Abstract
IGF1 signaling is supposedly a key lifespan determinant in metazoans. However, controversial lifespan data were obtained with different means used to modify IGF1 or its receptor (IGF1R) expression in mice. The emerging puzzle lacks pieces of evidence needed to construct a coherent picture. We add to the available evidence by using the Gompertz model (GM), with account for the artifactual component of the Strehler-Mildvan correlation between its parameters, to compare the survival patterns of female FVB/N and FVB/N-derived K14/mIGF1 mice. In K14/mIGF1 vs. FVB/N mice, the rate of aging (γ) is markedly increased without concomitant changes in the initial mortality (μ0). In published cases where IGF1 signaling was altered by modifying liver or muscle IGF1 or whole body IGF1R expression, lifespan changes are attributable to μ0. The accelerated aging and associated tumor yield in K14/mIGF1 mice are consistent with the finding that the age-associated decreases in thymus weight and serum thymulin are accelerated in K14/mIGF1 mice. Our results underscore the importance of accounting for the mathematical artifacts of data fitting to GM in attempts to resolve discrepancies in survival data and to differentiate the contributions of the initial mortality and the rate of aging to changes in lifespan.
Highlights
Within species or strain comparisons suggest that, in mammals that feature reduced signaling through the key components of the somatotropic neuroendocrine axis, i.e. growth hormone (GH) and insulin-like growth factor-1 (IGF1), lifespan is increased, tumor incidence is decreased, and aging may be slowed down [1, 2]
The accelerated aging and associated tumor yield in K14/mIGF1 mice are consistent with the finding that the age‐ associated decreases in thymus weight and serum thymulin are accelerated in K14/mIGF1 mice
The divergences between the trends seen in the two cohorts lead to initially small differences, which increase to statistical significance at later ages. Body weights and their changes with age are virtually identical in both cohorts, so as spleen weights, the latter being constant through the adult lifespan
Summary
Within species or strain comparisons suggest that, in mammals that feature reduced signaling through the key components of the somatotropic neuroendocrine axis, i.e. growth hormone (GH) and insulin-like growth factor-1 (IGF1), lifespan is increased, tumor incidence is decreased, and aging may be slowed down [1, 2]. Transgenic male FVB/N mice, in which IGF1 overexpression under α-myosin heavy chain promoter is confined in adults to the heart and skeletal musculature, feature a range of beneficial changes in the heart and live significantly longer while www.aging‐us.com having serum IGF1 level twofold higher than in controls [8]. In male but not female mice in which IGF1 production in the liver is downregulated at adult ages, lifespan is decreased and tumor incidence is increased [9, 10]. The conundrum of beneficial vs. adverse effects of increased IGF1 signaling on lifespan is further complicated by reports about the gender- and- strainspecific effects of IGF1 receptor underexpression in mice [11,12,13]
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