Research Perspective Volume 2, Issue 12 pp 1017—1022

Figure 1. Proposed model for the somatotroph axis alterations of Zmpste24^−/− progeroid mice. Nuclear envelope abnormalities present in Zmpste24-deficient cells cause chromatin detachment from the nuclear envelope and a profound structural disorganization. This genomic instability activates a chronic DNA damage response, which in turn triggers an adaptive response aimed at re-allocating resources from growth to somatic preservation. Hepatocytes are involved in this adaptive response through its ability to modulate the somatotropic axis and respond to the chronic DNA damage altering the expression of some key genes that affect Igf1-signaling at several levels. First, the reduced growth-hormone receptor (Ghr) transcription and the up-regulation of suppressor of cytokine signaling-2 (Socs2), diminishes the Gh-mediated Igf1 transcription. In addition, miR-1 over-activation represses Igf1 synthesis, reinforcing the already reduced Igf1 transcription and compromising the circulating levels of Igf1. The availability and stability of free Igf1 is reduced through up-regulation of insulin-like growth factor binding protein-1 (Igfbp1) and down-regulation of Igfbp-acid labile subunit (Igfals), respectively. Consequently, Igf1-signaling is diminished in the whole organism, which in turn leads to a metabolic switch towards somatic maintenance at the expense of somatic growth. In parallel, the low levels of Igf1 fail to inhibit Gh secretion at the pituitary gland, generating the high levels of circulating Gh present in these progeroid mice, which could aggravate the situation through its deleterious effects. Dotted lines represent disrupted pathways and blunt arrows indicate inhibitory actions.