How can we explain the sexual dimorphism that we observed in the association of reduced IIS activity and longevity? In mam- mals, sex differences are known to exist for the activity of the GH/IGF-1 axis. Recently, GH was shown to be the major deter- minant of sexually dimorphic gene expression in the rat liver (Ahluwalia et al., 2004). Entropy analysis has revealed that in humans a large gender difference exists in the regularity of GH pulsatility, with irregularity being greater in the female sex. Oes- trogen increases the irregularity of GH release, and in both sexes the growth spurt that occurs at puberty is sex hormone driven (reviewed in Giustina & Veldhuis, 1998).

The analysis of the combined cohorts of the Leiden 85-plus Study contained 866 females and 379 males. Bold: significant result. The polymorphisms were analysed as independent covariates in a left-censored Cox proportional hazards model.

are indeed additive. In contrast, in males, no survival benefit was observed for any of the three lower IIS3 scores compared with the reference category. The IIS3 score was also associated with reduced body height in females (P for linear trend = 0.003) but not in males (P for linear trend = 0.076).

Given the existence of sex differences in GH/IGF-1 signalling, how can we explain the association observed in females between reduced GH/IGF-1 signalling and longevity? When interpreting the effects of GH/IGF-1 signalling on longevity two factors should be taken into account; cumulative exposure to GH/IGF-1 over an individual’s lifetime (Parr, 1996) and the effect of GH/IGF-1 at different time points in an individual’s life history (Holzenberger, 2004). There are several indications that increased cumulative exposure to GH/IGF-1 has adverse effects. In mice, overexpression of GH is associated with a reduced lifespan and increased insulin resistance (Steger et al., 1993). In humans, states of GH excess are correlated with insulin resist- ance (reviewed in Dominici & Turyn, 2002), which is associated with the development of diabetes mellitus type II and metabolic syndrome, conditions that reduce life expectancy. Moreover, a continuously higher exposure to the mitogenic effects of IGF-1 could influence the development of cancer. In female mice overexpressing GH the incidence of mammary tumours was increased (Steger et al., 1993).

We also determined the effect of a selected number of polymorphisms from genes implicated in the oxidative stress response on mortality in the Leiden 85-plus Study. We detected no differences in relative mortality risk in females or in males for the polymorphisms affecting the oxidative stress response when these polymorphisms were analysed as independent covariates in a left-censored Cox proportional hazards model (Table 6). We also failed to detect an association between com- posite oxidative stress response (OSR) score and relative mor- tality risk in the combined cohorts of the Leiden 85-plus Study, the estimates being 1.11 for women (P for linear trend = 0.14) and 1.03 for men (P for linear trend = 0.72) for each increase

Discussion

However, reduced GH/IGF-1 signalling may also have adverse effects, especially in old age, as increased induction of apoptosis is associated with growth factor withdrawal. Throughout

The relationship between IIS signalling and longevity in mam- mals is complex and controversial (Rincon et al., 2004). Here we show in a prospective study of older people from the population

adulthood, serum GH concentration and pulsatile GH secretion rates fall steadily, with an estimated 14% per decade in men, a phenomenon known as somatopause (Iranmanesh et al., 1991). The reduced GH secretion is believed to contribute to many age-related diseases, such as loss of muscle mass, increased adiposity, reduced bone mineral density and a decline in cognition (reviewed in Bartke et al., 2003). In these para- meters too, sex differences have been found. Premenopausal women are significantly better protected than men from the negative impact of increasing age on GH levels (reviewed in Giustina & Veldhuis, 1998). Our results suggest that in females but not in males the beneficial effects of reduced cumulative exposure to GH/IGF-1 outweigh the possible detrimental effects of lower GH/IGF-1 levels at old age.

The strengths of this study are several fold. First, the analysed polymorphisms were selected on the basis of known effects on gene expression. Second, the effects on longevity were detected in a prospective analysis, which contained a high number of events (deaths) during the time of follow-up. Third, these effects were detected despite the fact that gene-by-environment inter- actions are important and human studies are uncontrolled with respect to environmental exposure. A first weakness of the study is that the results have not been replicated in another cohort of elderly, as cohorts of similarly aged people are not readily available. A second weakness is that we cannot com- pletely exclude the possibility that differences in birth cohorts have confounded our results. However, such problems are of greater importance in cross-sectional studies than in prospective studies, whereas allele frequencies were not statistically differ- ent between cohort ’87 (birth cohorts 1883–1902) and cohort ’97 (birth cohorts 1912–1914). A third drawback is related to our selection of analysed polymorphisms on the basis of published effects on gene expression. This approach implies that we may have missed other existing (but not yet published) functional polymorphisms and that therefore our analyses are not exhaustive.