The collective influence on aging of insulin, insulin-like growth factor (IGF-1), growth hormone, and the receptors for these signal molecules is well studied. It is arguably the most well studied area of cellular biochemistry and metabolism in the context of aging, a central set of mechanisms that regulate the evolved trade-off between growth and maintenance, and which is strongly influenced by the equally well studied intervention of calorie restriction. Numerous animal studies have demonstrated that interfering in various specific parts of this collection of signaling processes is capable of at least modestly slowing aging. In the case of the growth hormone receptor, genetic engineering to cause life-long loss of function produced what remain the longest lived mouse lineages to be generated in the laboratory. These dwarf mice live up to 70% longer than unmodified peers.
Humans with Laron syndrome exhibit essentially the same loss of function and dwarfism, but while they may prove to be more resistant to some age-related diseases, they unfortunately do not exhibit a sizable increase in life span. The same is true for the practice of calorie restriction; humans may gain a few years, but clearly not the 40% extension of life span that has been observed in mouse studies. The evolution of mechanisms relating to growth, maintenance, and availability of food has led to a great plasticity of life span in short-lived species, but not in long-lived species. The health benefits resulting from the practice of calorie restriction in humans are considerable relative to what can be achieved using near all existing forms of medicine, but fall far short of our aspirations for the future.
Nonetheless, the development of calorie restriction mimetic drugs is a major focus in the research and development communities, an attempt to indirectly interfere in the regulation of growth versus maintenance by provoking some of the same reactions as take place in an environment of a reduced calorie intake. Another area of interest is the development of drugs that interfere more directly with the IGF-1 signaling involved in regulating growth versus maintenance. Today's open access paper is an example of a proof of concept study aimed at inhibition of the IGF-1 receptor, using drug candidates that would not be suitable for further development due to their side-effect profiles. They nonetheless produce a modest slowing of aging in mice.
Small-molecule IGF1R inhibitors extend healthspan in a mouse model
Antagonistic pleiotropy of the IGF-1 signaling cascade is well recognized, as it promotes growth and development at younger ages and delays aging later in life. The goal of this study is to test in a mouse longevity experiment whether orally delivered small-molecule IGF1R inhibitors have promise as an anti-aging therapy. C57BL/6 mice (25 male and 25 female mice per treatment) were treated with selective IGF1R inhibitors, picropodophyllin (PPP) or 5-[3-(phenylmethoxy)phenyl]-7-[trans-3-(1-pyrrolidinylmethyl)cyclobutyl]-7H-pyrrolo[3-d]pyrimidin-4-amine (NVP-ADW742), via powdered diets starting at 13 months of age, and physiological and behavioral parameters, as well as survival, were assessed.
Both compounds protected both sexes from short-term memory decline; reduced systolic blood pressure in males and pulse rate in both sexes; rescued declining glucose tolerance in males; and abolished grey hair development, reduced frailty, and protected against decline in grip strength in female mice. There were no sex differences in survival curves within groups. No significant differences between groups were observed in the Kaplan-Meier analysis of survival. However, the survival curve in the NVP-ADW742 group was "squarer" than in controls, indicating a 93-day longer healthspan. PPP treatment was associated with toxicity (gastrointestinal bleeding). Additional analysis of the drug likeness of NVP-ADW742 demonstrated potential cardiotoxicity and brain bioaccumulation.
To conclude, small-molecule IGF1R inhibitors hold promise as a therapy that may improve human health span and lifespan; however, both molecules tested in this study have side effects that may outweigh their anti-aging effects.
View the full article at FightAging
