Background: It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease. Objective: The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals. Methods: We compared the number of disease-associated alleles, and the proportion of alleles predicted to be functionally damaging, between the centenarian brothers and published population data. Mitochondrial sequence reads were extracted from the exome data in order to analyze mitochondrial variants. Results: The brothers carry a similar number of common disease-associated variants and predicted damaging variants compared to reference groups. They did not carry any high-penetrance clinically actionable variants. They carry mitochondrial haplogroup T, and one brother has a single heteroplasmic variant. Conclusion: Although our small sample size does not allow for definitive conclusions, a healthy aging and longevity phenotype is not necessarily due to a decreased burden of common disease-associated variants. Instead, it may be rare ‘positive' variants that play a role in this desirable phenotype.

Keywords:
Centenarians, Exome sequencing, Healthy aging, Longevity, Genetics
1.
Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L: Siblings of centenarians live longer. Lancet 1998;351:1560.
2.
Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G, Barzilai N: Clinical phenotype of families with longevity. J Am Geriatr Soc 2004;52:274-277.
3.
Brooks-Wilson AR: Genetics of healthy aging and longevity. Hum Genet 2013;132:1323-1338.
4.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
5.
Podsiadlo D, Richardson S: The timed ‘Up & Go': a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991;36:142-148.
6.
Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:179-186.
7.
Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, et al: Genetic variation in healthy oldest-old. PLoS One 2009;4:e6641.
8.
Hindorff LA, MacArthur J, Morales J, et al: A catalog of published genome-wide association studies. http://www.genome.gov/gwastudies (accessed March 2014).
9.
Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073-1081.
10.
Exome Variant Server: NHLBI GO Exome Sequencing Project (ESP). http://evs.gs.washington.edu/EVS/ (accessed May, 2014).
11.
International HapMap Consortium: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007;449:851-861.
12.
Green RC, Berg JS, Grody WW, et al: ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-574.
13.
Guo Y, Li J, Li CI, Shyr Y, Samuels DC: MitoSeek: extracting mitochondria information and performing high-throughput mitochondria sequencing analysis. Bioinformatics 2013;29:1210-1211.
14.
Ostrer H, Skorecki K: The population genetics of the Jewish people. Hum Genet 2013;132:119-127.
15.
Kiezun A, Garimella K, Do R, et al: Exome sequencing and the genetic basis of complex traits. Nat Genet 2012;44:623-630.
16.
Beekman M, Nederstigt C, Suchiman HE, et al: GWAS identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci USA 2010;107:18046-18049.
17.
Stevenson M, Bae H, Schupf N, et al: Burden of disease variants in participants of the long life family study. Aging 2015;7:123-132.
18.
Sebastiani P, Riva A, Montano M, et al: Whole genome sequences of a male and female supercentenarian, ages greater than 114 years. Front Genet 2011;2:90.
19.
Sebastiani P, Solovieff N, Dewan AT, et al: Genetic signatures of exceptional longevity in humans. PLoS One 2012;7:e29848.
20.
Cash TP, Pita G, Domínguez O, et al: Exome sequencing of three cases of familial exceptional longevity. Aging Cell 2014;13:1087-1090.
21.
Ledwoń JK, Hennig EE, Maryan N, et al: Common low-penetrance risk variants associated with breast cancer in Polish women. BMC Cancer 2013;13:510.
22.
Johnson N, Fletcher O, Palles C, et al: Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet 2007;16:1051-1057.
23.
Landrum MJ, Lee JM, Riley GR, et al: ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 2014;42(Database issue):D980-D985.
24.
Freudenberg-Hua Y, Freudenberg J, Vacic V, et al: Disease variants in genomes of 44 centenarians. Mol Genet Genomic Med 2014;2:438-450.
25.
Ye K, Lu J, Ma F, Keinan A, Gu Z: Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals. Proc Natl Acad Sci USA 2014;111:10654-10659.
26.
Kofler B, Mueller EE, Eder W, et al: Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study. BMC Med Genet 2009;10:35.
27.
SanGiovanni JP, Arking DE, Iyengar SK, et al: Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 2009;4:e5508.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.