tion enables the parameterization for disentangling the various components that are functioning towards longevity, even if the phenotypic effects sustained by the gene on the trait were very subtle (for example, beneficial effects sustained by allele 10*).

subtle effects of the gene variant on the complex trait could be revealed. The basic statistical model described in this paper has been introduced in recent publications (Yashin et al., 1998, 1999b, 2000; Tan et al., 2001b,c). However, the parame- terization in the present application shows the feasibility of detecting an allele(cid:2)allele interaction / (see Table 2 and Fig. 1) which implies dominant and additive beneficial effects on the risk of death (allele 10*). An important feature of this applica- tion is the combination of individual genetic data with population demographic information in de- termining the relative risks of the observed genes. The baseline hazard function in this approach is estimated non-parametrically so that no specific survival distribution is imposed on the likelihood function (Tan et al., 2001b). Parameter estimates in this procedure depend heavily on the propor- tional hazard assumption similar to that in Cox’s proportional hazard model. Problems of such an assumption when applied to the genetics of human longevity are discussed in Yashin et al. (1999b), Tan et al. (2001b). However, it can be seen from this study that the proportional hazard assump-

bility is implicated in human longevity, and in an allele-specific way. How could these effects be explained from a biological point of view? TH encodes the rate-limiting enzyme for the synthesis of cathecolamines, aminoacid-derived molecules that act both as hormones (adrenalin) and neuro- transmitters (dopamine and noradrenalin). The TH gene is therefore a master gene in the neuro- endocrine system (NES). Vertebrates have devel- oped a complex hierarchy of multi-organ NES, integrated with the immune system to form the immune-NES. This system governs the capability to cope with a variety of stress-factors and, consequently, rate and quality of aging (Fran- ceschi et al., 2000). The HUMTHO1 microsatellite acts, in vitro, as a transcription regulatory element showing a silencing effect which correlates with the

nese et al., 2001). In particular, the inhibition is proportional to the number of repeats up to allele 8, while by increasing the number of repeats up to 10, no further inhibitory effect is observed, but rather a relative enhancement depending on the cell lines used (Albanese et al., 2001). These findings support the idea that HUMTHO1 micro- satellite regulates TH transcription in an allelic- specific way, and modulates the activity of the TH gene acting as a quantitative genomic effector. These allele-specific effects would explain the dominant and dose-dependent beneficial effects we observed for allele 10* by our approach. This effect is not found for allele 10, likely because its low frequency with respect to the sample size. On the other hand, a large amount of data suggest the importance of an efficient production of catheco- lamines in healthy aging and longevity. Indeed, there are now numerous studies demonstrating that sympathetic factors play a central role not only in cardiovascular homeostatic control, but also in pathogenesis and/or in the progression of several cardiovascular diseases, such as essential hypertension (Rahn et al., 1999) and myocardial infarction (Bertel et al., 1982). Therefore, a good efficiency in TH gene transcription may be a key for an appropriate response towards stochastic and age-related stress factors, and consequently for longevity.

References Albanese, V., Faucon Biguet, N., Klefer, H., Bayard, E., Mallet, J., Meloni, R.,

Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsa- tellite. Hum. Mol. Genet.

,

(cid:

)

/ Aptech System,

Gauss: Mathematical and Statistical System, vol. I: System and Graphics Manual. Aptech Systems, Maple Valley, WA. Bertel, O., Buhler, F.R., Baitsch, G., Ritz, R., Burkart, F.,

Plasma adrenaline and noradrenaline in patients with acute myocardial infarction. Relationship to ventricular arhythmias of varying severity. Chest

,

(cid:

)

/ De Benedictis, G., Tan, Q., Jeune, B., Christensen, K., Ukraintseva, S.V., Bonafe, M., Franceschi, C., Vaupel, J.W., Yashin, A.I.,

Recent advances in human gene- longevity association studies. Mech. Ageing Dev.

,

(cid:

) /

De Benedictis, G., Carotenuto, L., Carrieri, G., De Luca, M., Falcone, E., Rose, G., Cavalcanti, S., Corsonello, F., Feraco, E., Baggio, G., Bertolini, S., Mari, D., Mattace, R., Yashin, A.I., Bonafe, M., Franceschi, C.,

Gene/ longevity association studies at four autosomal loci (REN, THO, PARP, SOD

). Eur. J. Hum. Genet.

,

(cid:

)

/ De Luca, M., Rose, G., Bonafe`, M., Garasto, S., Greco, V., Weir, B.S., Franceschi, C., De Benedictis, G.,

Sex- specific longevity associations defined by Tyrosine hydro- xylase-insulin(cid:

)insulin growth factor

haplotypes on the /

p

chromosomal region. Exp. Gerontol.

,

(cid:

) /

Evans, M., Hastings, N., Peacock, J.B.,

Statistical Distributions, Second edition. Wiley Interscience, New York,

(cid:

)

/ Franceschi, C., Valensin, S., Bonafe`, M., Paolisso, G., Yashin, A.I., Monti, D., De Benedictis, G.,

The network and remodeling theories of aging: historical background and new perspectives. Exp. Gerontol.

,

(cid:

)

/ Herskind, A.M., M

ue, M., Holm, N.V., Sorensen, T.I., Harvald, B., Vaupel, J.W.,

The heritability of human longevity: a population-based study of

Danish twin pairs born

(cid:

)

Hum. Genet.

,

(cid:

)

/ / Kobayashi, K., Kaneda, N., Ichinose, H., Kishi, F., Nakazawa, A., Kurosawa, Y., Fujita, K., Nagatsu, T.,

Structure of the human tyrosine hydroxylase gene: alternative splicing from a single gene accounts for generation of four

NA types. J. Biochem.

,

(cid:

)

/ M