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Posted on Nov 30, 2005, 5 a.m.
By Bill Freeman
From ScienceWeek, a grab bag of mainstream scientific thoughts on the mechanisms of aging; Klotho, oxidative damage, and senescence. "A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. The authors demonstrate that overexpression of Klotho in mice extends life span. ... overexpression of human catalase in the mitochondria of mice extends median and maximal lifespan by about 20%.
The following points are made by H. Kurosu et al (Science 2005 309:1829):
1) Klotho was originally identified as a mutated gene in a mouse strain that accelerates age-dependent loss of function in multiple age-sensitive traits[1]. An insertional mutation that disrupts the 5' promoter region of the Klotho gene resulted in a strong hypomorphic allele. Mice homozygous for the mutated allele (KL-/- mice) appeared normal until 3 to 4 weeks old but then began to manifest multiple age-related disorders observed in humans, including ectopic calcification, skin atrophy, muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema. KL-/- mice suffered premature death around two months of age.
2) The Klotho gene encodes a single-pass transmembrane protein that is detectable in limited tissues, particularly the distal convoluted tubules in the kidney and the choroid plexus in the brain. Because a defect in the Klotho gene leads to systemic age-dependent degeneration, the Klotho protein may function through a circulating humoral factor that regulates the development of age-related disorders or natural aging processes[2]. Notably, some single-nucleotide polymorphisms in the human KLOTHO gene are associated with altered life span[3] and altered risk for coronary artery disease[4], osteoporosis[5], and stroke.
3) Little is known about Klotho protein function and the molecular mechanism by which it suppresses the development of aging-like phenotypes. The extracellular domain of Klotho protein is composed of two internal repeats, KL1 and KL2, that share amino acid sequence homology to beta-glucosidases of bacteria and plants (20 to 40% identity) [1]. However, glucosidase activity is not present in recombinant Klotho protein, and the essential glutamate residue at the beta-glucosidase active center is replaced with asparagine and alanine in KL1 and KL2, respectively. The authors demonstrate that Klotho is an aging-suppressor gene whose product functions as a hormone that inhibits intracellular insulin and IGF1 signaling.
4) In summary: A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. The authors demonstrate that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.
References (abridged):
1. M. Kuro-o et al., Nature 390, 45 (1997)
2. Y. Takahashi, M. Kuro-o, F. Ishikawa, Proc. Natl. Acad. Sci. U.S.A. 97, 12407 (2000)
3. D. E. Arking et al., Proc. Natl. Acad. Sci. U.S.A. 99, 856 (2002)
4. D. E. Arking et al., Am. J. Hum. Genet. 72, 1154 (2003)
5. N. Ogata et al., Bone 31, 37 (2002)
Science http://www.sciencemag.org
--------------------------------
Related Material:
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
ScienceWeek http://scienceweek.com
Read Full Story
1) Klotho was originally identified as a mutated gene in a mouse strain that accelerates age-dependent loss of function in multiple age-sensitive traits[1]. An insertional mutation that disrupts the 5' promoter region of the Klotho gene resulted in a strong hypomorphic allele. Mice homozygous for the mutated allele (KL-/- mice) appeared normal until 3 to 4 weeks old but then began to manifest multiple age-related disorders observed in humans, including ectopic calcification, skin atrophy, muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema. KL-/- mice suffered premature death around two months of age.
2) The Klotho gene encodes a single-pass transmembrane protein that is detectable in limited tissues, particularly the distal convoluted tubules in the kidney and the choroid plexus in the brain. Because a defect in the Klotho gene leads to systemic age-dependent degeneration, the Klotho protein may function through a circulating humoral factor that regulates the development of age-related disorders or natural aging processes[2]. Notably, some single-nucleotide polymorphisms in the human KLOTHO gene are associated with altered life span[3] and altered risk for coronary artery disease[4], osteoporosis[5], and stroke.
3) Little is known about Klotho protein function and the molecular mechanism by which it suppresses the development of aging-like phenotypes. The extracellular domain of Klotho protein is composed of two internal repeats, KL1 and KL2, that share amino acid sequence homology to beta-glucosidases of bacteria and plants (20 to 40% identity) [1]. However, glucosidase activity is not present in recombinant Klotho protein, and the essential glutamate residue at the beta-glucosidase active center is replaced with asparagine and alanine in KL1 and KL2, respectively. The authors demonstrate that Klotho is an aging-suppressor gene whose product functions as a hormone that inhibits intracellular insulin and IGF1 signaling.
4) In summary: A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. The authors demonstrate that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.
References (abridged):
1. M. Kuro-o et al., Nature 390, 45 (1997)
2. Y. Takahashi, M. Kuro-o, F. Ishikawa, Proc. Natl. Acad. Sci. U.S.A. 97, 12407 (2000)
3. D. E. Arking et al., Proc. Natl. Acad. Sci. U.S.A. 99, 856 (2002)
4. D. E. Arking et al., Am. J. Hum. Genet. 72, 1154 (2003)
5. N. Ogata et al., Bone 31, 37 (2002)
Science http://www.sciencemag.org
--------------------------------
Related Material:
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
ScienceWeek http://scienceweek.com
Read Full Story
