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    • Our findings contribute to a better understanding of the rol

    2018-11-07

    Our findings contribute to a better understanding of the role of the insulin/IGF-1 system in CR. In lower eukaryotes disruption of IGF-1/insulin signaling increases lifespan (Kenyon, 2010; Johnson, 2013) and knockouts of regadenoson coding for several components of the GH/IGF-1–mTOR signaling network extend lifespan in rodents (Coschigano et al., 2000; Holzenberger et al., 2003, Taguchi et al., 2007; Selman et al., 2009). Furthermore, CR induced longevity in rodents correlates with decreased IGF-1 serum levels (Sonntag et al., 2012) and a decline in the GH/IGF-1 axis in mice and humans is associated with decreased incidence of cancer (Bartke et al., 2013). In contrast, reduced activity of the IGF-1 pathway, which has diverse physiological functions, leads often to detrimental effects. In fact, reduced IGF-1 serum levels correlate with higher incidence of T2DM, cardiovascular diseases and declining cognitive functions, suggesting that IGF-1 deficiency contributes to the pathology of aging (Broughton and Partridge, 2009; Sonntag et al., 2012). Supporting the notion, circulating IGF-1 levels decrease with age in humans and animals and a reduction in serum IGF-1 levels during aging impairs health span in mice (Gong et al., 2014). The dual, beneficial and deleterious actions of IGF-1 led to the current concept, that IGF-1 signaling is a complex endocrine, paracrine and autocrine network affecting organ development, homeostasis and function throughout life (Broughton and Partridge, 2009; Sonntag et al., 2012). Our study supports the hypothesis that the extent, tissue and cell type specific IGF-1 activity are determinants of the effect on health and lifespan. IGF-1 is produced by the liver as endocrine hormone and in peripheral tissues in a paracrine/autocrine fashion. Adipose tissue contains more IGF-1 than any other tissues except the liver (Stratikopoulos et al., 2008). It is secreted in WAT in a GH-dependent and -independent manner (Bartke et al., 2013) and by isolated ASCs and adipocytes (Wabitsch et al., 2000; Poulos et al., 2010; this study). Supporting our data that IGF-1 is highly expressed in ASCs of sWAT from WLDs it was demonstrated that IGF-1 levels are up-regulated in peripheral tissues of Ames dwarf mice, which show the typical longevity phenotype of chronically low IGF-1 serum levels (Bartke et al., 2013). In these mice, local production of IGF-1 was demonstrated in the hippocampus (Sun et al., 2005) correlating with neuroprotection (Schrag et al., 2008). Moreover, signaling by insulin-like peptides (ILPs) is beneficial in neurons of flies and worms, despite the paradox that lowered insulin/IGF-1 activity has the potential to both compromise the integrity of the CNS and extend lifespan (Broughton and Partridge, 2009). Furthermore, DR results in reduced expression of Drosophila ILP (DLIP) 5 in neurosecretory cells in the brain. Deletion of the genes DILP 2, 3 and 5 in these cells, which extends lifespan, is however accompanied by up-regulation of DLIP 6 in the fly fat body (Partridge et al., 2011). Thus, similar to our findings in human ASCs, other studies show increased IGF-1 levels in tissues of mammals and invertebrates in response to either CR/DR or mutations reducing insulin/IGF-1 signaling, which could reflect a compensatory response. Long-lived mutant flies with reduced DLIP signaling show increased loss of germline stem cells (Hsu and Drummond-Barbosa, 2009) while DR induces longevity and enhances germline stem cell maintenance in flies with age (Mair et al., 2010). The different mechanisms by which these apparently related interventions have opposite effects on stem cell maintenance are not precisely understood. Our data suggest that WL/CR optimizes the activity of the IGF-1–mTOR system with beneficial effects on ASCs and sWAT homeostasis. We demonstrated increased autophagy in sWAT of WLDs and showed that negative regulation of Akt–mTOR signaling by DIRAS3 in human ASCs increases autophagy, a hallmark of CR (de Cabo et al., 2014). This establishes a mechanism how WL/CR employs IGF-1/DIRAS3-mTOR signaling to induce autophagy. Increased autophagy leads to higher turn-over of cellular material and recycles misfolded or damaged cellular components. Thus, DIRAS3-induced autophagy in ASCs might facilitate homeostasis of cellular macromolecules, providing new cellular building blocks and energy for renewal and survival of these cells. According to the current model, nutrient overload in obesity stimulates mTOR, thereby attenuating autophagy (Stienstra et al., 2014). Increasing oxidative stress, hypoxia and inflammation induce however insulin resistance in adipose tissues of obese people, leading to inhibition of mTOR and consequently stimulation of autophagy. Studies showing increased autophagy in adipose tissue of obese people suggest that stimulatory effects for autophagy prevail over putative inhibitory effects of mTORC1 activation by overeating (Stienstra et al., 2014). Hereby, we have shown that activation of autophagy in sWAT is a response to long-term WL/CR in formerly obese people. Thus, autophagy in fat tissue is induced in both conditions, obesity and WL/CR, and should affect adipose tissue mass and homeostasis; however, most likely by different mechanisms and intensity.