hypothesis, calorie restriction, weight loss, and moderate daily exercise are the best studied strategies to reduce insu- lin levels and increase insulin sensitivity, improve metabolic regulation, and extend longevity (21,22). Our results reveal a starting point to understand the best ways to coordinate nutrient homeostasis and insulin signaling with strategies that consistently promote longevity and healthy aging (23).

Further studies will be necessary for replicating our find- ing in an independent larger population group with suffi- cient power before the association between IRS2 gene polymorphism and longevity can be regarded as proven. Furthermore, studies of interactions may be useful after basic replication is complete. Interaction with a different genetic and/or environmental background may, in fact, dif- ferently modulate the effect of a given gene in different populations.

Correspondence

Work with lower metazoans—mainly Caenorhabditis elegans and Drosophila—shows that diminished insulin- like signaling can extend the healthy life span. humans aged 85–90 years and older display increased insulin sensitivity— centenarians are particularly insulin sensitive (14). Thus, re- duced intensity and duration of the insulin signal—expression of an efficient insulin signaling—appears to be essential for healthy human aging. IRS2Asp signaling might have a similar effect to increase life span—at least when obesity or other causes of insulin resistance are absent—by attenuating insulin signaling through the IRS2 branch of the pathway.

Address correspondence to Giuseppe Paolisso, Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy. email: giuseppe.paolisso@unina2.it

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