Mice Producing Reduced Levels of Insulin-Like Growth Factor Type 1 Display an Increase in Maximum, but not Mean, Life Span

Abstract

Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system. We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice. The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

Altered metabolism and resistance to obesity in long-lived mice producing reduced levels of IGF-I

“…1B). Previously, we also reported significant reduction in levels of circulating IGF-I in the serum (25). These findings are consistent with studies on the relative contribution of IGF-I and GH to postnatal growth and body size in that IGF-I is thought to be responsible for 80 -90% of body growth (26).…”

“…This distinguishes these animals from mice in which the central, liver-specific production of IGF-I is ablated through gene deletion or loss of GH signaling or mice in which IGF-I signaling is decreased by reducing levels of the IGF-IR. We have reported previously that these IGF-I-deficient mice have reduced levels of circulating IGF-I, are smaller, and have a greater maximum, albeit not mean, lifespan than their littermate control mice (25). In this study, we tested the metabolic phenotype of these IGF-deficient mice and addressed whether global reduction in IGF-I directly alters metabolism.…”

hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling

“…As expected, circulating IGF-1 levels are significantly reduced in old female mice. In line with our findings, IGF-1 deficient mice also produce elevated levels of GH [31], suggesting a possible similarity of growth hormone resistance between hNAG-1 mice and GHR deficient mice. However, we did not detect any differences of GHR expression at mRNA and protein levels between hNAG-1 and WT mice in liver, brain, and adipose tissues.…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…Low serum IGF-1 levels is undoubtedly an important factor for increased lifespan of the GHRKO mice as IGF-1 deficiency alone is known to extend maximum but not mean lifespan (196,212,213). Additional factors that lead to the GHRKO mice being the longest-lived mouse in the world include the following -(i) increased stress resistance resulting from superior redox homeostasis due to upregulated expression and activity of glutaredoxin and thioredoxin detoxification systems (214,215,216,217) rather than changes in free-radical scavenging(218), (ii) reduced activity of TORC1 kinase complex (219, 220, 221), (iii) resistance to neoplastic incidence and growth(24, 97), (iv) suppressed hypothalamic inflammation(222) -an end-goal of anti-ageing drugs(223), (v) an anti-inflammatory adipokine profile, inverted liver-WAT lipid distribution and reduced senescent cell burden in WAT(62, 68, 70, 72), (vi) increased markers of mitochondrial biogenesis including higher levels of AMPK, SIRT1, and SIRT3 in heart and increased eNOS and PGC1α levels in skeletal muscle and kidney (224), (vii) detrimental effects of GH/IGF axis on very small embryonic-like stem cell pools in adult tissues (225,226) where age-related changes in DNA methylation patterns lead to increased sensitivity to circulating GH, IGF-1 and insulin with age with concomitant depletion of stem-cell pool and impaired tissue regeneration(225), (viii) resistance to diabetogenic effects of a HF diet (14), and (ix) improved insulin sensitivity(15).…”