In conclusion, we have: (1) Generated a list of SNP candi- dates linked to longevity in a GWAS conducted on a south Italian population; (2) provided evidence that the longevity- associated rs10491334 variant of CAMKIV negatively influ- ences CAMKIV protein expression; and (3) provided evidence suggesting a prolongevity role of native CAMKIV through the activation of AKT, SIRT1, and FOXO3A proteins.

Acknowledgments

We thank all of the patients and medical doctors of the Cilento Health District ASL SA3 that participated in this study. We are grateful to Elixir Pharmaceuticals for access to the DNA samples. We thank Michael Latronico for careful revision of the manuscript. This work was sponsored by Italian Ministry of Health (1% funds), Italian Ministry of Research and University (FIRB RBIN04X9XE), and by the FIRB project ITALBIONET, Rete Italiana di Bioinformatica.

Author Disclosure Statement

rs10491334, a SNP on CAMKIV, was previously associated with high diastolic blood pressure in the Framingham study.31 Hypertension and longevity share regulatory pathways, as underlined by improved survival and increased SIRT3 ex- pression in mice knocked out for angiotensin II type1 receptor, a key protein for vascular dysfunction and maintenance of hypertension via activation of the cyclic (c) AMP response el- ement-binding (CREB)/histone deacetylase 4 (HDAC4)/ myocyte enhancer factor-2 (MEF2) pathway.42,43

The authors declare that they have no competing financial interests.

References

1. Terry DF, Sebastiani P, Andersen SL, Perls TT. Disen- tangling the roles of disability and morbidity in survival to exceptional old age. Arch Intern Med 2008;168:277–283.

Silver MH, Jilinskaia E, Perls TT. Cognitive functional status of age-confirmed centenarians in a population-based study. J Gerontol B Psychol Sci Soc Sci

;

:P

–P

Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, Sedgewick A, Arai Y, Bergman A, Barzilai N, Terry DF, Riva A, Anselmi CV, Malovini A, Kitamoto A, Sawabe M, Arai T, Gondo Y, Steinberg MH, Hirose N, Atzmon G, Ruvkun G, Baldwin CT, Perls TT. RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PL

One

;

:e

Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet

;

:

–

Marchini J, Howie B, Myers S, M

ean G, Donnelly P. A new multipoint method for genome-wide association stud- ies by imputation of genotypes. Nat Genet

;

:

–

Barrett JC, Fry B, Maller J, Daly MJ. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics

;

:

–

Gauderman WJ MJ. QUANTO

: A computer program for power and sample size calculations for genetic-epidemiology studies. http://hydra.usc.edu/gxe,

Devlin B, Roeder K. Genomic control for association studies. Biometrics

;

:

–

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: A tool set for whole-genome association and pop- ulation-based linkage analyses. Am J Hum Genet

;

:

–

Iaccarino G, Barbato E, Cipolletta E, De Amicis V, Margulies KB, Leosco D, Trimarco B, Koch WJ. Elevated myocardial and lymphocyte GRK

expression and activity in human heart failure. Eur Heart J

;

:

–

Kitsos CM, Sankar U, Illario M, Colomer-Font JM, Duncan AW, Ribar TJ, Reya T, Means AR. Calmodulin-dependent protein kinase IV regulates hematopoietic stem cell mainte- nance. J Biol Chem

;

:

–

Consiglio A, Gritti A, Dolcetta D, Follenzi A, Bordignon C, Gage FH, Vescovi AL, Naldini L. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. Proc Natl Acad Sci USA

;

:

–

Ioannidis JP, Thomas G, Daly MJ. Validating, augmenting and refining genome-wide association signals. Nat Rev Genet

;

:

–

Borowiec AS, Hague F, Harir N, Guenin S, Guerineau F, Gouilleux F, Roudbaraki M, Lassoued K, Ouadid-Ahidouch H. IGF-

activates

AG K(þ) channels through an Akt- dependent signaling pathway in breast cancer cells: role in cell proliferation. J Cell Physiol

;

:

–

Levy D, Larson MG, Benjamin EJ, Newton-Cheh C, Wang TJ, Hwang SJ, Vasan RS, Mitchell GF. Framingham Heart Study

K Project: Genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet

;

(Suppl

):S

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, M

uinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van

Paolisso G, Gambardella A, Ammendola S, D’Amore A, Balbi V, Varricchio M, D’Onofrio F. Glucose tolerance and insulin action in healthy centenarians. Am J Physiol

;

(

Pt

):E

–E

Zulfiqar U, Jurivich DA, Gao W, Singer DH. Relation of high heart rate variability to healthy longevity. Am J Cardiol

;

:

–

Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, Bogan H, Joyce E, Brewster S, Kunkel L, Puca A. Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci USA

;

:

–

Perls T, Shea-Drinkwater M, Bowen-Flynn J, Ridge SB, Kang S, Joyce E, Daly M, Brewster SJ, Kunkel L, Puca AA. Ex- ceptional familial clustering for extreme longevity in hu- mans. J Am Geriatr Soc

;

:

–

Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet

;

:

–

Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO

A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA

;

:

–