is likely a matter of number of subjects in the two groups (women in population aging studies usually outnumber men) rather than a real biological differ- ence. In any case we detected a significant increase of the heterozygous Klotho genotype in the class of elderly people, but not in the class of long-living people. On the whole these results show that the heterozygous genotype exerts a beneficial effect on survival when population mortality begins to acceler- ate (Ukraintseva and Yashin 2001), indeed it is found to be more frequent in the group of people aged from 66 to 91 years,while,on the contrary, in the group of long- living people its frequency is nearly identical to that of young people. Thus the KL-VS/wt heterozygous genotype modulates survival according to an age- specific complex pattern, probably shaped by physio- logical age-related variations (Passarino et al. 2006).

A possible explanation for these figures is that the heterozygous genotype is favorable at old age but less favorable, if not detrimental later on at very old age. Such a non-monotonic trend may be due to an age- specific effect of the genotypes, similar to that originally described for alleles in the ‘‘antagonistic pleiotropy’’ theory (Williams 1957), a hot topics that some of us recently critically revisited (Leroi et al.

association of genetic variation in peroxisome proliferator- activated receptor (PPAR) gamma-

with longevity. Exp Gerontol

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/j.exger.

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) New findings in transgenic, gene knockout and mutant mice. Exp Gerontol

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/ j.exger.

Bonafe` M, Olivieri F, Cavallone L, Giovagnetti S, Mayegiani F, Cardelli M, Pieri C, Marra M, Antonicelli R, Lisa R, Rizzo MR, Paolisso G, Monti D, Franceschi C (

) A gender- dependent genetic predisposition to produce high levels of IL-

is detrimental for longevity. Eur J Immunol

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–

doi:

/

-

(

)

:

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::AID-IMMU

[

CO;

-X Cardelli M, Cavallone L, Marchegiani F, Oliveri F, Dato S, Montesanto A, Lescai F, Lisa R, De Benedictis G, Franceschi C (

) A genetic-demographic approach reveals male-specific association between survival and tumor necrosis factor (A/G)-

polymorphism. J Ger- ontol A Biol Sci Med Sci

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Cederholm T, Persson M, Andersson P, Stenvinkel P, Nordfors L, Madden J, Vedin I, Wretlind B, Grimble RF, Palmblad J (

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x Dato S, Carotenuto L, De Benedictis G (

) Genes and longevity: a genetic-demographic approach reveals sex- and age-specific gene effects not shown by the case– control approach (APOE and HSP

loci). Biogeron- tology

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De Benedictis G, Franceschi C (

) The unusual genetics of human longevity. Sci Aging Knowl Environ

:pe

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pe

De Luca M, Rose G, Bonafe` M, Garasto S, Greco V, Weir BS, Franceschi C, De Benedictis G (

) Sex-specific lon- gevity associations defined by Tyrosine Hydroxylase- Insulin-Insulin Growth Factor

haplotypes on the

p

chromosomal region. Exp Gerontol

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(

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Franceschi C, Motta L, Valensin S, The Italian Multicenter Study on Centenarians (

) Do men and women follow different trajectories to reach extreme longevity? Aging Clin Exp Res

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Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y (

) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett

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Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro-o M, Kawaguchi H (

) Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res

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Kuro-o M (

) Klotho as a regulator of oxidative stress and senescence. Biol Chem

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Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai

2005). This theory proposes that individuals with alleles that are beneficial for reproductive fitness could be selected for by evolution even if the same alleles may have negative effects at later ages. We surmise that the same considerations may apply to genotypes and indeed it is not unusual to find non- monotonic age-related trajectories of genotype fre- quencies, in which centenarians display frequencies quite similar to those of young people (De Benedictis and Franceschi 2006). In conclusion, all the available data and those reported in the present study indicate that Klotho genetic variability has likely a role on human survival that is more complex than previously thought, since it appears that the same genotype has different effects (positive or negative for survival) according to the age of the subjects. On the basis of these data, we suggest that Klotho genetic variants may influence human longevity in a peculiar, unex- pected way. The Klotho polymorphism here exam- ined may be one example of a larger category of genes and gene variants exerting their effects at specific time windows.

activated receptor (PPAR) gamma-

with longevity. Exp Gerontol

:

–

doi:

/j.exger.

Bartke A (

) New findings in transgenic, gene knockout and mutant mice. Exp Gerontol

:

–

doi:

/ j.exger.

Bonafe` M, Olivieri F, Cavallone L, Giovagnetti S, Mayegiani F, Cardelli M, Pieri C, Marra M, Antonicelli R, Lisa R, Rizzo MR, Paolisso G, Monti D, Franceschi C (

) A gender- dependent genetic predisposition to produce high levels of IL-

is detrimental for longevity. Eur J Immunol

:

–

doi:

/

-

(

)

:

\

::AID-IMMU

[

CO;

-X Cardelli M, Cavallone L, Marchegiani F, Oliveri F, Dato S, Montesanto A, Lescai F, Lisa R, De Benedictis G, Franceschi C (