An Example of Reducing or Altering Cellular Senescence

Researchers have demonstrated a number of genetic and pharmacological approaches that seem to modulate cellular senescence, either by somewhat lowering the number of cells that become senescent or by somewhat reducing the impact of the senescence-associated secretory phenotype (SASP). Senescent cells are one of the root causes of aging. They produce damage and age-related disease through the signals they secrete, which cause inflammation, remodel surrounding tissue structures, and alter the behavior of normal cells for the worse. Many of the methods that over the years have been demonstrated to modestly slow aging in laboratory animals have some sort of effect on the properties of cellular senescence, but a potential therapy based on these methods would have to be far, far more effective in order to compete with selective destruction of senescent cells as an approach to the problem. The cell culture research here is an example of present explorations into altering the processes of senescence rather than simply destroying the unwanted cells, but I can't say that I see it as being all that promising for anything other than the production of greater knowledge of the senescent state.

Cellular senescence is a hallmark of aging and senescent cells accumulate with age in vivo in mammals; this is thought to drive aging by limiting tissue replicative capacity and causing tissue dysfunction. Developing strategies to delay the onset of senescence or remove senescent cells may provide a route to preventing age-related disease. Targeting senescence as a means to combat aging and age-related diseases is, however, challenging due to its antagonistically pleiotropic nature - any treatment needs to limit the deleterious impacts of senescent cells without impacting the potent barrier against tumorigenesis. While caloric restriction has been reported to extend healthspan in macaques, the most promising candidate for a longevity therapeutic in mammals is rapamycin.

Rapamycin mechanistically acts by binding the protein FKBP12, producing a complex which can bind and inhibit mTOR. mTOR constitutes the point at which diverse environmental signals are coordinated into a cellular response, regulating pathways including cell growth, proliferation, survival, motility and protein synthesis. mTOR is present in two complexes in metazoa, mTORC1 and mTORC2, which have different components and functions. Rapamycin inhibits mTORC1, but chronic treatment may also disrupt mTORC2. While rapamycin extends lifespan in mice even when administered in middle age, it has significant side-effects that may limit its use in humans. We have therefore explored the potential of second generation rapalogs i.e. pharmacological agents that inhibit mTORC but act not through binding to FKBP12 but instead as mTORC-specific ATP mimetics. AZD8055 is an ATP-competitive inhibitor of mTOR kinase in both mTORC1 and mTORC2. AZD8055 has anti-proliferative effects similar to those of rapamycin and has been taken forward into clinical trials against various forms of cancer.

Here, we test whether acute mTORC inhibition can alter features of senescence in cells that have already undergone a large number of population doublings (PD) - as they are about to undergo senescence but are currently still proliferating, we term these populations 'near-senescent'. Such high cumulative PD (CPD) near-senescent cells show many signs characteristic of senescence including increased size and granularity, SA-β-gal staining, high lysosomal content and accumulation of actin stress fibers. They are still capable of cell proliferation, albeit with a reduced rate of proliferation compared with cells at lower CPD. Here, we test the effect of inhibiting both mTORC1 and mTORC2 using the TOR-specific ATP mimetic AZD8055. Remarkably, we demonstrate significant reversal of major phenotypes of senescence on short term low dose pan-TOR inhibition. We therefore suggest that AZD8055 may prove useful in modulating health outcomes in late life.

Link: https://dx.doi.org/10.18632/aging.100872

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