http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5
How I understand it, the burden of a continuously build up inflammatory senescent cells in old age causes permanent inflammation and a lot of aging issues. Those cells can't repair itself anymore, so they should kill themself. The mechanism to kill themself actually already began in those senescent cell, but the last step to initiate apoptosis is blocked by FOXO4. FOXO4 binds to p53, so that p53 never is able to reach the mitochrondia (which would destroy the mitochrondia and so initiate apoptosis).
By fixing this broken mechanism, this would free the aging individual of the build up of inflammatory senescent cells and so be effective against some aging issues (which is very visible in the pictures below).
"Senescent cells are permanently withdrawn from the cell cycle and generally develop a persistent pro-inflammatory phenotype, called the senescence-associated secretory phenotype (SASP) (Coppé et al., 2008)."
"Together, these show that after acute damage FOXO4 favors senescence over apoptosis and maintains viability of senescent cells by repressing their apoptosis response."
...
"Together, these results show that by competing with endogenous FOXO4 for p53 binding, FOXO4-DRI disrupts senescence-associated FOXO4/PML/DNA-SCARS and causes nuclear exclusion of active p53."
...
"Together, these data show that FOXO4-DRI potently and selectively reduces the viability of senescent cells by competing with FOXO4-p53 binding, thereby triggering release of active p53 to the cytosol and inducing cell-intrinsic apoptosis through caspase-3/7. This establishes FOXO4-DRI as a genuine inducer of TASC. (targeted apoptosis of senescent cells)."
...
Together, these data indicate that FOXO4-DRI is effective in reducing doxorubicin-induced senescence in vitro and in vivo and in doing so neutralizes the doxorubicin-induced loss in body weight and liver toxicity. Thus, FOXO4-DRI is effective against chemotoxicity.
...
Together, these results indicate that FOXO4-DRI can reduce cellular senescence and counteract hair loss and general frailty in fast-aging XpdTTD/TTD mice.
...
Thus, FOXO4-DRI targets high SASP-expressing senescent cells that have naturally developed in the kidneys of fast-aging XpdTTD/TTD mice and in doing so restores kidney homeostasis.
...
By inducing TASC, FOXO4-DRI may thus be a potent drug to restore loss of health after natural aging and is an attractive option to explore further in the battle against those age-related diseases that are at least in part driven by senescence.
How I understand it, the burden of a continuously build up inflammatory senescent cells in old age causes permanent inflammation and a lot of aging issues. Those cells can't repair itself anymore, so they should kill themself. The mechanism to kill themself actually already began in those senescent cell, but the last step to initiate apoptosis is blocked by FOXO4. FOXO4 binds to p53, so that p53 never is able to reach the mitochrondia (which would destroy the mitochrondia and so initiate apoptosis).
By fixing this broken mechanism, this would free the aging individual of the build up of inflammatory senescent cells and so be effective against some aging issues (which is very visible in the pictures below).
"Senescent cells are permanently withdrawn from the cell cycle and generally develop a persistent pro-inflammatory phenotype, called the senescence-associated secretory phenotype (SASP) (Coppé et al., 2008)."
"Together, these show that after acute damage FOXO4 favors senescence over apoptosis and maintains viability of senescent cells by repressing their apoptosis response."
...
"Together, these results show that by competing with endogenous FOXO4 for p53 binding, FOXO4-DRI disrupts senescence-associated FOXO4/PML/DNA-SCARS and causes nuclear exclusion of active p53."
...
"Together, these data show that FOXO4-DRI potently and selectively reduces the viability of senescent cells by competing with FOXO4-p53 binding, thereby triggering release of active p53 to the cytosol and inducing cell-intrinsic apoptosis through caspase-3/7. This establishes FOXO4-DRI as a genuine inducer of TASC. (targeted apoptosis of senescent cells)."
...
Together, these data indicate that FOXO4-DRI is effective in reducing doxorubicin-induced senescence in vitro and in vivo and in doing so neutralizes the doxorubicin-induced loss in body weight and liver toxicity. Thus, FOXO4-DRI is effective against chemotoxicity.
...
Together, these results indicate that FOXO4-DRI can reduce cellular senescence and counteract hair loss and general frailty in fast-aging XpdTTD/TTD mice.
...
Thus, FOXO4-DRI targets high SASP-expressing senescent cells that have naturally developed in the kidneys of fast-aging XpdTTD/TTD mice and in doing so restores kidney homeostasis.
...
By inducing TASC, FOXO4-DRI may thus be a potent drug to restore loss of health after natural aging and is an attractive option to explore further in the battle against those age-related diseases that are at least in part driven by senescence.
