NF-κB and the Insulin Resistance of Aging

There are multiple mechanisms that contribute to the progression of insulin resistance with aging. The most significant contributions seem to stem from excess fat tissue and a sedentary lifestyle, and the metabolic consequences of those choices. (Yes, being fat is absolutely a choice for nearly all people, and one that they could begin to reverse at any point in time by changing the way they live their lives). Avoiding diabetes is a very plausible goal if you keep in shape - but even the most fit of elderly folk suffer some degree of rising insulin resistance and metabolic dysfunction as a consequence of the accumulating biological damage of aging. There is the insulin resistance you can escape, and then there is the insulin resistance you can't.

One line item that crops up when discussing the intersection of exercise, inflammation and insulin resistance, and the course of aging is NF-κB - one of the many machine parts in the cell that seems to have a finger in every pie by virtue of being involved in the process of manufacturing other machine parts. Manipulating NF-κB can extend life in flies, and has beneficial effects in other laboratory animals. Here, a couple of recently published papers look at NF-κB as a regulator of insulin resistance - avoidable and otherwise - and possible target for old-style drug development.

Endothelial NF-κB in Obesity and Aging: Is Endothelial NF-κB a Master Regulator of Inflammation and Insulin Resistance?

Insulin resistance is a major characteristic of type 2 diabetes and develops in multiple organs including skeletal muscle, liver, adipose tissue, and heart. Insulin resistance is caused by obesity and therefore establishes an important causal relationship between obesity and type 2 diabetes. Insulin resistance also develops in aging, but this process is less well understood.

Blockade of the NF-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Lifespans

To examine the role of endothelial NF-κB signaling in vivo, we generated transgenic mice [that] exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although [the] mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetically-induced.


In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged lifespan. These anti-aging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity and aortic up-regulations of mitochondrial sirtuin-related proteins. ... Endothelial NF-κB signaling is a potential target for treating the metabolic syndrome as well as for anti-aging strategies.

At the present pace, by the late 2020s researchers will be able to tell you exactly why, how, and how much common lifestyle choices impact your future health and life expectancy. But it's worth noting that this won't help you live any longer - you could make the same smart choices now as you would if presented with a much thicker bundle of scary evidence. The 80/20 of present day widely available health practices is easy to achieve, after all: calorie restriction and regular exercise. None of this, however, gets us any close to true rejuvenation biotechnology. For that, we need more resources heading towards the work of the SENS Foundation and their allies in the research community.


This is very interesting...everyday I'm more and more convinced that calorie restriction is indeed the answer!

Posted by: Mike @TheIronYou at February 8th, 2012 1:05 AM

Blocking NFKB by any means seems more like the answer.

Posted by: Mike at February 10th, 2012 7:05 PM
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