Death-Resistant Cells: From Inhibiting SASP to Potential Geroprotector (Buck Institute for Research on Aging)
Non-dividing “senescent” cells in our bodies resist signals for apoptosis (programmed cell death) and secrete numerous inflammatory signaling molecules and protein-degrading enzymes into their local environment. The latter phenomenon is called the senescence- associated secretory phenotype, or SASP, and is thought to play a role in the chronic disease-promoting inflammation widespread in aging tissues. Additionally, although activation of the senescence program can pre-empt the initiation of cancer, the long-term effects of the SASP may make the local tissue environment more vulnerable to the spread of cancer.
With SENS Research Foundation funding, the Buck Institute senescent cell project has been screening small molecules for their effects on fibroblasts (a type of skin cell) rendered senescent by ionizing radiation and other causes of DNA damage, including replicative stress. Their goal is to identify agents that can selectively kill senescent cells or interrupt the SASP. Earlier work by the Buck team revealed that a compound called apigenin suppresses the secretion of a representative constituent of the SASP. As part of the research completed this last year, the team traced apigenin’s ability to shut down the vicious cycle that enforces ongoing SASP back to its root: IRAK4, a key part of the signaling cascade that is activated inside cells when the SASP component IL-1α engages its receptor. To keep the IL-1 α signal propagating, two separate IRAK4 structures must unite to engage a kinase domain, transferring a high-energy phosphate group from one part of the united structure to another. It is this higher- order active structure that then relays the inflammatory signal onward to NFκB. The team have now shown that apigenin acts by blocking IRAK4 from transferring that critical energy group, interrupting the signal and shutting the vicious cycle down.
Looking at existing published research, the Buck senescent cell team noted that — at least in cell culture — apigenin inhibits signaling through the “pro-growth” pathway regulated by the mammalian target of rapamycin (mTOR) protein. Inhibiting mTOR reduces protein synthesis and facilitates the breakdown of used or damaged proteins, and the mTOR-inhibiting compound rapamycin is the only drug yet shown to clearly slow down the degenerative aging process in mammals. Unfortunately, rapamycin’s potential to adversely affect immune function and increase diabetes risk seriously limits its clinical utility. Scientists are therefore looking for alternative drugs (“rapalogs”) that might have the beneficial effects of rapamycin without the side effects.
Following up on this new lead, the Buck team confirmed and expanded the previous findings on apigenin’s effects on mTOR. Because earlier experiments in the Campisi Lab showed that rapamycin could decrease the SASP in senescent cells, the team was intrigued to note that apigenin exhibited a similar effect and displayed signs of a similar mechanism of action. Unlike rapamycin, however, they found that apigenin does not work by directly blocking the activation of mTOR itself, but by inhibiting other steps along the pathway it regulates, and apigenin's inhibitory effect on the proliferation of non-senescent cells is much less severe. If studies in living organisms pan out similarly to these cell culture findings, apigenin (or drugs based on parts of its structure) could yield some of the benefits of rapamycin as well as dampen the SASP in senescent cells, making it an attractive prototype for a dual-action age-inhibiting drug.
Of course, we don’t yet know whether these effects will be seen in living, breathing organisms. Human apigenin studies suggest that the concentrations required for possible therapeutic benefit cannot be obtained from dietary supplements. The known side-effects of inhibiting mTOR with rapamycin may also emerge with apigenin analogs. To determine what actual potential exists in this area, this year, the senescent cell team at the Buck will test apigenin out for the first time in living organisms — the roundworm C. elegans. This study won’t necessarily tell us much about the effects in mammals, but the team is also going to propose apigenin for testing in gold-standard mouse lifespan studies under the NIA’s Intervention Testing Program — the same program that generated the earlier breakthrough with rapamycin.