<p>Frequencies of point mutations (A) and genome rearrangements (B) in liver, spleen and br... more <p>Frequencies of point mutations (A) and genome rearrangements (B) in liver, spleen and brain from <i>Ku80</i><sup>−/−</sup> and wt mice, as determined from the mutants collected from the results shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003458#pone-0003458-g001" target="_blank">Fig. 1</a>.</p
1Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA. 2Regeneron Pharm... more 1Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA. 2Regeneron Pharmaceuticals Inc., New York, NY, USA. 3School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy. 4Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany. 5Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA. 6Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Internal Medicine I, Kiel University, Kiel, Germany. 7Institute of Transfusion Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany. 8Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. 9Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. 10Department of Epidemiology & Population Health, Albert Einstein College of Medicine, New York, NY, USA. 11Department of Biology, University of Rochester, Rochester, NY, USA. 12Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA. 13Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA. 14Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA. 15Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. 16These authors contributed equally Jhih-Rong Lin, Patrick Sin-Chan. *A full list of members and their affiliations appears in Acknowledgements. ✉e-mail: zhengdong.zhang@einsteinmed.org Species-specific lifespan is limited by aging, a multifactorial process accompanied by a general decline in tissue function and increased risk for many diseases1. Rather than a passive, entropic process of deterioration, aging is subject to active modulation by signaling pathways and transcription factors conserved across species2,3. In model organisms, single-gene mutations have been demonstrated to affect lifespan4. For example, at the extreme end, the lifespan of nematode worms can be increased up to nearly tenfold by mutations in genes involved in insulin/ insulin-like growth factor 1 signaling (IIS)5,6. Even in more complicated organisms, however, such as flies and mice, lifespan can be extended up to 50% by mutations affecting the same pathway7–9 or other pathways involved in growth, metabolism and nutrient sensing, such as the mechanistic target of rapamycin (mTOR) and AMP-activating protein kinase (AMPK)10. On the basis of homo logy, it is widely hypothesized that these conserved signaling pathways are similarly involved in human aging and longevity. In humans, lifespan is a complex trait affected by multiple factors that vary considerably within human populations. While nongenetic factors, including diet, physical activity, health habits and psychosocial factors, are important, lifespan clearly has a genetic component as suggested by human population-based studies11,12. At increasingly older ages, especially beyond 100 years, this genetic component becomes exceedingly strong13,14. As a highly complex trait, the genetic underpinnings of human lifespan probably encompass different types of genetic variants and epistasis across the allele frequency spectrum. Common variants associated with human survival have been extensively searched for in many recent genomewide association studies (GWAS), using a variety of trait definitions and study designs15. Together, these studies have identified more than 50 longevity-associated genetic loci of genome-wide significance, among which only a few, especially APOE, were replicated by multiple studies16. On the other hand, several previous studies have detected an association of human longevity with variants in several aging genes—including insulin signaling genes17 and FOXO3 (refs. 18,19)—using candidate gene approaches. Most of these longevity-associated SNPs have small effect sizes, and currently common variants collectively explain only a very small proportion Rare genetic coding variants associated with human longevity and protection against agerelated diseases
Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum ... more Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum lifespans among mammals. However, measurements of individual DNA repair activities in cells and animals have not substantiated such a relationship because utilization of repair pathways among animals-depending on habitats, anatomical characteristics, and life styles-varies greatly between mammalian species. Recent advances in high-throughput genomics, in combination with increased knowledge of the genetic pathways involved in genome maintenance, now enable a comprehensive comparison of DNA repair transcriptomes in animal species with extreme lifespan differences. Here we compare transcriptomes of liver, an organ with high oxidative metabolism and abundant spontaneous DNA damage, from humans, naked mole rats, and mice, with maximum lifespans of ~120, 30, and 3 years, respectively, with a focus on genes involved in DNA repair. The results show that the longer-lived species, human and naked...
Functional genomics of aging is a comprehensive approach to study the dynamic network of genes th... more Functional genomics of aging is a comprehensive approach to study the dynamic network of genes that ultimately determines the physiology of an individual organism over its lifetime.
Aging is the single largest risk factor for chronic disease. Studies in model organisms have iden... more Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified ...
The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in ... more The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts…
Genetic association studies of age-related, chronic human diseases often suffer from a lack of po... more Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed /genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed...
Sir2 proteins slow ageing in yeast by locking chromatin - the DNA and proteins in chromosomes - i... more Sir2 proteins slow ageing in yeast by locking chromatin - the DNA and proteins in chromosomes - into a stable, silent state. Inactivating a Sir2 family protein in mice causes premature ageing and genome instability.
Longevity, i.e., the property of being long-lived, has its natural limitation in the aging proces... more Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of gene...
Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice defi... more Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apopt...
<p>Frequencies of point mutations (A) and genome rearrangements (B) in liver, spleen and br... more <p>Frequencies of point mutations (A) and genome rearrangements (B) in liver, spleen and brain from <i>Ku80</i><sup>−/−</sup> and wt mice, as determined from the mutants collected from the results shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003458#pone-0003458-g001" target="_blank">Fig. 1</a>.</p
1Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA. 2Regeneron Pharm... more 1Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA. 2Regeneron Pharmaceuticals Inc., New York, NY, USA. 3School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy. 4Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany. 5Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA. 6Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Internal Medicine I, Kiel University, Kiel, Germany. 7Institute of Transfusion Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany. 8Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. 9Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. 10Department of Epidemiology & Population Health, Albert Einstein College of Medicine, New York, NY, USA. 11Department of Biology, University of Rochester, Rochester, NY, USA. 12Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA. 13Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA. 14Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA. 15Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. 16These authors contributed equally Jhih-Rong Lin, Patrick Sin-Chan. *A full list of members and their affiliations appears in Acknowledgements. ✉e-mail: zhengdong.zhang@einsteinmed.org Species-specific lifespan is limited by aging, a multifactorial process accompanied by a general decline in tissue function and increased risk for many diseases1. Rather than a passive, entropic process of deterioration, aging is subject to active modulation by signaling pathways and transcription factors conserved across species2,3. In model organisms, single-gene mutations have been demonstrated to affect lifespan4. For example, at the extreme end, the lifespan of nematode worms can be increased up to nearly tenfold by mutations in genes involved in insulin/ insulin-like growth factor 1 signaling (IIS)5,6. Even in more complicated organisms, however, such as flies and mice, lifespan can be extended up to 50% by mutations affecting the same pathway7–9 or other pathways involved in growth, metabolism and nutrient sensing, such as the mechanistic target of rapamycin (mTOR) and AMP-activating protein kinase (AMPK)10. On the basis of homo logy, it is widely hypothesized that these conserved signaling pathways are similarly involved in human aging and longevity. In humans, lifespan is a complex trait affected by multiple factors that vary considerably within human populations. While nongenetic factors, including diet, physical activity, health habits and psychosocial factors, are important, lifespan clearly has a genetic component as suggested by human population-based studies11,12. At increasingly older ages, especially beyond 100 years, this genetic component becomes exceedingly strong13,14. As a highly complex trait, the genetic underpinnings of human lifespan probably encompass different types of genetic variants and epistasis across the allele frequency spectrum. Common variants associated with human survival have been extensively searched for in many recent genomewide association studies (GWAS), using a variety of trait definitions and study designs15. Together, these studies have identified more than 50 longevity-associated genetic loci of genome-wide significance, among which only a few, especially APOE, were replicated by multiple studies16. On the other hand, several previous studies have detected an association of human longevity with variants in several aging genes—including insulin signaling genes17 and FOXO3 (refs. 18,19)—using candidate gene approaches. Most of these longevity-associated SNPs have small effect sizes, and currently common variants collectively explain only a very small proportion Rare genetic coding variants associated with human longevity and protection against agerelated diseases
Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum ... more Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum lifespans among mammals. However, measurements of individual DNA repair activities in cells and animals have not substantiated such a relationship because utilization of repair pathways among animals-depending on habitats, anatomical characteristics, and life styles-varies greatly between mammalian species. Recent advances in high-throughput genomics, in combination with increased knowledge of the genetic pathways involved in genome maintenance, now enable a comprehensive comparison of DNA repair transcriptomes in animal species with extreme lifespan differences. Here we compare transcriptomes of liver, an organ with high oxidative metabolism and abundant spontaneous DNA damage, from humans, naked mole rats, and mice, with maximum lifespans of ~120, 30, and 3 years, respectively, with a focus on genes involved in DNA repair. The results show that the longer-lived species, human and naked...
Functional genomics of aging is a comprehensive approach to study the dynamic network of genes th... more Functional genomics of aging is a comprehensive approach to study the dynamic network of genes that ultimately determines the physiology of an individual organism over its lifetime.
Aging is the single largest risk factor for chronic disease. Studies in model organisms have iden... more Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified ...
The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in ... more The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts…
Genetic association studies of age-related, chronic human diseases often suffer from a lack of po... more Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed /genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed...
Sir2 proteins slow ageing in yeast by locking chromatin - the DNA and proteins in chromosomes - i... more Sir2 proteins slow ageing in yeast by locking chromatin - the DNA and proteins in chromosomes - into a stable, silent state. Inactivating a Sir2 family protein in mice causes premature ageing and genome instability.
Longevity, i.e., the property of being long-lived, has its natural limitation in the aging proces... more Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of gene...
Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice defi... more Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apopt...
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