a) Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell

,

–

Deelen J, Uh HW, Monajemi R, van Heemst D, Thijssen PE, Bohringer S, van den Akker EB, de Craen AJ, Rivadeneira F, Uitterlinden AG, Westendorp RG, Goeman JJ, Slagboom PE, Houwing-Duistermaat JJ, Beekman M (

b) Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-

signaling and telomere maintenance pathways. Age (Dordr.) [Open Access]. Derhovanessian E, Maier AB, Beck R, Jahn G, Hahnel K, Slagboom PE, de Craen AJ, Westendorp RG, Pawelec G (

) Hallmark features of immunosenescence are absent in familial longevity. J. Immunol.

,

–

Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (

) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res.

,

–

Fang Z, Zhang T, Dizeyi N, Chen S, Wang H, Swanson KD, Cai C, Balk SP, Yuan X (

) Androgen receptor enhances p

degradation in prostate cancer cells through rapid and selective TORC

activation. J. Biol. Chem.

,

–

Fontana L, Meyer TE, Klein S, Holloszy JO (

) Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc. Natl Acad. Sci. U S A

,

–

Garcia-Martinez JM, Alessi DR (

)

OR complex

(

ORC

) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid- induced protein kinase

(SGK

). Biochem. J.

,

–

Goeman JJ, Oosting J (

) Globaltest R package, version

Ref Type: Computer Program. Goeman JJ, van de Geer SA, de Kort F, van Houwelingen JC (

) A global test for groups of genes: testing association with a clinical outcome. Bioinformatics

,

–

Goeman JJ, Oosting J, Cleton-Jansen AM, Anninga JK, van Houwelingen HC (

) Testing association of a pathway with survival using gene expression data. Bioinformatics

,

–

Barzilai N, Gabriely I, Gabriely M, Iankowitz N, Sorkin JD (2001) Offspring of centenarians have a favorable lipid profile. J. Am. Geriatr. Soc. 49, 76–79. Brown J, Wang H, Suttles J, Graves DT, Martin M (2011) Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates toll-like receptor 4-med-

Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (

) Phosphorylation and regulation of Akt/PKB by the rictor-

OR complex. Science

,

–

Schoenmaker M, de Craen AJ, de Meijer PH, Beekman M, Blauw GJ, Slagboom PE, Westendorp RG (

) Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur. J. Hum. Genet.

,

–

Sengupta S, Peterson TR, Sabatini DM (

) Regulation of the

OR complex

pathway by nutrients, growth factors, and stress. Mol. Cell

,

–

Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G (

) Rictor/TORC

regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev.

,

–

Spindler SR (

) Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. Mech. Ageing Dev.

,

–

Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK (

) The TOR pathway comes of age. Biochim. Biophys. Acta

,

–

Stat

orp (

) Stata Statistical Software: Release

College Station, TX: Stat

orp LP. Strimpakos A, Saif MW, Syrigos KN (

) Pancreatic cancer: from molecular pathogenesis to targeted therapy. Cancer Metastasis Rev.

,

–

Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P, Arrieumerlou C, Hall MN (

) PRAS

and PRR

-like protein are new

OR interactors that regulate apoptosis. PL

One

, e

Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F (

) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature

,

Westendorp RG, van Heemst D, Rozing MP, Frolich M, Mooijaart SP, Blauw GJ, Beekman M, Heijmans BT, de Craen AJ, Slagboom PE (

) Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study. J. Am. Geriatr. Soc.

,

–

Wijsman CA, Rozing MP, Streefland TC, le Cessie S, Mooijaart SP, Slagboom PE, Westendorp RG, Pijl H, van Heemst D (2011) Familial longevity is marked by enhanced insulin sensitivity. Aging Cell 10, 114–121.

enhanced insulin sensitivity. Aging Cell 10, 114–121. Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 8, 393–412.

Supporting Information

Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.

Table S1 Analysed samples: genetic variation.

S2 Measured SNPs in the mTOR pathway.

S3 Results of gene set analysis of the mTOR pathway gene SNP

Table S4 Linear regression results of gene expression of offspring compared with controls, including adjustments for T-cell differentiation markers.

Table S5 Descriptives of prevalence of disease and metabolic syndrome related parameters in offspring and controls (n = 658).

T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620. RG, van Heemst D, Rozing MP, Frolich M, Mooijaart SP, Blauw GJ, Beekman M, Heijmans BT, de Craen AJ, Slagboom PE (2009) Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study. J. Am. Geriatr. Soc. 57, 1634–1637.

Table S6 Linear regression results of gene expression of offspring compared with controls, excluding diabetics and cancer patients.

Table S7 Linear regression results of gene expression of offspring compared with controls (without diabetics), including adjustments for glucose plasma levels.