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.
The finding that IGF1R levels in the brain are negatively correlated to lifespan, but not to body mass, may help resolve the paradox of species body mass and aging. Within species, body mass is inversely
correlated to lifespan, and the differences in body mass are sometimes driven by the IIS [17
]. Across species, however, body mass is positively correlated to lifespan, and it is not clear what drives this. Specifically how evolutionary forces shape IIS activity is unclear. One possible selective pressure that might increase IGF1R levels in the brain is a need to speed up development due to environmental or predatory constraints. This may lead to decreased lifespan due to increased activity of nutrient and growth factor-sensing pathways like mTOR. Recent evidence shows that male mice that have higher activation of mTOR and pAKT at 6 months of age, a time in their development when their body mass increases substantially (28%) when compared to females [28
]. This, in turn, may explain why male mice have shorter lifespans than female mice. Conversely, lower extrinsic mortality experienced by large species can drive the evolution of slower developmental rate, lower IIS signaling and longer lifespan. How is then lower IIS compatible with larger body mass? Our results show that to achieve longevity IIS needs to be low in the brain only, but not in the peripheral tissues allowing animals to grow large while keeping developmental rates low.
Earlier studies using model organisms support the notion that IIS signaling in the nervous system is particularly important in the context of aging. Removal of IIS from neurons is sufficient to extend lifespan by the same amount as a whole-worm knockout [29
]. The contribution of this pathway in the nervous system towards a systemic aging effect was also partially demonstrated in Drosophila
, where activation of FOXO in the pericerebral fat body increased lifespan [30
]. A brain-specific knock-out strategy in mice found that when IGF1R is heterozygously removed in the developing brain (causing a 50% reduction in total receptor), there is an extension of average lifespan in both males and females [22
]. Most recently, reduction of IGF1R signaling by an miRNA in the brain of mutant mice was also found to increase their lifespan [31
]. Another study on neural miRNAs has found that a group that includes IGF1R as a regulatory target affects proliferation and differentiation of neural progenitors [32
Our study establishes an association between IGF1R levels in the brain and maximum lifespan in across rodent species. The correlation between lifespan and IGF1R was maintained even when adjusting for the contribution of body mass, and when adjusting for phylogenetic relatedness between rodents. A conservative estimate is that differences of IGF1R expression in brain tissue accounts for about 20% of lifespan differences observed between rodents. There was approximately a 10-fold difference in intensities between highest and lowest IGF1R signals in the rodent brain. Given that a 50% reduction in protein expression was sufficient to observe lifespan effects in mice [22
] the 10-fold difference is likely to contribute to lifespan differences in vivo
between rodent species.
Exactly how, mechanistically, the IGF1R receptor modulates lifespan through the nervous system is still a mystery. Although aging is generally seen as a phenomenon that affects all organ systems, it is possible that degeneration specifically of nervous system organization as the animal ages leads to wider systemic effects that lead to increased mortality. In C. elegans
, inhibition of the daf-2
signaling pathway prevented the formation of ectopic neurite branches that normally appear as a result of aging [33
] and ablation of IIS in neurons is sufficient to extend lifespan [34
]. In Drosophila
, overexpression of antioxidant genes such as SOD1
in motorneurons is sufficient to increase lifespan, possibly indicating that ROS damage in the nervous system can be a major lifespan determinant in insects [35
]. In mammals, a growth factor that promotes neural survival was recently found to correlate to maximum rodent lifespan, also independently of phylogeny [21
]. These results taken together with our data suggest that nervous system aging is important to overall longevity.
To date, there are no studies looking at the incidence of neurodegeneration of any kind in IGF1R whole body, brain-specific, or somatotroph specific knock-out mice. A very recent study demonstrated that deviations in the circadian rhythm of mice can predict lifespan [36
]. This shows that variations in nervous system function can have systemic consequences leading to shortened lifespan.
Uncontrolled IGF1R signaling is an important hallmark of certain cancers and interfering with IGF1R signaling can help control malignancies [37
]. If high IGF1R expression is limiting lifespan by induction of tumorigenesis, one might expect IGF1R levels to be inversely correlated with lifespan in all organs that have a high incidence of neoplasia. The lack of correlation we observed between IGF1R levels and lifespan in the kidney and lung suggests that the receptor does not act as a limit to lifespan by promoting tumorigenesis. High receptor expression may promote tumors in some species, but the maximum lifespan is not inherently limited by this risk.
In summary, our study supports previous findings that lowered IGF1R activity is correlated to extended lifespan in mammals, and expands this paradigm to interspecies comparisons. Furthermore, we show that on the evolutionary scale IIS signaling in brain tissue only influences lifespan, and this relationship is independent of body mass. These findings benefit our general understanding of the evolution of aging, and can be useful in designing potential life extending interventions where IIS signaling could be targeted in specific brain regions only avoiding undesirable severe side effects on peripheral tissues.