mTOR Regulates Some of the Bad Behavior of Senescent Cells

Here the Buck Institute blog explains a recent paper on links between mTOR, a focus for research into modestly slowing aging by altering the operation of metabolism, and the bad behavior of senescent cells. Ever more cells become senescent with advancing age, and this contributes to degenerative aging because these cells act in ways that damage surrounding tissue. From where I stand, the best approach is to remove them, however, not modulate their activity. There is a lot left to understand in order to safely change the behavior of senescent cells for the better, while clearing them is a near-term prospect, for example by adapting targeted cell killing technologies developed by the cancer research community.

We showed that the mTOR inhibitor rapamycin blocks the senescence-associated secretory phenotype (SASP) by inhibiting translation of IL-1α, which prevents senescent fibroblasts from promoting cancer tumor growth. What we found is that after chemotherapy or radiotherapy, cancer cells and the cells surrounding them become senescent. That means that the cells surrounding the cancer cells are no longer performing their normal function and they begin to secrete cytokines and growth factors that stimulate cancer growth. We found that a small molecule called rapamycin can prevent this from happening.

So if we extend the findings of that story, this drug may be useful following chemotherapy as an adjuvant. By giving the patient rapamycin after chemotherapy, we might slow down the relapse of the tumor. The next step obvious step is to run a clinical trial with rapamycin or a rapalog. Rapamycin is already FDA approved, so this is exciting for clinical trials, but trials aren't really something that basic scientists are equipped to do. Our paper is showing is that rapamycin would work well as an adjuvant therapy. So after you have received chemotherapy, senescent cells have been induced, and rapamycin can be used to block those otherwise harmful senescent cells. So rapamycin treatment should, in theory, delay relapse.

Half of the people at the Buck Institute work in one way or another with mTOR. So everyone has some connection to translation or mTOR because of how important mTOR is in aging. We have various people working on different aspects of aging. Some are focusing on age-related pathologies, and others are working on aging in general using model organisms. We know that senescent cells accumulate at sites of age-related pathologies and in some pathologies that aren't age related. We are still finding these things out. What is being taught currently is that the deleterious effect that senescent cells have is due to a proinflammatory profile. It is possible that rapamycin extends lifespan because it reduces the low level of chronic inflammation. So if you can think that this is true for aging in general, this could also be true for various age-related pathologies. It will be interesting to see the follow up on rapamycin and modulation of the proinflammatory profile of senescent cells.



Reducing inflammaging is critically important on the short and middle term (i.e., next 50 years).

Realistically, don't we expect a process to remove senescent cells to be imperfect? Right now, we do not even have a viable way to remove them... in a couple of decades, we might have a way to remove most of them most of the time if we are lucky. Moreover, it is likely that inflammaging is not caused solely by senescent cells.

Posted by: Daniel Lemire at July 9th, 2015 8:00 AM

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