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Aging, Genetics of
Aging, Genetics of M Kaeberlein, University of Washington, Seattle, WA, USA
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by GJ Lithgow, volume 1, pp 21–23, © 2001, Elsevier Inc.
Glossary Cellular senescence Loss of the ability of a cell to divide. Also called replicative senescence.
Introduction Aging is the sum of multiple processes that increase the proba bility of death with age of an organism. Mortality rates increase with age in most organisms that have a distinct soma/germline division or exhibit asymmetric cell division. In addition to mortality rates, the incidence of multiple diseases also increases with age. Cardiovascular disease, neurodegenerative disorders including Alzheimer’s disease and dementia, kidney disease, diabetes, and most forms of cancer are among those disorders that show a strong age dependence. The rate of increase in age-dependent mortality and degenerative pathologies is strongly influenced by genes, resulting in distinctive species-specific life spans and healthspans.
Evolutionary Origins of Aging Extrinsic hazards such as disease and predation make indefinite survival of an animal unlikely. Hence, natural populations exhibit age structure in which young organisms outnumber old organisms. Such an age structure results in the decline in the force of natural selection with age. Therefore, the effect of genes on aging is not due to direct selection on aging characters. Rather, aging is a nonadaptive process in which the genes that influence the rate of aging either do not affect fitness or have been selected due to beneficial effects early in life. One predic tion of this evolution theory of aging is that aging is influenced by many genes and is caused by a range of distinct physio logical and molecular processes. In keeping with this view, genetic variants that exhibit extended life span usually exhibit phenotypic trade-offs such as reduced or delayed fertility.
Molecular Mechanisms of Aging The precise molecular mechanisms of aging are unknown; however, several types of molecular damage accumulate with age in different organismal systems and are proposed to play a causal role in the aging process. These include mutation of nuclear and mitochondrial DNA, misfolded and aggregated proteins, terminally shortened telomeres, and a variety of types of oxidatively damaged macromolecules. Mutations that influence the repair/degradation of each of these types of damage have been shown to modulate life span in model organisms. For example, defects in DNA repair or telomere elongation cause reduced longevity and early onset of
48
Healthspan The period of life in which an individual exists in relatively good health, free of chronic disease or disability.
age-related phenotypes in mice, while enhanced clearance of aggregated or misfolded proteins is sufficient to extend life span in Caenorhabditis elegans or Drosophila melanogaster. The free radical theory of aging, which posits that a primary cause of aging is damage resulting from oxidative free radicals, is the most prominent theory of aging. In addition to the correlation between age and oxidative damage, increased activ ity of antioxidant enzymes has been reported to extend life span in a variety of organisms. The free radical theory of aging has been challenged, however, by studies on mouse models with very high levels of oxidative stress that have life spans comparable to wild-type controls. In general, overexpres sion of antioxidant enzymes is not sufficient to extend life span in mice; although, targeted overexpression of catalase in mito chondria has been shown to improve survival and cardiac function. In humans, there is little evidence that antioxidant dietary supplements reduce mortality or age-related disease risk. Thus, it seems likely that multiple types of age-related damage contribute to phenotypes of aging, including oxidative damage from free radicals, and that the relative importance of different types of damage differs depending on cell or tissue type, genetic background, and environment.
Aging in Model Genetic Systems Life span differences between species are believed to result from multiple genetic and epigenetic factors. Body size is one trait that has been found to correlate positively with maximum longevity among a wide diversity of organisms; larger animals live, on an average, longer than smaller animals. There are exceptions to this rule, however. Bats and birds, for example, tend to live much longer than expected based on their size. Naked mole rats, which live about 10 times longer than simi larly sized rodents such as mice and rats, represent another example of a species that is exceptionally long-lived for its size. A few animals show no detectable signs of aging or senes cence. These include the Hydra, a simple freshwater animal that appears able to undergo unlimited cell division, and the Galapagos tortoise, which is reported to live more than 170 years. Molecular and genetic studies of such animals may yield insights into the mechanisms of aging and prospects for extending healthy life span in people. Most knowledge of aging mechanisms is based on studies of commonly used model organisms, including the budding yeast Saccharomyces cerevisiae, the nematode C. elegans, the fruit fly D. melanogaster, and the mouse Mus musculus. Single gene
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 1
doi:10.1016/B978-0-12-374984-0.00023-1
Aging, Genetics of mutations capable of extending population median and max imum life span by 30–50% have been identified in each of these organisms. S. cerevisiae and C. elegans have proven to be particu larly amenable to genome-scale longevity screens using gene deletion and RNAi interference libraries, resulting in the identi fication of several hundred genetic loci that modulate longevity. Although the degree to which aging mechanisms are evolutio narily conserved remains unknown, it is now clear that similar genetic and environmental factors can extend life span in yeast, worms, flies, and mice. Such conserved modifiers of longevity include dietary restriction, reduced insulin-like signaling, and inhibition of the target of rapamycin (TOR) signaling pathway.
Modulation of Aging by Nutrient Response Pathways Dietary restriction (also referred to as caloric restriction or calorie restriction) can be defined as a reduction in nutrient availability without malnutrition. In addition to extending life span in the four model organisms listed above, dietary restriction has been shown to extend life span in a variety of other organisms, includ ing rats, fish, spiders, and dogs. Dietary restriction appears to delay a variety of age-related diseases and pathologies, which is interpreted as suggesting that the aging process itself has been slowed or delayed. An ongoing long-term (>30 years) study of dietary restriction in rhesus monkeys supports the idea that similar effects can be obtained in primates, with monkeys sub jected to dietary restriction showing an increase in median survival and reduced incidences of diabetes, cardiovascular dis ease, and cancer. In C. elegans and D. melanogaster, life span extension from dietary restriction appears to involve both reduced caloric intake and decreased signaling through sensory neurons that mediate the response to food. In mice and rats, a global reduction in calories or restriction of specific amino acids such as methionine or tryptophan can extend life span. Human studies of dietary restriction, while unable to demonstrate a reduction in the rate of aging, are consistent with generally improved health in individuals practicing such a regimen. The mechanisms by which dietary restriction exerts its effects on aging are not well understood, although genetic studies have implicated nutrient and growth signaling path ways as key mediators of this response. Specific mutations that reduce growth hormone, insulin, and insulin-like growth factor 1 (IGF-1) signaling have been shown to extend life span in mice, and reduced insulin/IGF-1-like signaling can also pro mote longevity in nematodes and fruit flies. The TOR pathway, in particular, has been linked to life span extension from diet ary restriction; dietary restriction decreases TOR signaling; and inhibition of TOR is sufficient to increase life span in yeast, nematodes, flies, and mice.
Human Aging A genetic underpinning of aging in humans is revealed by rare diseases that resemble premature aging and by heritability estimates of longevity in normal populations. Hutchinson–Gilford progeria syndrome is a rare autosomaldominant condition of childhood characterized by balding, skin wrinkling, subcutaneous fat loss, and atherosclerosis, resulting in cardiovascular-associated death. There is no
49
acceleration in brain aging, illustrating that premature aging is segmental with some tissue types remaining unaffected. This syndrome is caused by a mutation in the LMNA gene coding for a nuclear filament protein important for nuclear structure. Werner syndrome is an adult-onset progeria and is character ized by skeletal muscle atrophy, premature graying of hair, heart valve calcification, intense atherosclerosis, and hypogo nadism. It is caused by mutation of the WRN gene that encodes a member of the RecQ family of DNA helicases. Genetic factors have been estimated to account for ∼25% of variance in life span in human populations, and several poten tially contributing loci have been reported. Alleles associated with longevity have been identified from gene association studies, including the ε2 variant of the APOE gene, which not only is overrepresented in centenarian populations but is also associated with type III and IV hyperlipidemia. Alleles of the Foxo3a tran scription factor have also been linked to longevity in multiple association studies. Foxo3a is a stress-responsive transcription factor, homologues of which are known to influence life span in worms and flies downstream of insulin-like signaling. Human cells cultured in vitro undergo a limited number of cell divisions, and the mechanism of this replicative senescence may be informative regarding aging in vivo. Senescent human cells display altered characteristics, including the secretion of a variety factors that can influence neighboring cells. A limited number of such senescent cells also occur in the tissues of aged humans and may contribute to age-related changes and func tional deficits. Cellular senescence in vitro results primarily from telomere shortening during replication and can be prevented by restoration of the telomere-synthesizing enzyme, telomerase. There are reports that short telomeres are associated with some age-related diseases and increased risk of death. With recent advances in the understanding of genetic and mechanistic factors that modulate aging, attention has turned to potentially translating these finding into therapies for human use. A major initiative toward this goal is the National Institute on Aging Interventions Testing Program. As part of this program, several compounds with putative antiaging properties are being tested for effects on life span in mice. The first major success of this program was the finding that feeding mice the TOR inhibi tor rapamycin significantly extends life span of both male and female mice, even when started late in life. This has led to speculation that rapamycin, and perhaps other drugs that target aging-related pathways, may ultimately be used to delay the onset and progression of multiple age-related diseases in people.
See also: Cancer Genetics; Genetic Alzheimer’s Disease; Telomeres.
Further Reading Austad SN (1999) Why We Age: What Science Is Discovering about the Body’s Journey Through Life, 1st edn. New York: John Wiley & Sons. Fontana L, Partridge L, and Longo VD (2010) Extending healthy life span – from yeast to humans. Science 328: 321–326. Kenyon CJ (2010) The genetics of ageing. Nature 464: 504–512. Masoro E and Austand SN (eds.) (2011) Handbook of the Biology of Aging. San Diego: Academic Press. Vaupel JW (2010) Biodemography of human ageing. Nature 464: 536–542. Wolf NS (ed.) (2010) Comparative Biology of Aging. Dordrecht: Springer.
50
Aging, Genetics of
Relevant Websites http://www.americanaging.org – American Aging Association. http://www.afar.org – American Federation for Aging Research.
http://genomics.senescence.info – Human Ageing Genomic Resources (HAGR). http://www.nia.nih.gov – National Institute on Aging. http://www.sageweb.org – Sageweb. http://www.geron.org – The Gerontological Society of America.
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by GJ Lithgow, volume 1, pp 21–23, © 2001, Elsevier Inc.
Glossary Cellular senescence Loss of the ability of a cell to divide. Also called replicative senescence.
Introduction Aging is the sum of multiple processes that increase the proba bility of death with age of an organism. Mortality rates increase with age in most organisms that have a distinct soma/germline division or exhibit asymmetric cell division. In addition to mortality rates, the incidence of multiple diseases also increases with age. Cardiovascular disease, neurodegenerative disorders including Alzheimer’s disease and dementia, kidney disease, diabetes, and most forms of cancer are among those disorders that show a strong age dependence. The rate of increase in age-dependent mortality and degenerative pathologies is strongly influenced by genes, resulting in distinctive species-specific life spans and healthspans.
Evolutionary Origins of Aging Extrinsic hazards such as disease and predation make indefinite survival of an animal unlikely. Hence, natural populations exhibit age structure in which young organisms outnumber old organisms. Such an age structure results in the decline in the force of natural selection with age. Therefore, the effect of genes on aging is not due to direct selection on aging characters. Rather, aging is a nonadaptive process in which the genes that influence the rate of aging either do not affect fitness or have been selected due to beneficial effects early in life. One predic tion of this evolution theory of aging is that aging is influenced by many genes and is caused by a range of distinct physio logical and molecular processes. In keeping with this view, genetic variants that exhibit extended life span usually exhibit phenotypic trade-offs such as reduced or delayed fertility.
Molecular Mechanisms of Aging The precise molecular mechanisms of aging are unknown; however, several types of molecular damage accumulate with age in different organismal systems and are proposed to play a causal role in the aging process. These include mutation of nuclear and mitochondrial DNA, misfolded and aggregated proteins, terminally shortened telomeres, and a variety of types of oxidatively damaged macromolecules. Mutations that influence the repair/degradation of each of these types of damage have been shown to modulate life span in model organisms. For example, defects in DNA repair or telomere elongation cause reduced longevity and early onset of
48
Healthspan The period of life in which an individual exists in relatively good health, free of chronic disease or disability.
age-related phenotypes in mice, while enhanced clearance of aggregated or misfolded proteins is sufficient to extend life span in Caenorhabditis elegans or Drosophila melanogaster. The free radical theory of aging, which posits that a primary cause of aging is damage resulting from oxidative free radicals, is the most prominent theory of aging. In addition to the correlation between age and oxidative damage, increased activ ity of antioxidant enzymes has been reported to extend life span in a variety of organisms. The free radical theory of aging has been challenged, however, by studies on mouse models with very high levels of oxidative stress that have life spans comparable to wild-type controls. In general, overexpres sion of antioxidant enzymes is not sufficient to extend life span in mice; although, targeted overexpression of catalase in mito chondria has been shown to improve survival and cardiac function. In humans, there is little evidence that antioxidant dietary supplements reduce mortality or age-related disease risk. Thus, it seems likely that multiple types of age-related damage contribute to phenotypes of aging, including oxidative damage from free radicals, and that the relative importance of different types of damage differs depending on cell or tissue type, genetic background, and environment.
Aging in Model Genetic Systems Life span differences between species are believed to result from multiple genetic and epigenetic factors. Body size is one trait that has been found to correlate positively with maximum longevity among a wide diversity of organisms; larger animals live, on an average, longer than smaller animals. There are exceptions to this rule, however. Bats and birds, for example, tend to live much longer than expected based on their size. Naked mole rats, which live about 10 times longer than simi larly sized rodents such as mice and rats, represent another example of a species that is exceptionally long-lived for its size. A few animals show no detectable signs of aging or senes cence. These include the Hydra, a simple freshwater animal that appears able to undergo unlimited cell division, and the Galapagos tortoise, which is reported to live more than 170 years. Molecular and genetic studies of such animals may yield insights into the mechanisms of aging and prospects for extending healthy life span in people. Most knowledge of aging mechanisms is based on studies of commonly used model organisms, including the budding yeast Saccharomyces cerevisiae, the nematode C. elegans, the fruit fly D. melanogaster, and the mouse Mus musculus. Single gene
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 1
doi:10.1016/B978-0-12-374984-0.00023-1
Aging, Genetics of mutations capable of extending population median and max imum life span by 30–50% have been identified in each of these organisms. S. cerevisiae and C. elegans have proven to be particu larly amenable to genome-scale longevity screens using gene deletion and RNAi interference libraries, resulting in the identi fication of several hundred genetic loci that modulate longevity. Although the degree to which aging mechanisms are evolutio narily conserved remains unknown, it is now clear that similar genetic and environmental factors can extend life span in yeast, worms, flies, and mice. Such conserved modifiers of longevity include dietary restriction, reduced insulin-like signaling, and inhibition of the target of rapamycin (TOR) signaling pathway.
Modulation of Aging by Nutrient Response Pathways Dietary restriction (also referred to as caloric restriction or calorie restriction) can be defined as a reduction in nutrient availability without malnutrition. In addition to extending life span in the four model organisms listed above, dietary restriction has been shown to extend life span in a variety of other organisms, includ ing rats, fish, spiders, and dogs. Dietary restriction appears to delay a variety of age-related diseases and pathologies, which is interpreted as suggesting that the aging process itself has been slowed or delayed. An ongoing long-term (>30 years) study of dietary restriction in rhesus monkeys supports the idea that similar effects can be obtained in primates, with monkeys sub jected to dietary restriction showing an increase in median survival and reduced incidences of diabetes, cardiovascular dis ease, and cancer. In C. elegans and D. melanogaster, life span extension from dietary restriction appears to involve both reduced caloric intake and decreased signaling through sensory neurons that mediate the response to food. In mice and rats, a global reduction in calories or restriction of specific amino acids such as methionine or tryptophan can extend life span. Human studies of dietary restriction, while unable to demonstrate a reduction in the rate of aging, are consistent with generally improved health in individuals practicing such a regimen. The mechanisms by which dietary restriction exerts its effects on aging are not well understood, although genetic studies have implicated nutrient and growth signaling path ways as key mediators of this response. Specific mutations that reduce growth hormone, insulin, and insulin-like growth factor 1 (IGF-1) signaling have been shown to extend life span in mice, and reduced insulin/IGF-1-like signaling can also pro mote longevity in nematodes and fruit flies. The TOR pathway, in particular, has been linked to life span extension from diet ary restriction; dietary restriction decreases TOR signaling; and inhibition of TOR is sufficient to increase life span in yeast, nematodes, flies, and mice.
Human Aging A genetic underpinning of aging in humans is revealed by rare diseases that resemble premature aging and by heritability estimates of longevity in normal populations. Hutchinson–Gilford progeria syndrome is a rare autosomaldominant condition of childhood characterized by balding, skin wrinkling, subcutaneous fat loss, and atherosclerosis, resulting in cardiovascular-associated death. There is no
49
acceleration in brain aging, illustrating that premature aging is segmental with some tissue types remaining unaffected. This syndrome is caused by a mutation in the LMNA gene coding for a nuclear filament protein important for nuclear structure. Werner syndrome is an adult-onset progeria and is character ized by skeletal muscle atrophy, premature graying of hair, heart valve calcification, intense atherosclerosis, and hypogo nadism. It is caused by mutation of the WRN gene that encodes a member of the RecQ family of DNA helicases. Genetic factors have been estimated to account for ∼25% of variance in life span in human populations, and several poten tially contributing loci have been reported. Alleles associated with longevity have been identified from gene association studies, including the ε2 variant of the APOE gene, which not only is overrepresented in centenarian populations but is also associated with type III and IV hyperlipidemia. Alleles of the Foxo3a tran scription factor have also been linked to longevity in multiple association studies. Foxo3a is a stress-responsive transcription factor, homologues of which are known to influence life span in worms and flies downstream of insulin-like signaling. Human cells cultured in vitro undergo a limited number of cell divisions, and the mechanism of this replicative senescence may be informative regarding aging in vivo. Senescent human cells display altered characteristics, including the secretion of a variety factors that can influence neighboring cells. A limited number of such senescent cells also occur in the tissues of aged humans and may contribute to age-related changes and func tional deficits. Cellular senescence in vitro results primarily from telomere shortening during replication and can be prevented by restoration of the telomere-synthesizing enzyme, telomerase. There are reports that short telomeres are associated with some age-related diseases and increased risk of death. With recent advances in the understanding of genetic and mechanistic factors that modulate aging, attention has turned to potentially translating these finding into therapies for human use. A major initiative toward this goal is the National Institute on Aging Interventions Testing Program. As part of this program, several compounds with putative antiaging properties are being tested for effects on life span in mice. The first major success of this program was the finding that feeding mice the TOR inhibi tor rapamycin significantly extends life span of both male and female mice, even when started late in life. This has led to speculation that rapamycin, and perhaps other drugs that target aging-related pathways, may ultimately be used to delay the onset and progression of multiple age-related diseases in people.
See also: Cancer Genetics; Genetic Alzheimer’s Disease; Telomeres.
Further Reading Austad SN (1999) Why We Age: What Science Is Discovering about the Body’s Journey Through Life, 1st edn. New York: John Wiley & Sons. Fontana L, Partridge L, and Longo VD (2010) Extending healthy life span – from yeast to humans. Science 328: 321–326. Kenyon CJ (2010) The genetics of ageing. Nature 464: 504–512. Masoro E and Austand SN (eds.) (2011) Handbook of the Biology of Aging. San Diego: Academic Press. Vaupel JW (2010) Biodemography of human ageing. Nature 464: 536–542. Wolf NS (ed.) (2010) Comparative Biology of Aging. Dordrecht: Springer.
50
Aging, Genetics of
Relevant Websites http://www.americanaging.org – American Aging Association. http://www.afar.org – American Federation for Aging Research.
http://genomics.senescence.info – Human Ageing Genomic Resources (HAGR). http://www.nia.nih.gov – National Institute on Aging. http://www.sageweb.org – Sageweb. http://www.geron.org – The Gerontological Society of America.