Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan
This week we profile a recent publication in Cell Reports from the laboratory of Dr. James Johnson at UBC’s Life Sciences Institute.
Can you provide a brief overview of your lab’s current research focus?
My lab in Vancouver is pretty unfocused actually. We have projects in a large number of areas including pancreatic beta-cell survival and function in type 1 diabetes and type 2 diabetes, stem cell differentiation towards beta-cells, insulin receptor trafficking, pancreatic cancer, cardiomyocyte metabolism, and Alzheimer’s disease. We are generally interested in physiology, from the cellular level to integrated physiology of the whole organism. We have a special interest in insulin, which touches so many areas of physiology.
The new paper in Cell Reports is about the effects of modest changes in circulating insulin, made by reducing the insulin gene dosage in mice, on insulin sensitivity and longevity.
What is the significance of the findings in this publication?
Our well-powered study had two major findings, both of which have profound implications across multiple fields.
First, we found that mild life-long reduction in circulating insulin improves glucose homeostasis and insulin sensitivity in old mice. This demonstrates that at least some age-dependent insulin resistance is caused by the hypersecretion of insulin itself. This simple observation is the first clear evidence of causality to one of the most important chicken-and-egg debates in the metabolism field – specifically whether hyperinsulinemia causes insulin resistance by a desensitization-like process (which makes physiological sense but had never been demonstrated), or whether insulin resistance drives compensatory hyperinsulinemia and glucose intolerance with age (which is the current dogma in diabetes/obesity research, and in textbooks). Our work helps answer this question, which has the potential to change prevention and treatment strategies for one of the world’s most common and economically devastating diseases, type 2 diabetes.
Second, we found that modestly reduced insulin significantly extended mammalian lifespan, reproducibly across multiple diets. We also employed RNAseq to identify new mechanistic correlates of the improved healthspan in mice with lowered insulin. Although previous studies in worms, flies and mice have shown that mutating some components of the insulin/IGF‑1‑like signaling pathway can extend lifespan, none of the previous studies could distinguish whether the key upstream ligand is insulin or IGF-1, with the latter being the favoured responsible ligand. Our data are the first to unambiguously implicate the insulin ligand itself, as we have the first long-lived mouse model where IGF-1 levels do not change.
Importantly, the modest (~15%) changes in circulating insulin that we create genetically are uniquely attainable in human populations with dietary/lifestyle modifications. In contrast, it is not clear that other manipulations suggested to extend lifespan in mammals are desirable (severe caloric restriction) or safe (rapamycin) for humans.
Until this paper, the role of insulin in mammalian longevity has remained controversial and not directly tested, likely because insulin is an essential metabolic hormone, and drastic reductions in insulin levels are widely associated with diabetes and lethality. Furthermore, although lowered insulin levels and enhanced insulin sensitivity are widely demonstrated to be common characteristics of many long-lived mammals, these two conditions are interrelated, making it unclear which might play a causal role in lifespan extension. In our new paper, we not only demonstrate that slightly reducing circulating insulin is sufficient to extend mammalian lifespan, but we also provide the first direct evidence that having lowering insulin can cause enhanced insulin sensitivity with aging. Thus, our study resolves the insulin resistance paradox, and unifies two key concepts in aging and metabolism research.
What are the next steps for this research?
We are taking next steps in a few directions. On the translational front, we are collaborating with local physicians, pharmacists and other scientists to test diets that keep insulin low for their ability to treat type 2 diabetes. We are doing this with a new entity called the Institute for Personalized Therapeutic Nutrition, which I helped found in 2016. On the basic science front, we are setting up to ask a few more key questions. For example, to complement our published studies on obesity ‘prevention’ in mice with life long insulin reduction, we have completed a study showing that acutely reducing insulin levels in already obese mice, can cause weight loss. We are also gearing up to test the hypothesis that modestly reducing insulin early in a mouse model of type 1 diabetes may have beneficial effects. We are already studying whether tunable insulin production in human embryonic stem cells is possible.
This research is funded by:
The research reported in the recent Cell Reports paper was funded by a 5 year CIHR grant.