Senolytics — The Anti-Aging Drugs?

Several years ago, Xu had a thought that he couldn’t shake. If senescent cells were at least partially responsible for the physical and cognitive dysfunction typically observed in aged animals, young mice should experience accelerated aging if injected with already senescent cells. Xu and colleagues eventually tested this idea by transplanting senescent preadipocytes (stem cells from adipose or fat tissue) extracted from transgenic mice into young, healthy mice. The researchers made these fat tissue cells senescent by exposing them to high levels of radiation or a chemotherapy drug after extracting the cells from their transgenic mice.

Xu and his colleagues were surprised to see that when they transplanted these senescent cells into young mice, they observed an onset of physical dysfunction including weakness and frailty. It was as if the young mice were aging before their eyes.

“This is the first time, to our knowledge, that researchers have transplanted senescent cells into young, healthy mice and observed an age-related phenotype as a result,” Xu said. “I actually developed the idea for this experiment several years ago. We’ve observed for some time now that removing senescent cells from aged animals has beneficial effects. I thought, maybe we can do the opposite. By transferring senescent cells into healthy, young animals, we could confirm the causal effects of senescent cells on aging and physical dysfunction, if the young animals ended up looking more like aged animals.”

Xu’s lab specializes in investigating physical function, so they focused on this aspect of aging and senescent cell accumulation in mice. While the exact mechanisms whereby senescent cells lead to physical dysfunction are still unclear, Xu suspects that inflammation plays a big role.

“Transplanting senescent cells into young mice increases their senescent cell burden,” Xu said. “In other words, the transplanted cells induce other cells in the host to become senescent. All of these senescent cells together contribute to the physical dysfunction we see.”

“Previously healthy young adult mice transplanted with [one million] senescent cells had significantly lower maximal walking speed, hanging endurance, and grip strength by 1 month after transplantation compared to mice transplanted with control cells. […] Reduced walking speed began as early as 2 weeks following a single implantation of senescent cells and persisted for up to 6 months, yet the transplanted cells survived in vivo for only approximately 40 days, consistent with the possibility that senescent cells might induce senescence in normal host cells.” — Xu et al., 2018

A photo from Xu’s lab showing a sick mouse (treated with transplanted senescent cells, left), next to a relatively healthy mouse (treated with transplanted senescent cells as well as a senolytic drug cocktail, right).

Xu and his colleagues were able to measure how many of the host organism cells in young mice became senescent following transplantation by looking for genetic markers present only in the transgenic mice that they extracted the cells from. Being able to differentiate the senescent cells they found in their young mice by the cells’ origin, they had proof that the transplanted senescent cells created many more senescent cells in the host mice.

While inflammation may be the primary mechanism whereby transplanted senescent cells cause more host cells to become senescent, this turns out to be a difficult idea to prove. Inflammation and levels of cytokines are difficult to measure and compare between individual animals because of their innate variability. It’s best to compare levels of cytokines and inflammation across different time points but within the same individuals, for example before and after events or exposures known to promote cellular senescence.

The transplantation experiments prompted Xu and colleagues to further explore how targeted clearance of senescent cells could improve the healthspan and physical function of aged mice. But instead of targeting inflammation like many other researchers have tried to do with drugs such as rapamycin, Xu and colleagues are looking to kill the source of these Zombie-spreading signals.

Where Are You When We Need You, Immune System?

Our immune systems normally keep an eye out for mis-folded proteins, damaged and senescent cells, to clear them from our bodies before they wreak havoc. So why couldn’t Xu’s young mice simply rid their bodies of the transplanted senescent cells? Their immune systems should technically have been able to clear these “zombie” cells as soon as they were introduced.

But if the senescent cell burden becomes too great, these “zombie” cells and their inflammatory secretions can compromise a mouse’s (or a human’s) immune system, leaving it prone to an over-accumulation of senescent cells. Aged mice with weakened immune systems are less able to defend themselves against cellular senescence than healthy young mice.