blood collected from nonagenarians and centenarians living in the Mediterranean area, including Italy, Greece, and Tunisia. The study aimed to investigate the association between human phagocyte-specific chitotriosidase (CHIT-1) polymorphism and human longevity. CHIT-1 is an enzyme that cleaves chitin, a polysaccharide found in fungi, nematodes, and insects. CHIT-1 is mainly secreted by activated macrophages and could be used as a marker of macrophage accumulation and activity in several lysosomal lipid storage diseases.

The study found that the heterozygous frequency for the 24-bp duplication in the CHIT-1 gene was not significantly different among the oldest old subjects of Mediterranean populations, whereas it was significantly different between oldest old subjects and control subjects. Moreover, no subject in the oldest old group was observed to be homozygous for CHIT-1 deficiency. These data indicate that heterozygosis for a 24-bp duplication in the CHIT-1 gene could have a protective effect on human longevity.

The study also revealed that Chit activity is related to the severity of atherosclerotic lesions and may serve as a marker of atherosclerotic extension. Moreover, Chit could play a crucial role in pathological conditions such as coronary artery disease, acute ischemic stroke, cerebrovascular dementia (CVD), Alzheimer's disease (AD), and nonalcoholic steatohepatitis.

In conclusion, this study suggests that CHIT-1 could be a plausible candidate gene responsible for human longevity. The heterozygosis for a 24-bp duplication in the CHIT-1 gene could have a protective effect on human longevity, particularly on cardiovascular disease and dementia.and cognitive function. The study found that the heterozygosity of the 24-bp duplication in the CHIT-1 gene had a protective effect on human longevity. The frequency of the mutant allele was highest among oldest old subjects and lowest among control groups. The mean enzymatic activity for the oldest subjects was lower than that in control groups. The absence of homozygous individuals in the very old group deviates significantly from the expectations of Hardy-Weinberg equilibrium. The study indicates that CHIT-1 could have widespread effects on aging phenotypes, particularly on cardiovascular disease and dementia, and may influence the ability to achieve a long and healthy life.Functions, 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 infections, microorganisms containing chitin and Gram-negative infections, other studies indicate that CHIT-1 deficiency is not a disadvantage but rather a selective advantage. 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. The evidence showing that chitins stimulate macrophages to produce interleukin (IL)-12, IL-18 and TNF-a 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, 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.

This study utilized a case-control design selecting 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 centenarians, which have found evidence for phenotypes suggestive of slower aging, could suffer from significant recall bias. Namely, older participants 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 cognitive function were used to supplement self-reports, and evidence was found for such a healthy aging phenotype.

In conclusion, we found that a common, natural genetic variation within the CHIT-1 gene was strongly associated with human longevity and was also associated with several phenotypes of healthy aging. A further study of the CHIT-1 polymorphism and aging phenotypes is warranted in other populations.

ACKNOWLEDGEMENTS

This study was supported by an FIRS grant No 9775 from MIUR (Ministero dell'Università e Ricerca Scientifica).