PMID- 25830335 OWN - NLM STAT- MEDLINE DCOM- 20151223 LR - 20220726 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 4 DP - 2015 TI - A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. PG - e0120738 LID - 10.1371/journal.pone.0120738 [doi] LID - e0120738 AB - 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. FAU - Barger, Jamie L AU - Barger JL AD - LifeGen Technologies LLC, Madison, Wisconsin, United States of America. FAU - Anderson, Rozalyn M AU - Anderson RM AD - 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. FAU - Newton, Michael A AU - Newton MA AD - Departments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin, United States of America. FAU - da Silva, Cristina AU - da Silva C AD - LifeGen Technologies LLC, Madison, Wisconsin, United States of America. FAU - Vann, James A AU - Vann JA AD - Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America. FAU - Pugh, Thomas D AU - Pugh TD AD - Department of Medicine, SMPH, University of Wisconsin, Madison, Wisconsin, United States of America. FAU - Someya, Shinichi AU - Someya S AD - Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America. FAU - Prolla, Tomas A AU - Prolla TA AD - LifeGen Technologies LLC, Madison, Wisconsin, United States of America; Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin, United States of America. FAU - Weindruch, Richard AU - Weindruch R AD - 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. LA - eng GR - R21 HG006568/HG/NHGRI NIH HHS/United States GR - R01 AG037000/AG/NIA NIH HHS/United States GR - R01 DC012552/DC/NIDCD NIH HHS/United States GR - R01AG037000/AG/NIA NIH HHS/United States GR - P30 AG028740/AG/NIA NIH HHS/United States GR - P01 AG011915/AG/NIA NIH HHS/United States GR - R01 DC014437/DC/NIDCD NIH HHS/United States GR - R03 DC011840/DC/NIDCD NIH HHS/United States GR - R01AG038679/AG/NIA NIH HHS/United States GR - R21HG006568/HG/NHGRI NIH HHS/United States GR - P01AG011915/AG/NIA NIH HHS/United States GR - R01 AG038679/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150401 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Sirt3 protein, mouse) RN - EC 3.5.1.- (Sirtuin 3) SB - IM MH - Aging/*genetics/metabolism MH - Animals MH - *Caloric Restriction MH - *Conserved Sequence MH - Evolution, Molecular MH - *Gene Expression Profiling MH - Genetic Predisposition to Disease/*genetics MH - Longevity/genetics MH - Male MH - Mice MH - Models, Genetic MH - Organ Specificity MH - Sirtuin 3/deficiency/*metabolism MH - *Transcription, Genetic PMC - PMC4382298 COIS- Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TAP and RW are founders of LifeGen Technologies, LLC, a company focused on the use of gene expression profiling to understand the mechanisms of action of caloric restriction. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. EDAT- 2015/04/02 06:00 MHDA- 2015/12/24 06:00 PMCR- 2015/04/01 CRDT- 2015/04/02 06:00 PHST- 2014/11/17 00:00 [received] PHST- 2015/02/06 00:00 [accepted] PHST- 2015/04/02 06:00 [entrez] PHST- 2015/04/02 06:00 [pubmed] PHST- 2015/12/24 06:00 [medline] PHST- 2015/04/01 00:00 [pmc-release] AID - PONE-D-14-46114 [pii] AID - 10.1371/journal.pone.0120738 [doi] PST - epublish SO - PLoS One. 2015 Apr 1;10(4):e0120738. doi: 10.1371/journal.pone.0120738. eCollection 2015.