title: A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3.
abstract: Aging is the most significant risk factor for a range of diseases, including many cancers, neurodegeneration, cardiovascular disease, and diabetes. Caloric restriction (CR) without malnutrition delays aging in diverse species, and therefore offers unique insights into age-related disease vulnerability. Previous studies suggest that there are shared mechanisms of disease resistance associated with delayed aging, however quantitative support is lacking. We therefore sought to identify a common response to CR in diverse tissues and species and determine whether this signature would reflect health status independent of aging. We analyzed gene expression datasets from eight tissues of mice subjected to CR and identified a common transcriptional signature that includes functional categories of mitochondrial energy metabolism, inflammation and ribosomal structure. This signature is detected in flies, rats, and rhesus monkeys on CR, indicating aspects of CR that are evolutionarily conserved. Detection of the signature in mouse genetic models of slowed aging indicates that it is not unique to CR but rather a common aspect of extended longevity. Mice lacking the NAD-dependent deacetylase SIRT3 fail to induce mitochondrial and anti-inflammatory elements of the signature in response to CR, suggesting a potential mechanism involving SIRT3. The inverse of this transcriptional signature is detected with consumption of a high fat diet, obesity and metabolic disease, and is reversed in response to interventions that decrease disease risk. We propose that this evolutionarily conserved, tissue-independent, transcriptional signature of delayed aging and reduced disease vulnerability is a promising target for developing therapies for age-related diseases.
authors.affiliation: LifeGen Technologies LLC, Madison, Wisconsin, United States of America.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Barger
authors.affiliation: Department of Medicine, SMPH, University of Wisconsin, Madison, Wisconsin, United States of America; Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America.
authors.forename: Rozalyn M
authors.initials: RM
authors.lastname: Anderson
authors.affiliation: Departments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Newton
authors.affiliation: LifeGen Technologies LLC, Madison, Wisconsin, United States of America.
authors.forename: Cristina
authors.initials: C
authors.lastname: da Silva
authors.affiliation: Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Vann
authors.affiliation: Department of Medicine, SMPH, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Pugh
authors.affiliation: Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Someya
authors.affiliation: LifeGen Technologies LLC, Madison, Wisconsin, United States of America; Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.affiliation: LifeGen Technologies LLC, Madison, Wisconsin, United States of America; Department of Medicine, SMPH, University of Wisconsin, Madison, Wisconsin, United States of America; Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Weindruch
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D017124:Conserved Sequence; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009928:Organ Specificity; D056566:Sirtuin 3 / Q000172:deficiency / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C525046:Sirt3 protein, mouse; D056566:Sirtuin 3
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