Oxidative damage, the pancreas, and aging

When we think of the ways in which oxidation contributes to age-related decline, it’s usually in the context of individual cells: Throughout the body, oxygen radicals accumulate within cells, perhaps as a result of damage to mitochondria, and these reactive oxygen species in turn wreak havoc throughout the cell. This happens, certainly, but the picture is incomplete until we take into account the active cellular response to oxidative damage. Much of this response is beneficial — e.g., upregulation of antioxidant defenses — but some can be deleterious.

An excellent example of a deleterious response to oxidative damage is provided by Laurent et al., who describe how a failure in antioxidant defenses (here the result of knockout of the JunD transcription factor) causes angiogenesis in the pancreas. The increase in blood flow causes hyperinsulinemia, which causes downregulation of pro-longevity factors throughout the body:

Oxidative Stress Contributes to Aging by Enhancing Pancreatic Angiogenesis and Insulin Signaling

JunD, a transcription factor of the AP-1 family, protects cells against oxidative stress. Here, we show that junD−/− mice exhibit features of premature aging and shortened life span. They also display persistent hypoglycemia due to enhanced insulin secretion. Consequently, the insulin/IGF-1 signaling pathways are constitutively stimulated, leading to inactivation of FoxO1, a positive regulator of longevity. Hyperinsulinemia most likely results from enhanced pancreatic islet vascularization owing to chronic oxidative stress. Indeed, accumulation of free radicals in β cells enhances VEGF-A transcription, which in turn increases pancreatic angiogenesis and insulin secretion. Accordingly, long-term treatment with an antioxidant rescues the phenotype of junD−/− mice. Indeed, dietary antioxidant supplementation was protective against pancreatic angiogenesis, hyperinsulinemia, and subsequent activation of insulin signaling cascades in peripheral tissues. Taken together, these data establish a pivotal role for oxidative stress in systemic regulation of insulin and define a key role for the JunD protein in longevity.

One wonders whether chronic hyperinsulinemia might further stress pancreatic beta cells, as cells throughout the body downregulate the insulin response and become insulin resistant, generating a vicious cycle in which even more insulin resistance is required. Such a mechanism could provide a bridge between oxidation and late-life diabetes, one of the scourges of old age.


  1. This is a stretch, but I really started wondering about pancreatic cancer when I heard Patrick Swayze has it at age 55. I read he smokes a lot, so maybe that’s a factor for him. But maybe his diet (whatever it is) contributes via high insulin levels.

  2. I think it could be linked to the typical american high-fat high-simple carb diet (pancreatic cancer). I’m still trying to find answers about mid-life reactive hypoglycemia. I wonder, could it be linked to oxidative damage? Steph

Comments are closed.