Age‐dependent loss of insulin‐like growth factor‐1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice

Abstract

Both life-long caloric restriction (CR) and the suppression of insulin-like growth factor-1 (IGF-1) signaling reliably extend the mammalian lifespan. The neuroendocrine system, regulated by the hypothalamus, remains the most convincing site of action for both these modes of life extension. Yet, determining whether CR actions are mediated by the modulation of neuroendocrine IGF-1 signaling remains unclear. Of the hypothalamic nuclei that express the IGF-1 receptor (IGF-1R), the cells of the supraoptic nucleus (SON) display some of the most robust IGF-1R expression. Taking IGF-1R immunoreactivity as an index of sensitivity to IGF-1, we counted IGF-1R immunoreactive and non-immunoreactive cells in the SON of young-ad-libitum fed (young-Al, 6 weeks), old-ad-libitum fed (Old-Al, 22 months), and old-calorie-restricted (Old-CR, 22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each section of supraoptic hypothalamus. Results show that while the total number of cells in the SON of ad-libitum fed mice does not change significantly with aging, a significant reduction in IGF-1R immunoreactive cells does occur in ad-libitum fed mice with aging. In contrast to this, calorie restricted mice show both a decline in the total number of cells and IGF-1R immunoreactive cells in the SON with age, but with the decrease in the latter being notably attenuated when compared to the degree of loss seen in ad-libitum fed mice. Thus, while CR induces greater loss in the total number of cells in the SON with age, it reduces the degree of age-dependent loss seen in IGF-1R expressing cells. As a result, when compared to Old-AL mice, the SON of Old-CR mice displays a greater proportion of IGF-1R cells and thus possibly enhanced IGF-1 sensitivity with aging.

Insulin‐like growth factor‐1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice

“…The major finding yielded by this investigation is that CR attenuates the deterioration of IGF‐1 signaling in the PVN with age. This finding is consistent with studies showing that IGF‐1 sensitivity in the Supraoptic nucleus is also selectively maintained with CR (Yaghmaie et al, 2006). Taken together, such observations suggest that the mechanism behind CR's life extending affect could be via preserving IGF‐1 sensitivity in the hypothalamus, thereby maintaining neuroendocrine profiles more conducive to the youthful phenotype and longevity.…”

Oxytocin is lower in African American men with diabetes and associates with psycho-social and metabolic health factors

“…Administration of IGF-1 within the SON in rats acutely inhibits the activity of OXT neurons[ 27 ]. Additionally, circulating OT has been shown to be higher in older compared to younger mice, possibly explained by the loss of approximately one-third of IGF-1 receptor immunoreactive cells in both SON and PVN in older compared to younger mice[ 28 ]. There are, however, reported region specific differences in IGF-1 regulation of OT, with stimulatory effects shown within ovarian tissues[ 29 ].…”

A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIα Phosphorylation

“…Therefore, we asked whether an age-related change in IGF-1/IGF-1R axis is related to changes in synaptic function through age-related alterations of MAPK/ErK/CaMKIIα and KCa2.2 in the hippocampus and PFC (Figure 1 )? A decline in IGF-1 and IGF-1R expression has been described in age-related neuropsychiatric and degenerative diseases (Carro et al, 2002 ; Yaghmaie et al, 2006 ; Piriz et al, 2011 ; Puche and Castilla-Cortázar, 2012 ; Green et al, 2014 ; Werner and LeRoith, 2014 ). Therefore, in this study we assessed the differential expression of these synaptic kinases (i.e MAPK/ErK and CaMKIIα) with age in the hippocampus and medial prefrontal cortex (mPFC).…”