The drop in circulating IGF-1 with age did not correlate with survival in our analysis. However, the actual pro-survival sig- nificance of a low level of IGF-1 is debated [34,35]. While low IGF-1 reduction might counteract cancer, it correlates with an increased risk of all-cause mortality and cardiovascular disease [36,37]. Moreover, a low level alone might be inadequate as a predictor of survival, as reported by Maggio et al. in another Italian population of elderly men, where IGF-1 as well as also testosterone and dehydroepiandrosterone sulfate (DHEA-S) was evaluated; they found a cumulative negative effect on survival for these anabolic hormones [38]. Our data on IGF-1 may be inconclusive due to the lack of multiple hormone assessment.

We also addressed the contribution of an inflammatory pathway to longevity. Since aging involves chronic increases in pro-inflammatory molecules, an aspect that is particularly evident for men and is partly under genetic control [39], we looked for a sex-specific pattern in biochemical or genetic elements related to IL-6. Our prospective approach found that the IL-6 plasma level influenced survival more in men, and no genetic contribution was found from the polymor- phism rs1800795, though we cannot exclude that a fuller genetic investigation of IL-6 promoter region might uncover additional genetic variability correlating with male or female

expressed in quartiles). We obtained four groups whose main demographic and clinical features are summarized in Table III. A high level of IL-6 was associated with increased disability and co-morbidity, while high IGF-1 was associated with increased percentage of cancer in association to low IL-6 only. We con- sidered the group with low IL-6 and high IGF-1 (that had an apparent reduced rate of mortality) as reference and plotted a survival curve for the whole population classified according

Table III. Classification of the TRELONG population according to circulating levels of IGF-1 and IL-6. p-value was calculated from Chi-square test for binary variables and ANOVA for continuous variables. CVD: cardiovascular disease (including myocardial infarction, ischemic cardiopathy, peripheral vasculopathy and chronic heart failure); VC: vascular cerebral disease (including stroke and cerebral vasculopathies); CCI: Charlson’s comorbidity index.

High IGF-1 and Low IGF-1 and High IGF-1 and Low IGF-1 and low IL-6 low IL-6 high IL-6 high IL-6 Overall Age (mean) 82.68 86.13 85.81 88.48 84.13 0.000 Women (%) 52.30 55.67 48.04 71.88 53.44 0.116 BMI (mean) 25.14 24.09 24.76 24.23 24.77 0.127 VC(%) 14.80 20.62 18.63 9.38 15.57 0.339 CVD (%) 24.67 24.74 32.35 21.88 25.6 0.426 Cholesterol (total, mean) 223.50 210.70 206.30 180.50 213.8 0.000 Diabetes (%) 15.46 18.56 17.65 15.62 15.57 0.884 Cancer (%) 20.07 8.25 11.76 12.50 16.92 0.021 ADL (mean) 5.32 4.88 4.57 4.13 5.002 0.000 CCI (mean) 5.59 5.85 6.16 6.25 5.766 0.005 Smoking (%) 41.58 42.71 41.58 25.00 41.17 0.293

noking (%)IL-6 (pg/mL) 41.58 42.71IGF-1 and IL-6 level scatterplot    41.58 25.00Total population41.17                             g3=o4P-value for Log-rank test<0.001Hh = aw iteLow IGF-1 and low IL6oo Hang akoSf an. Ula anaaniesIGF-1 (ng/mL) B5 _ 5: ia 3: :a azWoh GF ae ew ke High GF ant ow bs(EGE arabs towiGe ance| Rightcar | Hong sets|. HENCE angah ts 31 Ueto1500 2000 2500Days since interviewD Days since interview  

Figure 3. Assessment of combined effect of IGF-1 and IL-6 on survival. (A) The TRELONG population was divided according to low or high levels of circulating IL-6 and IGF-1 (divided into quartiles). (B) Survival curve of the entire population classified according to high/low level of IL-6 and IGF-1 (C) Survival curve as in (B) for males only; (D) Survival curve for females classified according to IL-6 and IGF-1 assessed level. For the

Our combined analysis, looking at the same time the effect of different levels of IL-6 and IGF-1, has confirmed that high levels of IL-6 are detrimental for survival, while in combina- tion with high IGF-1, low IL-6 seems to be associated with increased longevity. The power of this analysis is reduced by limited sample size, even if the conclusion is in good agree- ment with Cappola et al. [40], showing a deleterious synergis- tic effect of high IL-6 and low IGF-1 in survival and disability in older women.

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