FOXO, Fasting and Slowing Senescent Cell Growth Arrest

Senescent cells accumulate with aging and function poorly, like sleeping growth arrested babies, in producing more waste than work.  They are one putative "cause" of aging.

Moreover senescent growth arrested cells are toxic to the environment of regional cells.

Senescent cell development is  countered by FOXO genes which are inhibited by insulin and insulin growth factor during feeding and released to work during fasting.

Fasting 12 hours daily allows FOXO and autophagy to repair and remove waste.  

It allows a new start, the forgiveness of metabolic debts and a roll back of the aging odometer.

In a balanced cell environment then, why does aging and senescent cells still accumulate albeit much slower?

Clock genes.  Spermidine synthetase winds down and slows proteostasis.  This slow down may be slowed down itself by microbiome or dietary supplementation with spermidine/wheat germ.  In effect, spermidine stops or reverses the clock and let's the game continue.  This was the effect represented in the movie Adeline, in which Blake Lively no longer aged until the clock was restarted.

Would one live forever if this was operational? No.  Injury, acute and subacute, would sufficiently damage cell function ultimately.  Nonetheless, Sulphoraphane which stimulates the antioxidant response element would reduce the magnitude and rate of accumulated oxidative stresses produced by the environment.

Once again we arrive at anti-aging being Autophagy, Sulphoraphane and Spermidine; a strategy to prevent inflamaging and improve resilience.

http://www.sciencedirect.com/science/article/pii/S1471491416301721

The Fountain of Youth by Targeting Senescent Cells?

The potential to reverse aging has long been a tantalizing thought, but has equally been considered mere utopia. Recently, the spotlights have turned to senescent cells as being a culprit for aging. Can these cells be therapeutically eliminated? When so? And is this even safe? Recent developments in the tool box to study senescence have made it possible to begin addressing these questions. It will be especially relevant to identify how senescence impairs tissue rejuvenation and to prospectively design compounds that can both target senescence and stimulate rejuvenation in a safe manner. This review argues that to fulfill this niche, cell-penetrating peptides may provide promising therapeutics. As a candidate approach, the author also highlights the potential of targeting individual FOXO signaling pathways to combat senescence and stimulate tissue rejuventaion.

Semigenetic clearance of senescent cells delays features of aging in fast and naturally aged mice establishing senescence as their underlying cause.

Viability screens with existing compounds lead to discovery of the first generation of antisenescence compounds as quercetin/dasatinib and pan-BCL inhibitors. Further optimization is required due to suboptimal selectivity or toxicity.

Cell-penetrating peptides can steer very specific protein–protein interactions and have been successful in various clinical trials. They are a potent option for forward design of antisenescence therapies.

Senescent cells can impair their environment through juxtacrine and paracrine signaling of SASP factors. This may be caused by keeping neighboring cells permanently locked in a state of dedifferentiation (Figure 3), leading to reduced tissue rejuvenation potential.

FOXOs regulate p21^Cip1, a prominent factor in senescence growth arrest, and they inhibit the stemness regulator β-catenin. As such, they could be ideal therapeutic targets to counter senescence, while promoting tissue rejuvenation.