ScienceWeek

CELL BIOLOGY: YEAST AND AGEING

The following points are made by S. Nemoto and T. Finkel (Nature 2004 429:149):

1) Yeast would seem an unlikely model system for learning about human ageing. A single-celled organism, essential perhaps for our daily bread and our favorite brew, it seems to lack the complexity that we associate with higher-order functions such as ageing. Nonetheless, yeast "replicative lifespan" -- a measure of the number of divisions a mother yeast cell can undergo -- has become a useful surrogate for mammalian ageing. Early in life, a mother yeast cell can readily divide, asymmetrically, to produce a daughter cell. Later on, when the mother cell has divided many times, it begins to enlarge and its capacity to produce progeny diminishes. The fact that middle-aged yeast as well as middle-aged humans are generally slower, fatter and less interested in reproduction provides our first (albeit broad) clue that certain biological markers of ageing -- and so, perhaps, the underlying mechanisms -- might have been conserved during evolution.

2) So what determines how many times a mother yeast cell can divide? Numerous environmental and genetic determinants have been identified. Among the environmental factors are several non-lethal stresses, for example reducing the glucose levels in the growth medium from 2% to 0.5%; such "caloric restriction" can significantly increase the replicative lifespan of yeast. This concept of "less is more" when it comes to calories and longevity is a theme that we see again and again, from yeast to mice.

3) In yeast, low-glucose conditions extend lifespan through the action of a gene termed SIR2 (1). Strikingly, a similar lengthening of lifespan ensues when yeast are simply manipulated to produce too much of the protein product of this gene(2). This product, Sir2, was first identified as a protein that modifies the physical state of DNA, causing a phenomenon known as genetic silencing ("Sir" stands for "silent information regulator"). Most evidence now supports the idea that Sir2 extends lifespan in yeast by regulating gene expression or suppressing recombination (the exchange of chunks of DNA between chromosomes), although the relevant genetic targets of Sir2 are unknown.

4) But what is the link between caloric restriction and Sir2? The protein's effects on DNA are achieved through its histone deacetylase activity -- its ability to remove specific acetyl groups from histones and other proteins that wrap up DNA. This activity of Sir2 in turn depends on the cellular levels of nicotinamide adenine dinucleotide (NAD) (2). NAD and its reduced form, NADH, represent a sort of basic energy currency in cells. Caloric restriction in yeast might increase Sir2 activity by altering either the NAD:NADH ratio or the levels of the NAD derivative nicotinamide. In other simple organisms, such as the fruitfly Drosophila melanogaster, caloric restriction might not only increase the activity of Sir2, but also directly regulate its levels(3). Increased Sir2 levels and activity might then dampen gene expression and recombination, leading (somehow) to an extension in lifespan.(4,5)

References (abridged):

1. Lin, S. J. et al. Science 289, 2126-2128 (2000)

2. Hekimi, S. & Guarente, L. Science 299, 1351-1353 (2003)

3. Rogina, B., Helfand, S. L. & Frankel, S. Science 298, 1745 (2002)

4. Murakami, S. et al. Ann. NY Acad. Sci. 908, 40-49 (2000)

5. Lee, S. S. et al. Science 300, 644-647 (2003)

Nature http://www.nature.com/nature

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CELLULAR SENESCENCE, CANCER, AND AGING

The following points are made by A. Krtolica et al (Proc. Nat. Acad. Sci. 2001 98:12072):

1) Multicellular organisms have evolved mechanisms to prevent the unregulated growth and malignant transformation of proliferating cells. One such mechanism is "cellular senescence", which arrests proliferation (essentially irreversibly) in response to potentially oncogenic events. Cellular senescence appears to be a major barrier that cells must overcome to progress to full-blown malignancy.

2) Cellular senescence was first described as a process that limits the proliferation of cultured human fibroblasts ("replicative senescence"). Proliferating cells progressively lose telomere DNA, and short telomeres, which are potentially oncogenic, elicit a senescence response. In addition, DNA damage, expression of oncogenes, and supraphysiological mitogenic signals also cause cellular senescence. Cellular senescence is controlled by tumor suppressor genes and seems to involve a checkpoint that prevents the growth of cells at risk for neoplastic transformation. In this regard, cellular senescence is similar to apoptosis. However, whereas apoptosis kills and eliminates damaged or potential cancer cells, cellular senescence involves a stable arrest of growth.

3) Cellular senescence is also thought to contribute to aging, although how it does so is poorly understood. In addition to arresting growth, senescent cells show changes in function. Because senescent cells accumulate with age, they may contribute to age-related declines in tissue function. If so, cellular senescence may be an example of "antagonistic pleiotropy". Aging phenotypes are thought to result from the declining force of natural selection with age. Consequently, traits selected to maintain early life fitness can have unselected deleterious effects late in life, a phenomenon termed "antagonistic pleiotropy". The senescence-induced growth arrest may suppress the development of cancer in young organisms. The functional changes, by contrast, may be unselected consequences of the growth arrest and thus compromise tissue function as senescent cells accumulate.

Proc. Nat. Acad. Sci. http://www.pnas.org

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MYTHS CONCERNING AGING

The following points are made by David Concar (New Scientist 2001 22 September):

1) Myth #1: Thanks to modern medicine and scientific advances, adults today can expect to live into their 70s or 80s, whereas our ancestors mostly died in early middle age. Reality: The great increase in average life expectancy at birth in the 20th century is primarily due to the great reduction in infant mortality. In actuality, many people in the 18th and 19th centuries lived into their 70s and 80s.

2) Myth #2: Given the health improvements and longevity gains of the 20th century, people may soon live routinely to 120 years. Reality: Again, the main apparent recent changes in longevity are due to changes in infant mortality rates. Only a small proportion of the longevity changes came from attacks on killer diseases of adults. According to death rate statistics, medical science would have to eliminate every single current common cause of human death merely to reach a life expectancy of 100.

3) Myth #3: Researchers can make worms and flies live much longer than normal, so some kind of treatment that will slow down aging in humans is inevitable. Reality: Nematode worms and flies are quite different from humans, and their use as "models" for aging research is questionable. For the most part, these animals have been useful in aging research because they have short lifespans, which makes experiments easier and faster. But this is also considered the major flaw of research into longevity: such research is based on animals that lack longevity. The evidence from aging research on longer-lived species does not support the idea that scientific manipulation of aging in humans is inevitable.

4) Myth #4: Human lifespan can be dramatically extended simply by ingesting protective antioxidant vitamins to improve the defenses of the body against free radicals. Reality: This is an overly optimistic idea. Free radicals are constantly produced in all biological cells, and virtually all organisms have natural antioxidants and enzymes to prevent DNA damage and other damage by free radicals. The problem is that there is no way that antioxidant supplements can remove all free radicals, and even if this could be accomplished it would probably damage the workings of the immune system, which apparently requires free radicals for some of its pathways. In general, experiments involving the use of free-radical quenchers that have produced some increase in longevity in lower animals have produced no increases or even decreases in mammals.

5) Myth #5: Semi-starved rats and mice live up to 50 percent longer, so humans should be able to live to 120 by reducing calorie intake. Reality: There is no hard evidence for this in humans. Caloric restriction experiments are now underway with monkeys, but it will be 10 years before the results are apparent. Meanwhile, severe caloric restriction in humans produces debilitation and disease, rather than longevity.

6) Myth #6: Growth hormone supplements can help forestall aging. Reality: There is no evidence to support this idea, and in fact recent evidence suggests that people with lower growth hormone levels live longer, and that growth hormone supplements have serious side effects.

7) But despite the realities above, there are certainly puzzles that need to be solved by research. Okinawa, a chain of islands stretching from Japan to Taiwan, has 1.3 million people in a population with the longest life expectancy on the planet, with 4 times the percentage of centenarians found in Western countries. Researchers are currently attempting to determine the factors (diet, lifestyle, genetics, etc.) responsible for Okinawa's vital statistics.

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