SYK Inhibitors as a Novel Class of Senolytics, Mechanisms of Action Yet to Be Determined

Senescent cells accumulate with age, and this accumulation is an important contributing cause of aging. These errant cells secrete a potent mix of signal molecules that spur chronic inflammation and tissue dysfunction. Animal studies demonstrate that targeted removal of as little as a third of senescent cells in old individuals can produce a sizable reversal of many aspects of aging, as well as of a broad range of age-related diseases. A number of companies have been funded to commercialize senolytic therapies, those capable of selective destruction of senescent cells. Therapies present under development target a range of mechanisms, such as Bcl-2 family influence over apoptosis, and markers, such as p16 and senescence-associated beta-galactosidase.

At this early stage in the development of a senolytics industry, in which comparatively few classes of senolytic treatment exist, any discovery of a novel senolytic mechanism is likely to produce sizable rewards for the organization and researchers involved. Hence many research groups are either digging deeper into the biochemistry of cellular senescence, in search of gold, or screening large numbers of compounds for senolytics that might work in novel ways. Today's open access paper is an example of the second class of initiative. The authors note their discovery of a senolytic small molecule that employs none of the known mechanisms of senolysis, but nonetheless can push senescent cells to self-destruct via apoptosis.

This state of comparative ignorance about how a compound functions is one of the interesting outcomes that can result from screening compound libraries. A team finds a compound that works to kill senescent cells, and they can determine whether or not it works through known mechanisms employed by other senolytics, but if it doesn't, then a fair amount of effort lies ahead. It may well take years to understand exactly how this new senolytic works to selectively provoke apoptosis in senescent cells. In this context, the discussion section of the paper is well worth a closer read; it gives a sense of the complexity of the challenge.

Identification of SYK inhibitor, R406 as a novel senolytic agent

Selective clearance of senescent cells has been suggested to induce rejuvenation and longevity. In animal models, senolytic drugs have been shown to delay several age-associated disorders, to improve physical and cognitive function, and to extend lifespan. Because known senolytic drugs have limited diversity for their mode-of-action and affect change in a cell-type-specific manner, novel senolytic drugs are needed to improve efficacy and expend medical application against senescent cells.

Major classes of senolytic drugs typically focus on inhibiting pro-survival pathways or triggering pro-apoptosis signaling in senescent cells. The combination of dasatinib and quercetin, which reduced p21, PAI-2, and BCL-xL, and Navitoclax (ABT263), which targets the Bcl-2 family, belong to this class of senolytics. In other classes, the mimicry of forkhead box protein O4 (FOXO4) peptide selectively disrupted the p53-FOXO4 interaction, which induced p53-dependent apoptosis in senescent cells. Recently, a HSP90 inhibitor was identified as a novel class of senolytic drugs that downregulated the phosphorylation of PI3K/AKT, an anti-apoptotic factor. Despite intensified efforts to develop drugs targeting senescent cells, however, the number of senolytic agents is still limited in comparison with the number of drugs against other age-related diseases like cancer or fibrosis.

In this study, using high-throughput screening to measure the variation of cell proliferation and reactive oxygen species (ROS) levels, we identified a novel senolytic agent R406, also known as tamatinib. This agent was effective in the replicative senescence model of diploid human dermal fibroblasts. R406 induced the caspase-9-mediated intrinsic apoptotic pathway, similar to other known senolytic drugs; however, R406 did not significantly change the level of Bcl-2 family in senescent cells. Alternatively, R406 inhibited the phosphorylation of focal adhesion kinase (FAK) as well as p38 mitogen-activated protein kinase (MAPK), which both regulate cell survival. Our results demonstrate that R406 is a new class of senolytics that targets multiple regulatory pathways for senescent cell survival.

Comments

" Animal studies demonstrate that targeted removal of as little as a third of senescent cells in old individuals can produce a sizable reversal of many aspects of aging, as well as of a broad range of age-related diseases." ... in mice ... none of those results are translating to humans

Posted by: sens at May 19th, 2020 5:34 PM

@sens

Has anyone achieved this level (33%-66%) of senscenced cells' removal in the whole body in humans? Removing up to half (50%) in certain tissue do not translate into all tissues in the whole body. When SASP drops below some yet unknown level, and this translation won't happen then we can moan that mouse studies "none of those results are translating to humans". Before empirical testing of this hypothesis to proclaim it to be false (contrary to encouraging improvements with weaker senolytics so far in humans) it is far and away pessimistically premature.

Posted by: SilverSeeker at May 20th, 2020 9:37 AM

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