It is increasingly recognized that young,chow-fed inbred mice poorly model the com-plexity of human carcinogenesis.In humans,age and adiposity are major risk factors for malignancies,but most genetically engineered mo...It is increasingly recognized that young,chow-fed inbred mice poorly model the com-plexity of human carcinogenesis.In humans,age and adiposity are major risk factors for malignancies,but most genetically engineered mouse models(GEMM)induce car-cinogenesis too rapidly to study these influences.Standard strains,such as C57BL/6,commonly used in GEMMs,further limit the exploration of aging and metabolic health effects.A similar challenge arises in modeling periodontitis,a disease influenced by aging,diabesity,and genetic architecture.We propose using diverse mouse popula-tions with hybrid vigor,such as the Collaborative Cross(CC)×Apc ^(Min) hybrid,to slow disease progression and better model human colorectal cancer(CRC)and comorbidi-ties.This perspective highlights the advantages of this model,where delayed car-cinogenesis reveals interactions with aging and adiposity.Unlike Apc ^(Min) mice,which develop cancer rapidly,CC×Apc ^(Min) hybrids recapitulate human-like progression.This facilitates the identification of modifier loci affecting inflammation,diet susceptibility,organ size,and polyposis distribution.The CC×Apc ^(Min) model offers a transformative platform for studying CRC as a disease of adulthood,reflecting its complex inter-play with aging and comorbidities.The insights gained from this approach will en-hance early detection,management,and treatment strategies for CRC and related conditions.展开更多
It is central to biology that sequence conservation suggests functional conservation.Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions afte...It is central to biology that sequence conservation suggests functional conservation.Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions after reproductive maturity.Though the yeast SIR2 gene was nominated as a longevity gene based on extended replicative longevity of old mother cells,this is not a selected trait:SIR2 is selected against in chronological aging and the direct targets of SIR2 in replicative lifespan are not conserved.Though it would be difficult to imagine how a gene that advantages 1 in 5 million yeast cells could have anticipated causes of aging in animals,overexpression of SIR2 homologs was tested in invertebrates for longevity.Because artifactual positive results were reported years before they were sorted out and because it was not known that SIR2 functions as a pro-aging gene in yeast chronological aging and in flies subject to amino acid deprivation,a global pursuit of longevity phenotypes was driven by a mixture of framing bias,confirmation bias,and hype.Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes.Acknowledging that a few positive associations between sirtuins and longevity have been identified after thousands of person-years and billions of dollars of effort,we review the data and suggest rejection of the notions that sirtuins(i)have any specific connection to lifespan in animals and(ii)are primary mediators of the beneficial effects of NAD repletion.展开更多
基金Israel Cancer Research FoundationSamuel Waxman Cancer Research FoundationCore funding from Tel Aviv University。
文摘It is increasingly recognized that young,chow-fed inbred mice poorly model the com-plexity of human carcinogenesis.In humans,age and adiposity are major risk factors for malignancies,but most genetically engineered mouse models(GEMM)induce car-cinogenesis too rapidly to study these influences.Standard strains,such as C57BL/6,commonly used in GEMMs,further limit the exploration of aging and metabolic health effects.A similar challenge arises in modeling periodontitis,a disease influenced by aging,diabesity,and genetic architecture.We propose using diverse mouse popula-tions with hybrid vigor,such as the Collaborative Cross(CC)×Apc ^(Min) hybrid,to slow disease progression and better model human colorectal cancer(CRC)and comorbidi-ties.This perspective highlights the advantages of this model,where delayed car-cinogenesis reveals interactions with aging and adiposity.Unlike Apc ^(Min) mice,which develop cancer rapidly,CC×Apc ^(Min) hybrids recapitulate human-like progression.This facilitates the identification of modifier loci affecting inflammation,diet susceptibility,organ size,and polyposis distribution.The CC×Apc ^(Min) model offers a transformative platform for studying CRC as a disease of adulthood,reflecting its complex inter-play with aging and comorbidities.The insights gained from this approach will en-hance early detection,management,and treatment strategies for CRC and related conditions.
基金supported by R01HL147545 and the Alfred E.Mann Family Foundation.
文摘It is central to biology that sequence conservation suggests functional conservation.Animal longevity is an emergent property of selected traits that integrates capacities to perform physical and mental functions after reproductive maturity.Though the yeast SIR2 gene was nominated as a longevity gene based on extended replicative longevity of old mother cells,this is not a selected trait:SIR2 is selected against in chronological aging and the direct targets of SIR2 in replicative lifespan are not conserved.Though it would be difficult to imagine how a gene that advantages 1 in 5 million yeast cells could have anticipated causes of aging in animals,overexpression of SIR2 homologs was tested in invertebrates for longevity.Because artifactual positive results were reported years before they were sorted out and because it was not known that SIR2 functions as a pro-aging gene in yeast chronological aging and in flies subject to amino acid deprivation,a global pursuit of longevity phenotypes was driven by a mixture of framing bias,confirmation bias,and hype.Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes.Acknowledging that a few positive associations between sirtuins and longevity have been identified after thousands of person-years and billions of dollars of effort,we review the data and suggest rejection of the notions that sirtuins(i)have any specific connection to lifespan in animals and(ii)are primary mediators of the beneficial effects of NAD repletion.
