The Zombie Mechanics of Human Aging

SQ SPRING INSIDER 2020

COVER ILLUSTRATION BY YICHEN WANG

the zombie mechanics of human aging

written by anjali iyangar

illustrated by fatimah khan

Zombies: frightening creatures that are both living and dead. They wreak havoc in society and give rise to more zombies by transmitting the so-called “zombie virus.” Cell biology has allowed us to find the real-life counterparts of these horrific science fiction characters: senescent cells. These are frightening cells that deviate from the behavior of healthy cells, yet they are not disposed of by the body. They wreak havoc by discontinuing their assigned duties (such as growing, dividing, and manufacturing proteins properly) and by emitting toxic chemicals that turn surrounding healthy cells into senescent cells. The accumulation of senescent cells impedes tissue functionality, which results in many characteristics associated with aging.

Dr. Dorota Skowronska-Krawczyk, an assistant professor of ophthalmology at UC San Diego, studies the components of aging in various eye diseases. One of her lab’s recent publications, “Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension” in Aging Cell, is one of the first in its field to showcase neuronal cell senescence. The paper offers insights into the role of senescent cells in agerelated diseases of the eye, such as glaucoma. Dr. Skowronska-Krawczyk was recently awarded the Shaffer Prize by the Glaucoma Research Foundation for this research.

“Let’s say you have three cells, and the one in the middle responds to stress by becoming senescent,” Dr. Skowronska-Krawczyk explains. “The other two cells might have been very healthy... but because this middle cell is now sending them signals, the other two cells either become sick, senescent, or die.” According to Dr. Skowronska-Krawczyk, healthy cells become senescent in response to stress factors, such as pressure inside the eye in the case of glaucoma. These newly-senescent cells actively produce and secrete factors that inform local tissue or cells about the stressor. Just as zombies can pass on a virus to create more zombies, senescent cells are able to convert healthy cells into senescent cells through the factors they release.

Therefore, removing senescent cells from the system in early stages of their propagation may be a solution for saving local cells from cell death and senescence. In fact, this is one of the hypotheses Dr. Skowronska-Krawczyk and lab members tested in the model of a rat eye. The specific type of cells they focused on were retinal ganglion cells (RGCs), which are neurons that are crucial to the perception of visual stimuli. When RGCs have already been exposed to ocular pressure and turned senescent, would the early removal of senescent cells reduce overall RGC loss?

To study this, Dr. Skowronska-Krawczyk’s lab used senolytic drugs to target and remove senescent cells. Senolytic drugs sensitize senescent cells to apoptotic factors, leading to increased programmed cell death of senescent cells. Results showed that senolytics effectively removed senescent cells in the eyes of mice and that removing these cells may contribute to the treatment of age-related diseases. In this case, these signals would kill the zombie cells once and for all.

If removing senescent cells can contribute to the treatment for age-related diseases, can senolytics possibly be used to reverse aging on a broader scale? This depends on how we define aging. From a biological perspective, Dr. Skowronska-Krawczyk explains, “Aging is the ongoing process through which a tissue or organ becomes less effective in performing its functions due to accumulation of chronic damage caused by exposure to either environmental or internal processes.” This process of biological aging cannot be reversed by senolytic drugs alone.

Although senolytics can kill some senescent cells, not all cell types can regenerate to replace the lost cells. A lack of cellular regeneration will cause the tissue to have a net loss in function. Neurons, for example, do not regenerate. Unless the cells that have been removed are unnecessary (in their healthy state) for the proper function of the tissue, Dr. Skowronska-Krawczyk believes that reversing biological aging through senolytic drugs alone is very unlikely. For example, if every single living member of Planet Z is a zombie, removing all the zombies would not necessarily increase the productivity and wellbeing of the planet. In order to have a positive impact on the zombie-ridden community, two things must happen: zombies must be removed, and healthy life must be introduced into Planet Z. Similarly, senolytic drugs would have to be supplemented with a therapy that replaces the removed cells with healthy cells in order to have any significant positive impact on the aging process.

Although some aspects of biological aging can be addressed through senolytic drugs, we are far from using these drugs to reverse the process itself, considering how aging is far more than just a biological process. The process of aging is also detrimentally affected by many sociological factors, such as low household income and unequal access to healthcare, which cannot be fixed by drug-induced apoptosis of senescent cells.

Although zombies are partially alive, replacing the slow-walking, brain-eating, dying flesh from a society with live beings would be beneficial for the well-being of the whole community. Similarly, the death of senescent cells could ensure that healthy tissue is left alive—scientists are increasingly realizing that in order for tissues to thrive, some cells must die.

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