Loss of function mutations in insulin signaling have been shown to slow aging and extend life, but at the cost of slow growth and insulin resistance. Researchers recently discovered in flies a mutation that slows aging while retaining insulin signaling function. Flies have a single receptor for their versions of insulin and insulin-like growth factor (IGF-1), while mammals have two receptors, the insulin receptor and IGF-1 receptor. Thus here researchers introduce the same mutation into one or other of the mouse receptors and conduct a relatively short study in order to assess whether it is worth conducting a much longer life span study in these engineered mice.
Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. Yet, long-lived loss-of-function mutants often produce insulin-resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin sensitivity, growth, and reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R).
We produced two knock-in mouse strains that carry the homologous KID Arginine/Cysteine substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce phospho-ERK but ERK was less phosphorylated in cells with IGF-1R heterodimers.
Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At four months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin, FGF21, and reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.
Link: https://doi.org/10.1172/jci.insight.189683
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