A strategy for disentangling this complexity is to focus on robust human models of longevity such as centenarians.
This new technology applied to powerful models of longevity, such as centenarians and their offsprings, is expected to answer some of the open questions in this hot topic.
Further evidence for the role of VSELs and imprinted genes on lifespan comes from our recent studies on murine models of longevity [ 15].
We studied the correlation between HN and lifespan using various mouse models with mutations in the GH/IGF-I axis, as these are among the most well-characterized genetic models of longevity.
However, data from dietary, genetic, and pharmacological studies in animal models of longevity and accelerated aging indicate that metabolism plays a crucial role in regulating health and survival (Kenyon, 2005; Russell & Kahn, 2007; Buffenstein & Pinto, 2009; Fontana et al., 2010; Selman & Withers, 2011).
The most widely studied model of longevity is calorie restriction (CR) [ 6].
The Klotho overexpressing mouse, a classical model of longevity [ 54], shares its characteristics of low levels of endogenous oxidative stress with the Ames and Snell dwarf mice.
We found that AC5KO delayed age-related tumor incidence significantly, as well as protecting against mammary tumor development in AC5KO × MMTV-HER-2 neu mice, and B16F10 melanoma tumor growth, which can explain why AC5KO is a model of longevity.
Its longevity has been characterized on three different genetic backgrounds (Coschigano et al., 2000, 2003; Bonkowski et al., 2006), on 30% caloric restriction (Bonkowski et al., 2006), on intermittent fasting (Arum et al., 2009), and on diets of differing composition (Bartke et al., 2004), making it the sole genetic model of longevity that has been validated under a variety of conditions.
Attenuation of insulin signaling leads per se to reduced oxidative burden, by Daf-16/FoxO dependent up-regulation of antioxidant defenses [ 6]; thus, the oxidant-resistant phenotype of p66KO mice could still fit in the genetic model of longevity centered on the insulin/Igf signaling cascade.
One of the largest European projects aimed at identifying genes involved in healthy ageing, the Genetics of Healthy Ageing (GEHA) project, was focused on a sophisticated familial model of longevity, that is, nonagenarian sib pairs, that is, two or more siblings aged 90 years or older [ 49, 50].
