Read the Popular Science Press With a Careful Eye

A recent brief release over at EurekAlert! nicely illustrates the need for caution - and a little context - when reading through descriptions of new research:

Csiszar and collegues treated aged rats with etanercept to test the hypothesis that anti-TNFa treatment exerts vasculoprotective effects in aging. Etanercept (Enbrel) is an FDA-approved drug that binds and inactivates circulating TNFa. Recent studies have demonstrated that anti-TNFa therapies, including etanercept, may improve inflammation-related vascular disease, including heart failure.

Csiszar and colleagues made four notable findings in their study. First, they confirmed that in advanced aging, increased TNFa levels were associated with significant impairment of vessel relaxation, which is required for proper regulation of blood pressure.

Second, blocking TNFa via chronic etanercept treatment decreased cell death in aged vessels, demonstrating that increased TNFa levels likely contribute to age-related cardiovascular disease. Similar cell-protective effects were found when anti-TNFa antibodies were used in cell culture.

Third, not only was TNFa released into the blood, where it can have systemic effects, but it is also expressed within blood vessel walls, where it can exert specific local effects.

Lastly, administration of TNFa to young arteries reproduced the features of vascular aging, such as blood vessel dysfunction and cell death, further confirming the role of TNFa in the aging of the cardiovascular system.

The knowledge that cardiovascular disease is the leading cause of death for both men and women in the U.S. underscores the significance of these findings. This treatment could one day lead us closer to better heart health as we age.

Sounds great, right? Existing already-approved drug to help with an aspect of aging! Well, maybe. Very maybe. Hold your horses and back up to read the notes above again. You'll see a bunch of correlations, but they don't add up to a demonstration that Embrel addresses the physiological changes of interest, such as age-related imparement of blood vessel relaxation. You can be pretty sure that if the research team had that under their belt, they'd be trumpeting it from the rooftops in the advance releases - compare the release above with that for much more convincing work on vascular hardening from earlier this year:

The research, which was done in test tubes and animal models, needs to be confirmed in humans before it could form the basis for new therapies. But the fundamental findings reveal an important insight into how blood vessels change with age and lose much of their ability to relax, contract, and facilitate the circulation of blood in the body. ... Basically, we've learned that in older blood vessels, the cellular signaling process is breaking down. The vessels still have the ability to relax much as they did when they were younger, but they are not getting the message ... The laboratory studies were very compelling. We were able to make aging blood vessels behave as if they were young again ... This overall process, the researchers said, is linked to a low-grade, chronic inflammation that occurs with aging, in blood vessels and probably many other metabolic functions.

Making old components behave in a young fashion is much more convincing than vice versa in a demonstration of mechanisms - there are many ways other than aging to damage young biological systems and make them show desired characteristic failures of age, but very few ways to make old systems show young characteristics.

Csiszar's group is announcing additional carefully derived and presented evidence for the involvement of TNFa in the overall process at the biochemical and cellular level. This, however, doesn't necessarily mean that an anti-TNFa strategy will be helpful, even if the signs are pointing towards inflammation as the root problem. Suppressing TNFa might be a step too far down the line of cause and result, for example, and do little to help with the real biochemical cause of blood vessel hardening. Or it may actually help, given the experiments with young blood vessels given TNFa - but the researchers haven't shown that here, which seems surprising, all things given. I'll bet they tried.

And this is not even to talk about the plausible role of AGEs in tying the controlling biochemistry of blood vessel activity into knots.

Anyway, on to the context. I'm always slightly more careful of the bevy of papers involving the search for additional uses for an approved drug. The weight given to such work is very much a creation of the FDA's regulatory burden - it is much cheaper to search extensively for a hole that maybe, somewhat fits an approved peg than to develop new pegs to better fit the holes you find. There is tremendous pressure at all levels of the funding and research community to bang that newly-approved peg into whatever hole will fit closely enough - hundreds of millions of dollars are at stake. This means entire research groups, all their support structure, management and other necessities for a decade can hinge on an existing peg and a not-quite-right hole. That degree of carrot and stick tends to make people adjust their behavior, collectively and individually.

This is what the heavy hand of government does to organizations that are, in concept, the most well meaning you're likely to find in this world - people coming together to cure disease and eliminate suffering by building the future of medicine. Regulation twists that ideal, aligning the incentives of all involved away from competing through novel research, away from competing to produce the best possible solution, and towards shortcuts, recycling of existing ideas and comparatively worse solutions.

So when I look at the work of Csiszar's group here, I see good work on TNFa, nicely done, but visions of holes and pegs are floating before my eyes. TNFa is ubiquitous in many aspects of degenerative aging, because inflammation is ubiquitous in many aspects of degenerative aging - and so there are a lot of places to look for that new hole for etanercept that's more round than square. It has that cast to it so far, in any case - but I will be delighted to be proven wrong, in this as in many other cynical views of the world.

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