Rapamycin [Sirolimus]
Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiology and extends longevity. We have shown that deficiency in Nrf2 in young Nrf2KO mice leads to an increase in senescent cells, with increased levels of pro-inflammatory cytokines in various tissues, including the brain. Both the cellular senescence and SASP decrease significantly when these mice are treated with rapamycin. Our current work focuses on determining whether cellular senescence contributes to premature AD-like pathogenesis in mouse models of AD. Indeed, it has been shown that Nrf2 deficiency in mouse models for AD leads to exacerbated pathology, suggesting that increased inflammation, due in part to the increased SASP-producing senescent cells, might be contribute to this phenotype. We are testing whether the burden of senescent cells in the brain on mouse models of AD can be reverted by rapamycin.
FOX04-DRI
FOX04 is a member if a larger group that produce transcription factor proteins that are important for growth and differentiation. The FOX04 protein is modified in normal biology by post-translational activities. These modifications alter DNA binding affinity of FOX04 and thus allow it to regulate a host of cellular pathways such as oxidative stress signaling, cellular senescence, apoptosis, insulin signaling, and the cell cycle itself.
FOX04 D-Retro-Inverso is identical to the protein product of the FOX04 gene, but the normal L amino acids have been exchanged for D amino acids. The result is that FOX04-DRI has reduced susceptibility to normal physiologic clearance mechanisms and thus remains in the body for longer periods of time. The modified protein is still capable, however, of affecting transcription and cellular pathways. In general, the FOX04-DRI protein interferes with the normal FOX04 function.
Of greatest interest in terms of aging and senescence is the ability of FOX04-DRI to interfere with normal FOX04 signaling in the cell cycle by preventing the binding of FOX04 to p53. The p53 protein is an important regulator of progression through the cell cycle as well as programmed cell death (apoptosis). When FOX04-DRI binds to p53, it prevents FOX04 from binding and allows p53 to bind to DNA. This, in turn, allows the cell to continue through the process of apoptosis and die. Interesting, FOX04-DRI appears to only have this effect in senescent cells, cells that are no longer functional or are dysfunctional as a result of aging. By targeting these dysfunctional cells, FOX04-DRI helps to rid tissue of cells that are nothing but dead weight. This, in turn, allows for better tissue functioning and helps to stimulate growth and differentiation to younger, healthier cells. The net result is better biological function and thus a decrease in “biological age”.