Greek 46 156.8±42 31.3±8.8* 209.6±17.6 53.7±16.3* Italian 50 177.2±16.3 49±21* 195.3±13.6 58.4±19* Wt/H versus WT:*Po0.001. 250 Tunisian Population 200 Control WT 150 Elderly WT Control WT/H Elderly WT/H 100 50 0 0 5 10 15 20 25 30 35 subjects Greek Population 300 250 200 Control WT 150 Elderly WT Control WT/H 100 Elderly WT/H 50 0 0 10 20 30 40 subjects 250 Italian Population 200 150 Control WT Elderly WT 100 Control WT/H Elderly WT/H 50 0 0 5 10 15 20 25 30 35 40 45 h/lm/lomnh/lm/lomnh/lm/lomn

Wt/H versus WT:*Po0.001.

It is noteworthy that CHIT-1, as an important factor in inflamma- tion,15 could have widespread effects on aging phenotypes, particularly on cardiovascular disease23–24 and dementia,26–27 and as such may influence the ability to achieve a long and healthy life. In fact, the baseline examination suggested that oldest old subjects were markedly healthier than controls, despite the fact that these subjects were, on an average, 30–37 years older. The oldest old subjects possessed signifi- cantly less age-related disease, including less prevalent CHD, stroke and degenerative diseases. They also had better self-rated health and generally high physical function, including less difficulty during walking. Interestingly, despite being more than three decades older than controls, the longevity cases had similar levels of cognitive function. This supports the existence of a ‘healthy aging’ phenotype in which individuals somehow delay or avoid major clinical disease and disability until late in life. Although previous studies have suggested that CHIT-1-deficient individuals show a certain degree of disadvantage, such as increased susceptibility to parasitic disease infections, to microorganisms containing chitin and to Gram-negative infections,17,31–35 other studies indicate that CHIT-1 deficiency is not a disadvantage but rather a selective advantage.36–37 Given the very high gene frequency of the main mutant allele, as shown in this study, it seems more likely that in humans, selection has occurred in the direction of decreasing or eliminating the activity of this enzyme. Therefore, it seems reasonable to look for an advantage, not of sufficient enzyme activity, but rather of deficient enzyme activity. In fact, in some Asian populations, the allele frequency of the insertion mutation is higher than that of the allele without the insertion.38 The evidence showing that chitins stimulate macrophages to produce interleukin (IL)-12, IL-18 and TNF-a39 supports the consideration that a deficiency of CHIT-1 confers a selective advantage. In addition, it has been demonstrated that chitins had T helper 1 (TH-1) adjuvant activity in developing immunity against a mycobacterial antigen,40 suggesting that Chit might modulate the circulating concentration of chitins and regulate immune responses. Therefore, Chit deficiency might provide individuals with an advantage in mounting an immune response against Mycobacterium. In summary, all evidence supports a potential role of CHIT-1 in human health, aging and longevity.

case–control design. This study design selects cases and controls from an ongoing cohort study with longitudinally collected data. Therefore, several phenotypes of interest (for example, disease prevalence, health status and functions) were obtained by direct clinical examination when participants were younger, making the data less subject to recall bias. Undeniably, studies on exceptional survivors, such as centenar- ians, which have found evidence for phenotypes suggestive of slower aging, could suffer from significant recall bias. Namely, older partici- pants may not precisely recall their past medical history and functional status. However, in this study, a morbidity committee adjudicated major diseases, and performance-based measures of physical and

Figure 1 The genotype of the 24-bp duplication in exon 10, homozygous wild-type (WT) and heterozygous mutant (WT/H) subjects was analyzed for Chit activity (value expressed as nmolml(cid:3)1h(cid:3)1) as described in Materials and methods: (a) Tunisian subjects, (b) Greek subjects and (c) Italian subjects. All zero (0) enzyme activity levels for homozygous mutant (HH) alleles were not included.

from the Mediterranean area: a longevity group (129 subjects) aged over 90 years and a control group aged 60–70 years. We found that the heterozygote frequency for a 24-bp duplication, leading to an in-frame

cognitive function were used to supplement self-reports, and evidence was found for such a healthy aging phenotype.

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