Toxic Entente: Aging, adipose tissue and TNF-alpha

The following study is a very interesting and neatly done research published in Journal of Experimental Medicine (JEM). Quite unusual results. It deals with aging, adipose tissue accumulation and susceptibility to cytokine storm.

A conceptual rationale for this study is a following: many cancers develop later in the life. Cancer treatments  now days incorporate immunotherapies. However, before immunotherapy is approved for human use, the scientists use it on young mice to test its efficacy. So the authors questioned what would happen if we were to try to test it on old mice? Exactly.

Now here is the surprise. This study, led by William Murphy from UC Davis, observed that unlike young mice, old mice (> 15 month) die rapidly when injected with a combination of anti-CD40 / IL-2 or CpG / IL-2. Why?

Usually, old mice of B6 mice become overweight with the aging. They accumulate a lot of adipose tissue (fat).

Interestingly, the authors found that when old B6 mice were artificially kept on a calorie-restricted diet, they became resistant to anti-CD40 / IL-2 injection.

Next, to validate the connection between adipose tissue and toxic response to anti-CD40 / IL-2 injection, the authors used leptin mutant ob/ob mice. This mice are very cute looking due to extreme overweight, even when young.

The authors found that similar to old B6 mice, ob/ob mice were highly susceptible to anti-CD40 / IL-2 injections.

Mechanistically, the authors found that a depletion of macrophages with Clodronate or neutralization of serum TNF-alpha with etanercept (FDA approved antibody) could rescue young ob/ob mice from toxic response to anti-CD40 / IL-2 injections.

Finally, the authors found that diet-induced obesity in young B6 mice also increased their susceptibility to anti-CD40 / IL-2 injections. However, unlike old B6 mice, only 50% of young obese B6 mice were sensitive to anti-CD40 / IL-2 injections.

  

In summary, the authors proposed that age-associated adipose tissue accumulation harbor macrophages that have heightened responsiveness to anti-CD40 / IL-2 injections leading to uncontrolled TNF-alpha release and death. This study also shows that calorie restriction during aging can have a beneficial, life-saving effect. 

It would be interesting to know if a gut microbiota played any role in the observed difference between young and old B6 mice. The fact that young obese B6 mice were not as susceptible to anti-CD40 / IL-2 injections as old B6 mice were suggests that age-associated susceptibility to cytokine storm is more complex than simple adipose tissue accumulation (still, in my opinion, this article should have been published in Nature Medicine even though it did not show a "perfect" correlation between adipose tissue and cytokine storm in young obese B6 mice). 

One drawback is that it is not completely clear whether anti-CD40 / IL-2 or CpG / IL-2 injection regimen is a typical immunotherapy regimen approved for human use. 

David Usharauli