Date Published: April 25, 2013
Publisher: Impact Journals LLC
Author(s): Jorge Azpurua, Jiang-Nan Yang, Michael Van Meter, Zhengshan Liu, Julie Kim, Aliny AB Lobo Ladd, Antonio Augusto Coppi, Vera Gorbunova, Andrei Seluanov.
The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species. However, when different species are compared, larger animals are typically longer-lived. Hence, the role of IIS in the evolution of life history traits remains unresolved. Here we used comparative approach to test whether IGF1R signaling changes in response to selection on lifespan or body mass and whether specific tissues are involved. The IGF1R levels in the heart, lungs, kidneys, and brains of sixteen rodent species with highly diverse lifespans and body masses were measured via immunoblot after epitope conservation analysis. We report that IGF1R levels display strong negative correlation with maximum lifespan only in brain tissue and no significant correlations with body mass for any organ. The brain-IGF1R and lifespan correlation holds when phylogenetic non-independence of data-points is taken into account. These results suggest that modulation of IGF1R signaling in nervous tissue, but not in the peripheral tissues, is an important factor in the evolution of longevity in mammals.
A major discovery in the field of aging research is that large differences in maximum lifespan can be attributed to the effects of a few major signaling pathways. The first ‘aging gene’ was discovered in the nematode worm, C. elegans, in a genetic screen for long-lived mutants  and later identified as a homolog of the insulin receptor . Similarly, in Drosophila, perturbation of the INR gene extended lifespan by up to 85% . In both systems, the lifespan phenotype was dependent on insulin/IGF1 signaling (hereafter IIS) mediated inhibition of the daf-16/FOXO transcription factor  which is involved in diverse processes such as stress response, immunity and metabolism.
We collected and dissected multiple adult specimens from sixteen rodent species (Table 1). The tissues were flash-frozen in liquid nitrogen immediately upon dissection. All of the collected individuals were young adults, although precise ages could not be established as most were wild-caught. Whole protein samples were prepared from heart, kidney, lung and brain sections. Sections from the brain were taken exclusively from the frontal cortex, with the olfactory bulb and the pituitary gland omitted. Protein samples were tested for total concentration via a Lowry assay and frozen at −80°C.
We have analyzed the levels of the IGF1R protein in the brain, lung, heart, and kidney tissues of 16 rodent species. We found that IGF1R levels are highly variable across species, and only correlate to lifespan in the brain tissue. The correlation was negative, meaning that longer-lived species had lower IGF1R levels in the brain, irrespective of body mass. Hence, even larger-bodied, long-lived species such as beaver expressed lower IGF1R levels in the brain. This finding agrees with earlier studies in model organisms where reduced IIS was associated with longevity. Furthermore, our results indicate that small body mass observed in IIS mutants may be a secondary consequence of artificially lowered IIS signaling, while on the evolutionary scale only IIS signaling in the brain contributes to longevity, whereas the body mass and IIS in peripheral tissues vary independently.