Abstract
Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8kgm(-2) ) young and middle-aged (20-50years age range) men and women. Average CR during the first 6months was 19.5±0.8% and 9.1±0.7% over the next 18months of the study. Weight loss averaged 7.6±0.3kg over the 2-years period of which 71% was fat mass loss (P<0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2years (P<0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1year only (P=0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration.
Highlights
Data from experimental and epidemiological studies indicate that insulinlike growth factor (IGF)-1 and its binding proteins play a role in the biology of aging and in the pathogenesis of several common cancers (Yu & Rohan, 2000; Renehan et al, 2004; Yakar et al, 2005; Fontana et al, 2010; Kopchick et al, 2014)
Of the more than 10 000 men and women assessed for eligibility, the screening procedures excluded 45% of them for their age or body mass index (BMI), 14% for health or medication reasons, and 30% refused to participate due to concerns about their ability to adhere to the protocol, and personal or study-related issues (Ravussin et al, 2015)
There was no difference in average energy intake between the calorie restriction (CR) [2467 (34) kcal dayÀ1] and ad libitum (AL) [2390 (45) kcal dayÀ1] groups (P = 0.15)
Summary
Data from experimental and epidemiological studies indicate that insulinlike growth factor (IGF)-1 and its binding proteins play a role in the biology of aging and in the pathogenesis of several common cancers (Yu & Rohan, 2000; Renehan et al, 2004; Yakar et al, 2005; Fontana et al, 2010; Kopchick et al, 2014). Data from several genetic animal models of longevity have shown that reduced function mutations in the IGF-1 signaling pathway have low circulating IGF-1 levels, reduced cancer incidence, and increased maximal lifespan (Fontana et al, 2010). IGF-1 is a potent mitogenic growth factor, which promotes cell proliferation and differentiation, and inhibits apoptosis (Yakar et al, 2005). The inhibition of the IGF-1 pathway causes several cellular and metabolic adaptations, including downregulation of growth pathways, upregulation of autophagic and apoptotic pathways, increased resistance to multiple toxic agents, and increased genome stability (Fontana et al, 2010; Bartke et al, 2013)
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