|
ScienceWeek
MEDICAL BIOLOGY: ON CATALASE AND ANTI-AGING
The following points are made by Richard A. Miller (Science 2005 308:1875):
1) New work [1] indicates that overexpression of human catalase in the mitochondria of mice extends median and maximal lifespan by about 20%. Catalase prevents the formation of reactive oxygen species (ROS) that can damage cellular constituents. Although 20% may not seem like much compared to the 50% life span extension seen in dwarf mice with hormone-altering mutations [2], it is roughly 5 times that predicted from complete abolition of human cancer or heart attack [3], and is thus significant.
2) The central mystery for biological gerontology is variable-rate synchrony: If everything must go to pot all at once as organisms approach emeritus status, why does it take 2 years to do so in mice, 10 years in dogs, 20 years in horses, 70 years in people, and longer still in whales and some seabirds? What process, or set of synchronous processes, sets the tempo of aging, and how does aging lead to its unwelcome symptoms? Schriner et al [1]. view their new data as support for the notion that oxidative damage is the key villain and, moreover, that mitochondria are a major source of toxic oxygen radicals. There are still a few gaps in their story -- most laboratory-bred mice die of tumors rather than of the cardiomyopathy on which Schriner et al focus (what are these mice dying of, then?) -- but the report is the first strong evidence that mouse aging can be delayed by antioxidant prophylaxis.
3) Is it safe to conclude that oxygen molecules are the true culprits in causing aging? Can we now turn our attention to the secondary questions of how they cause physiological decline in the superannuated? There are still some grounds for skepticism. The search for antioxidant drugs that slow aging and extend life span in mammals has produced much frustration and an absence of authentic anti-aging pills. Mice heterozygous for the mitochondrial form of superoxide dismutase, an enzyme that destroys a highly reactive derivative of oxygen called superoxide, show high levels of DNA oxidation in multiple organs. In spite of their abnormally oxidized DNA, these animals show no decline in lifespan and no acceleration in certain hallmarks of aging: cataracts, immune dysfunction, and protein modifications [4].
4) Thus, mice can live reasonably long and healthy lives despite unusually high levels of oxidative damage. Furthermore, skin-derived fibroblast cells from three different kinds of long-lived dwarf mice are resistant to multiple forms of stress, including oxidants, ultraviolet light, heat, the heavy metal cadmium, and a DNA alkylating agent [5]. Mutations that extend worm longevity also typically lead to, and perhaps act through, increased resistance to multiple forms of stress. Thus, it seems plausible that many age-retarding mutations may work by inducing cellular signaling pathways, still poorly defined, that augment defenses against a multitude of insults, including the oxidative ones.
References (abridged):
1. S. E. Schriner et al., Science 308 , 1909 (2005)
2. H. M. Brown-Borg, K. E. Borg, C. J. Meliska, A. Bartke, Nature 384 , 33 (1996)
3. S. J. Olshansky, B. A. Carnes, C. Cassel, Science 250 , 634 (1990)
4. H. Van Remmen et al., Physiol. Genomics 16 , 29 (2003)
5. A. B. Salmon et al., Am. J. Physiol. Endocrinol. Metab. (in press)
Science http://www.sciencemag.org
--------------------------------
Related Material:
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
--------------------------------
Related Material:
AGING, LIFESPAN, AND SENESCENCE
Notes by ScienceWeek:
Our knowledge of the basis of senescence of cells, tissues, and organisms (including humans) has entered a new phase in recent decades because of the new vistas opened by molecular biology. Model systems have started to provide insights, and one important approach has been the identification of genes that determine the lifespan of an organism. The very existence of genes that when mutated can extend lifespan suggests to many researchers that one or a few processes may be critical in aging, and that a slowing of these processes may slow aging itself.
The following points are made by L. Guarente et al (Proc. Nat. Acad. Sci. 1998 95:11034):
1) In the budding yeast Saccharomyces cerevisiae, aging results from the asymmetry of cell division, which produces a large mother cell and a small daughter cell arising from the bud. Much of the macromolecular composition of the daughter cell is newly synthesized, whereas the composition of the mother cell grows older with each cell division. It has been shown that mother cells of this yeast species divide a relatively fixed number of times, and exhibit a slowing of the cell cycle, cell enlargement, and sterility. Analysis of *ribosomal DNA in old cells reveals an accumulation of *extrachromosomal ribosomal DNA of discrete sizes, apparently representing a cumulative fragmentation of chromosomal ribosomal DNA. The authors suggest it will be of great interest to assess the generality of this process as an aging mechanism.
2) In Caenorhabditis elegans, the *neurosecretory system regulates whether animals enter the reproductive life cycle or arrest development at a primitive *diapause stage. Developmental arrest is apparently induced by a *pheromone and involves behavioral and morphological changes in many tissues of the animal, with the lifespan becoming 4 to 8 times longer than that of the normal 3-week lifespan of fully developed animals. Declines in pheromone concentration induce recovery to reproductive adults with normal metabolism and lifespan. Genes that regulate the function of the C. elegans diapause and the neuroendocrine aging pathway have been identified, and at least one of these genes codes for an *insulin-like receptor apparently involved in metabolism. The authors suggest that if the association of longevity and diapause is general, it is possible that *polymorphisms in the human insulin receptor-signaling pathway genes and related gene *homologues may underlie genetic variation in human longevity.
3) In plants, there is a large range of lifespans in the various plant kingdoms. Certain tree species live for well over a century, whereas other plants complete their life cycle in a few weeks. The "yellowing" of leaves is often referred to in the plant literature as leaf senescence or the "senescence syndrome" -- referring to the process by which nutrients are mobilized from the dying leaf to other parts of the plant to support their growth. The senescence syndrome is characterized by distinct cellular and molecular changes, with the chloroplast the first part of the cell to undergo disassembly (producing the "yellowing"). In many plant species, certain hormones can either enhance or delay senescence. Although the genes that are expressed during the plant senescence syndrome (as well as ways to manipulate such senescence) have been identified, much remains to be done to understand the molecular basis of aging in plants. For example, nothing is known about the signal transduction pathways that lead to altered gene expression during senescence, or how plant hormones such as *cytokinin influence senescence. But there are now many tools to explore this process. The authors conclude: "It remains to be seen whether common mechanisms link the aging process in diverse organisms."
Proc. Nat. Acad. Sci. http://www.pnas.org
--------------------------------
Notes by ScienceWeek:
ribosomal DNA: A ribosome (not to be confused with riboZYME) is a small particle, a complex of various ribonucleic acid component subunits and proteins that functions as the site of protein synthesis. The term "ribosomal DNA" refers to the gene or genes that code for the RNA in ribosomes. In other words, the term "ribosomal DNA" does not refer to any DNA in ribosomes (there is no DNA in ribosomes).
extrachromosomal: In general, this refers to anything outside of chromosomes, and in this case to DNA fragments unincorporated into chromosomal DNA.
neurosecretory system: In general, all neural systems contain both neurons that themselves secrete chemical messengers and neurons that signal special secretory cells to secrete chemical messengers. A neurosecretory pathway is a delineated signaling system that involves such a resultant secretion.
diapause: In general, this refers to any programmed period of suspended development in invertebrates.
pheromone: In general, a chemical substance which, when released into an animal's surroundings, influences the development or behavior of other individuals of the same species.
insulin: A protein hormone that promotes uptake by body cells of free glucose and/or amino acids, depending on target cell type.
polymorphisms: A genetic polymorphism is a naturally occurring variation in the normal nucleotide sequence of the genome within individuals in a population. Variations are denoted as polymorphisms only if they cannot be accounted for by recurrent mutation and occur with a frequency of at least about 1 percent.
homologues: In general, the term "homologous" means having the same structure. But the term has special uses in genetics and evolution biology.
cytokinin: A group of plant growth substances. They are chemically identified as derivatives of the purine base adenine. They stimulate cell division and determine the course of differentiation. They work synergistically with other plant hormones called "auxins".
ScienceWeek http://scienceweek.com
|