An Example of Senomorphic Drug Discovery
Senescent cell accumulation is a feature of aging, a growing imbalance between the rate of creation and rate of destruction. Senescent cells perform a number of useful tasks in the short-term, but when present for the long-term, their inflammatory secretions disrupt tissue function and contribute meaningfully to the onset and progression of age-related disease. A great many research groups are working towards the basis for therapies that can selectively destroy senescent cells (senolytics). Others are working on ways to prevent cells from becoming senescent, or suppress the worst of the bad behavior of existing senescent cells (senomorphics). The open access paper here is a representative example of the latter development process.
The senescence-associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro-inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence-associated diseases. Here, we identified a small molecule SR9009, a specific agonist of NR1D1/NR1D2, as a potent SASP suppressor in therapy-induced senescence (TIS) and oncogene-induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes.
We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation-induced and oncogene-induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence.
IIRC, SR9009 once touted as exercise in a pill, was abandoned b/c of it's lousy bioavailability.
SR9011 is the new candidate
It doesn't happen often but I'm quite hopeful that Rev-erbα agonists will have significant impact.
Mostly because of
Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy
https://natap.org/2013/HIV/nm.3213.pdf
'This study identifies Rev-erb-a as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.'
Which in turn could take care of pro aging mTOR deregulation due to mitochonrial dysfunction/distress.
'Senescent cells perform a number of useful tasks in the short-term, but when present for the long-term, their inflammatory secretions disrupt tissue function and contribute meaningfully to the onset and progression of age-related disease.'
I don't believe that senescent cells perform a number of useful tasks. It's probably just non-senescent cells with transient expression of senescense like markers which are falsely identified as senescent due to lack of senescent uniqueness of use markers.
According to this study targeting Rev-ERBa is a double edge sword
https://www.thno.org/v10p4168.htm
For new drug development, it is advocated that REV-ERBα should be targeted to treat local diseases and a targeting drug should be locally distributed, avoiding the adverse effects on other tissues"
@August33
There are unwanted effects or conditions in which Rev-erb-α modulation is detrimental. The paper names Alzheimers and hyperhomocysteinamia. Well, don't treat people with those diseases. Treatment duration should be considerd too. Beneficial effects might manifest before detrimental ones develop.
Thank you, August33. Interesting read, even though most of its conclusions is also true for any other drug.