appear to be important in the aging of other species as well. Two distinct metabolic control mechanisms play a role in yeast aging. One of them (retrograde response) appears to compensate for accumulating mitochondrial dysfunction. The other (caloric restriction) may help prevent dysfunction. Repeated bouts of stress reduce yeast life span. This can be overcome by enhancing the activity of certain longevity genes. An exposure to mild heat stress, on the other hand, appears to condition the yeast such that an extension of longevity occurs. Changes in the structure of the chromatin into which the DNA is packaged result in alterations in the normal activity of genes. This process intensifies with age. It can be prevented by manipulating certain genes, with an attendant increase in life span. Nuclear DNA can undergo rearrangements. Rearrangements that are not normally favored seem to occur with higher frequency as yeasts get older, constituting one of the causes of aging.
S. MICHAL JAZWINSKI
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