Age‐related behaviors have distinct transcriptional profiles in Caenorhabditis elegans

There has been a great deal of interest in identifying potential biomarkers of aging. Biomarkers of aging would be useful to predict potential vulnerabilities in an individual that may arise well before they are chronologically expected, due to idiosyncratic aging rates that occur between individuals. Prior attempts to identify biomarkers of aging have often relied on the comparisons of long‐lived animals to a wild‐type control. However, the effect of interventions in model systems that prolong lifespan (such as single gene mutations or caloric restriction) can sometimes be difficult to interpret due to the manipulation itself having multiple unforeseen consequences on physiology, unrelated to aging itself. The search for predictive biomarkers of aging therefore is problematic, and the identification of metrics that can be used to predict either physiological or chronological age would be of great value. One methodology that has been used to identify biomarkers for numerous pathologies is gene expression profiling. Here, we report whole‐genome expression profiles of individual wild‐type Caenorhabditis elegans covering the entire wild‐type nematode lifespan. Individual nematodes were scored for either age‐related behavioral phenotypes, or survival, and then subsequently associated with their respective gene expression profiles. This facilitated the identification of transcriptional profiles that were highly associated with either physiological or chronological age. Overall, our approach serves as a paradigm for identifying potential biomarkers of aging in higher organisms that can be repeatedly sampled throughout their lifespan.

[1]  A. Antebi,et al.  Genetics of Aging in Caenorhabditis elegans , 2007, PLoS genetics.

[2]  R. Hosono Age dependent changes in the behavior of Caenorhabditis elegans on attraction to Escherichia coli , 1978, Experimental Gerontology.

[3]  R. Bronson,et al.  Lesion biomarkers of aging in B6C3F1 hybrid mice. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[4]  S. Yan,et al.  Mitochondrial amyloid-beta peptide: pathogenesis or late-phase development? , 2006, Journal of Alzheimer's disease : JAD.

[5]  G. Zhou,et al.  Biomarkers of aging: correlation of DNA I-compound levels with median lifespan of calorically restricted and ad libitum fed rats and mice. , 1993, Mutation research.

[6]  L. Partridge,et al.  Interpreting interactions between treatments that slow aging , 2002, Aging cell.

[7]  L. Partridge,et al.  Beyond the evolutionary theory of ageing, from functional genomics to evo-gero. , 2006, Trends in ecology & evolution.

[8]  Richard Weindruch,et al.  Biomarkers of aging: from primitive organisms to humans. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  Steven N. Austad,et al.  Animal Behaviour , 44 , 6 Longevity , Senescence , and the Genome , 2017 .

[10]  P. Sebastiani,et al.  Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer , 2007, Nature Medicine.

[11]  J. McElwee,et al.  Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF‐16 , 2003, Aging cell.

[12]  R. Beaver,et al.  Temporal linkage between the phenotypic and genomic responses to caloric restriction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Cori Bargmann,et al.  Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans , 2003, Nature.

[14]  Xi Chen,et al.  ABAD enhances Aβ‐induced cell stress via mitochondrial dysfunction , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  John N. Weinstein,et al.  High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID) , 2005, BMC Bioinformatics.

[16]  Alan Hubbard,et al.  Dramatic age-related changes in nuclear and genome copy number in the nematode Caenorhabditis elegans , 2007, Aging cell.

[17]  Alan Hubbard,et al.  Microarrays as a tool to investigate the biology of aging: a retrospective and a look to the future. , 2004, Science of aging knowledge environment : SAGE KE.

[18]  Andrew G Fraser,et al.  Rates of Behavior and Aging Specified by Mitochondrial Function During Development , 2002, Science.

[19]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[20]  Alan Hubbard,et al.  Resistance Exercise Reverses Aging in Human Skeletal Muscle , 2007, PloS one.

[21]  E. Brown,et al.  Genomic analysis of gene expression in C. elegans. , 2000, Science.

[22]  P. Medawar UNSOLVED problem of biology. , 1953, The Medical journal of Australia.

[23]  Ramesh Ramakrishnan,et al.  High Throughput Gene Expression Measurement with Real Time PCR in a Microfluidic Dynamic Array , 2008, PloS one.

[24]  R. Hosono,et al.  Age-dependent changes in mobility and separation of the nematode Caenorhabditis elegans , 1980, Experimental Gerontology.

[25]  Age-related chromatin condensation in flight muscle nuclei of the adult male housefly, Musca domestica , 1985, Experimental Gerontology.

[26]  G. M. Nagaraja,et al.  Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics , 2006, Oncogene.

[27]  Yosef Gruenbaum,et al.  Age-related changes of nuclear architecture in Caenorhabditis elegans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  David Gems,et al.  Shared Transcriptional Signature in Caenorhabditis elegans Dauer Larvae and Long-lived daf-2 Mutants Implicates Detoxification System in Longevity Assurance* , 2004, Journal of Biological Chemistry.

[29]  David B. Goldstein,et al.  Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster , 2002, Current Biology.

[30]  S. Gerson,et al.  The role of DNA damage repair in aging of adult stem cells , 2007, Nucleic acids research.

[31]  D. Harrison,et al.  Biomarkers of aging: Tissue markers. Future research needs, strategies, directions and priorities , 1988, Experimental Gerontology.

[32]  E. Nakamura,et al.  Strategy for identifying biomarkers of aging in long-lived species , 2001, Experimental Gerontology.

[33]  Xi Chen,et al.  Materials and Methods Som Text Figs. S1 and S2 Table S1 References Abad Directly Links A␤ to Mitochondrial Toxicity in Alzheimer's Disease , 2022 .

[34]  Mark J. van der Laan,et al.  A new algorithm for hybrid hierarchical clustering with visualization and the bootstrap , 2003 .

[35]  D. Hall,et al.  Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans , 2002, Nature.

[36]  M. Pike,et al.  Maximum life span predictions from the Gompertz mortality model. , 1996, The journals of gerontology. Series A, Biological sciences and medical sciences.

[37]  Kyle Duke,et al.  Transcriptional Profile of Aging in C. elegans , 2002, Current Biology.

[38]  Hong Ma,et al.  [Biomarkers of aging]. , 2002, Sheng li ke xue jin zhan [Progress in physiology].

[39]  Simon Melov,et al.  Microarray analysis of gene expression with age in individual nematodes , 2004, Aging cell.

[40]  I L Johnstone,et al.  Cuticle collagen genes. Expression in Caenorhabditis elegans. , 2000, Trends in genetics : TIG.

[41]  B. Ames,et al.  The free radical theory of aging matures. , 1998, Physiological reviews.

[42]  George C. Williams,et al.  PLEIOTROPY, NATURAL SELECTION, AND THE EVOLUTION OF SENESCENCE , 1957, Science of Aging Knowledge Environment.

[43]  May D. Wang,et al.  GoMiner: a resource for biological interpretation of genomic and proteomic data , 2003, Genome Biology.

[44]  T. Johnson,et al.  Heat shock protein accumulation is upregulated in a long-lived mutant of Caenorhabditis elegans. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[45]  G. Lithgow,et al.  Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin‐like signals , 2003, Aging cell.

[46]  J. Barry,et al.  Temporal reiteration of a precise gene expression pattern during nematode development. , 1996, The EMBO journal.

[47]  J. Foekens,et al.  Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  Gary Ruvkun,et al.  A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity , 2003, Nature Genetics.

[49]  A. Fraser,et al.  Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. , 2002, Genetics.

[50]  Terry Speed,et al.  Normalization of cDNA microarray data. , 2003, Methods.