The possible association between YTHDF2 intron 4 microsatellite polymorphism and longevity can be inferred by the genomic background surrounding the locus. The portion of the 1p35 chromosomal region around YTHDF2 is rich with genes (mostly involved in signal transduction, gene expression regulation, and cell division); the possibility of a linkage disequilibrium between the considered (TG)n microsatellite and other functional polymorphisms in nearby genes should be carefully tested in future studies. Finally, it is important to remark that this locus lies in a genomic region with rare and atypical features. This polymorphism was originally identified through the analysis of anonymous inter-Alu sequences much shorter than the 3 kb average (60) genomic inter-Alu distance, and the reasonable expectation was to find it located in a genomic region with higher than average Alu density. Indeed, this locus is situated in a wide Alu-rich domain (1.6 Mb), and the 1 Mb region containing the YTHDF2 gene is the portion of chromosome 1 with the highest content of Alu elements (>40% of the sequence in this chromosomal region). In the whole genome, such a high Alu density is present in only four regions (of 1 Mb or more) which account for 0.17% of the human genome, whereas two-thirds of the genome show an Alu content about four times lower. This peculiarity in the genomic composition might affect the expression of YTHDF2 and other genes in the region, rendering it sensitive to Alu-induced epigenetic effects (18,23). Moreover, the very high Alu density could induce genomic instability, in germline as well as in somatic cells, due to unequal recombination events (18-20). Indeed, 1p35 has been described as one of the chromosomal sites most often involved in genomic instability in a variety of malignancies (61-63).

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Conclusion
This is the first study that provides evidence of an association of a new gene, i.e., YTHDF2, with human longevity. This gene has several unexpected peculiarities that are of potential interest, particularly its chromosomal context constituted by one of the regions with the highest content of Alu sequences, its high expression in reproductive organs and in highly proliferating tissues, and its possible involvement in glucose metabolism. Future studies should check the possibility that YTHDF2 is a cell-cycle regulator gene widely subjected to epigenetic regulation and dysregulation, in a chromosomal region potentially susceptible to epigenetic modification during life, as well as the possibility of involvement in the insulin-like growth factor I/insulin signaling pathway and in the trade-off between longevity and fertility.

ACKNOWLEDGMENTS
This work was partially supported by grants from the Italian Ministry of Health, Progetto Finalizzato 2002 Studio Multicentrico sui Determinanti Genetici e non Genetici di Salute nellEta` Avanzata; European Union Grants GEHA (LSHM-CT-2004-503270) and FP6 EU Project T-CIA; Italian Ministry of Education, University and Research PRIN 2003; Fondi Strutturali Obiettivo 2 and the PRRIITT Program of the Emilia-Romagna Region; and by University of Bologna Roberto Pallotti Legacy for Cancer Research. We thank Dr. Hester Mary Wain, of the HUGO Gene Nomenclature Committee, for the helpful collaboration in the choice of gene names and symbols of YTH Domain Family members.

Address correspondence to Maurizio Cardelli, PhD, Department Gerontological Research, Italian National Research Center on (I.N.R.C.A), Via Birarelli 8, 60100 Ancona, Italy. Email: libero.it

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