Spring Insider 2020: Understanding Aging

CONTENTS Zombie Mechanics pg 2

Saltman Quarterly

Longer and Healthier Life pg 3

High School Essay Contest pg 4

Volume 13 | Spring 2020

understanding

AGING

COVER ILLUSTRATION BY YICHEN WANG

SQ INSIDER

ombies: frightening creatures that are both living and dead. They wreak havoc in society and give rise to more zombies by transmitting the socalled “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

the zombie mechanics of human

written by anjali iyangar illustrated by fatimah khan 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

Editor-in-Chief: Emma Huie Executive Editor: Arya Natarajan Editor-at-Large: Sharada Saraf Head Production Editor: Zarina Gallardo UTS Production Editor: Julia Cheng Production Team: Nicole Adamson, Anvitha Soordelu, Tania Gallardo, Khulan Hoshartsaga

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.

Online Editors: Shreya Shriram, Daniel Lusk Research Editors: Xaver Audhya, Gayathri Kalla, Alejandro Dauguet SQ Features Editor: Nikhil Jampana UTS Features Editor: Andra Thomas Staff Writers: Anjali Iyangar, Lilit Vardanyan

Head Illustrator: Varsha Rajesh Staff Illustrators: Yichen Wang, Fatimah Khan, Phoebe Ann Tech Editors: Salma Sheriff, Lynn Nguyen, Juliana Fox, Noorhan Amani, Max Gruber, Rebecca Chen

illustrated by phoebe ahn

and

to a

A PATH LONGER HEALTHIER LIFE

written by lilit vardanyan

What if opting for a lower-calorie meal instead of calorierich food decreased your chances of disease and increased your lifespan? Although one meal may not be the gamechanger, it could be the beginning of a healthier life.

For years, scientists have been exploring the molecular processes behind aging and the human body’s overall degradation.

Dr. Clive Maine McCay, a prominent researcher in the field of aging, published a study on caloric restriction (CR) and its impact on life extension in 1935. Today, CR is theorized as a possible longevity enhancer and continues to be a discussion topic in the future of aging research.

CR, as defined by The National Institute on Aging, involves reducing daily calorie intake by 30 to 40 percent while still providing the nutrients needed to sustain a healthy life. This eating habit does not put boundaries on when one can eat, but rather how much one should consume in a day.

Cellular carbohydrate metabolism involves the breakdown of a simple sugar–glucose–in an individual cell. Glucose breakdown begins during a process called glycolysis, which is followed by further processing in the cell’s mitochondria via the Krebs cycle and the electron transport chain (ETC). Through this cellular journey, one molecule of glucose is completely broken down into carbon dioxide and water, and in the process, generates energy for the cell through moving electrons around. Removing electrons from molecules is known as an oxidative process, and this is the primary form of electron-shuffling that occurs throughout glucose breakdown. Dr. McCay states that CR may combat the pitfalls of this oxidative activity during metabolism, ultimately promoting longevity in the cells and the organism itself.

While metabolism is necessary to sustain life, certain parts of this energy production can hurt the cells. In particular, the ETC segment of the glucose-breakdown process can lead to some dangerous byproducts. In his paper “What is Oxidative Stress?,” Dr. John Betteridge describes oxidative stress as a process that occurs when byproducts such as reactive oxygen species (ROS) accumulate in the cell. These molecules can easily react with

important cellular structures, such as cell membranes, proteins, and DNA. Considering this, one established theory proposes that CR improves cell lifespan by decreasing the need for ROSproducing metabolism and lessening cell damage.

Applied physiologist Dr. John O. Holloszy, M.D. and physician scientist Dr. Luigi Fontana, M.D. significantly contributed to the field of aging studies through the paper “Caloric restrictions in humans.” Primary aging is the gradual deterioration of the body due to the accumulation of damaging biochemical products, whereas secondary aging is caused by disease and illness. According to Holloszy and Fontana, CR restriction in mice and rats has shown to slow primary aging and protect against secondary aging.

Although reducing the calorie intake of mice and rats shows results consistent with the ideas behind CR, the process must also be investigated in humans before full treatment plans are built.

CR studies have not been performed on humans yet; however, researchers have collected enough information from long-term observations to suggest that CR protects against secondary aging in humans, much like it does in mice and rats.

Throughout our busy lives, it is easy to lose track of what we eat and how it might impact us in the future. Investigating the details of metabolic processes and long-term health impacts can provide insight into what it means to live a healthier life through small, everyday changes. Swapping a high-calorie meal for a low-calorie salad is hard, but consistently making small changes can help decrease disease and increase lifespan.

This aging and CR research also highlights the need to support disadvantaged communities facing food insecurities. While a healthy and balanced diet is ideal, lower-calorie fresh foods are often not viable purchasing options for low-income people– sometimes, they are not even available in grocery stores. In crafting a path to a longer, healthier life, we must find equitable solutions.

Our understanding of human metabolism, nutrition, and healthy lifestyles is ever-growing; however, we do know that lifelong results arise from lifelong commitment.

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SQ INSIDER

SQ HIGH SCHOOL ESSAY CONTEST In the sixth annual High School Essay Contest, SQ asked high school students to write about how biological advancements may improve geriatric care. SQ hopes this experience will encourage and celebrate science communication among future scientists and inspire them to think about biology in a broader context.

2020 FIRST PLACE WINNER

ANJANA SHRIRAM CANYON CREST ACADEMY

PHARMACOGENOMICS: an indispensable tool in geriatric care In 5 years, every region of the United States is expected to face a shortage of geriatric physicians, according to the Department of Health and Human Services. As the number of geriatric caregivers dwindles and the elderly population grows, improving the overall quality of care for senior patients has become of paramount importance. A pervasive but frequently overlooked cause of mortality in geriatric patients are adverse drug reactions (ADRs).

Since their discovery, clinical drugs– including antibiotics, antivirals, and antiinflammatory agents–have become modern medicine’s most widespread and effective defense against disease, and they play an “in-dispenseable” role in the field of geriatrics. Nearly all chronic conditions are now treated or managed through the use of such drugs. However, the benefits of these medications are often hindered by the potentially lethal complications that can follow.

While ADRs affect people of all ages, geriatric patients are particularly vulnerable because they typically take several medications simultaneously, a practice known as polypharmacy. ADRs can, however, be averted by developing drugs that account for factors such as genetic predisposition, comorbid

illnesses, and medical history. According to the U.S. National Library of Medicine, the emerging field of pharmacogenomics aims to combat the increasing prevalence of ADRs in the elderly by combining “pharmacology and genomics to develop…safe medications that will be tailored to a person’s genetic makeup.”

The current method of prescribing medication is described as a “one-size-fits-all” approach, in which everyone suffering from a condition receives identical treatments. The non-specific nature of today’s drug therapy ignores the genetic, biological, and pathological diversity of communities; blindly administering the same drug to individuals with vastly different needs and genetic makeups can have disastrous implications for the health and safety of patients.

According to Amanda Hanora Lavan and Paul Gallagher’s paper “Predicting risk of adverse drug reactions in older adults,” the abundance of medical drug use and polypharmacy in geriatric patients also explains why “twice as many patients aged 65 and older [are]…hospitalized because of ADRs…than their younger counterparts.” Furthermore, as described in a 1998 meta-analysis, ADRs can increase geriatric mortality rates by almost 5%, and are between the fourth and sixth leading causes of death, globally.

Pharmacogenomics will drastically reduce ADR mortalities by creating drugs that cooperate with the patient’s genetic, biological, and chemical makeup. Beyond that, the budding field promises to cultivate a more comprehensive outlook on geriatric care by compensating for what our current healthcare system so desperately lacks—a focus on each patient as a unique individual with complex needs. Ultimately, this advancement will allow physicians to assess their patients from a more holistic perspective; by gauging the risks of an ADR prior to one actually occurring, geriatric mortality rates will decrease, and potent drugs can be used with more confidence.

One of the obstacles of this approach, however, is the “marked reluctance of the medical profession to treat the individual rather than the population. A treatment that is suitable for one person may not suit another,” as described by author Matt Ridley in Genome: the Autobiography of a Species in 23 Chapters.

Tailoring treatments to the needs of each patient might seem like a daunting task for both physicians and drug developers, but this innovation does not seek to create millions of new drugs; rather, the goal is to expand drug treatments to accommodate differences in the population, and by doing so, reduce ADRs. Recognizing that humans are more similar than they are different is critical to realizing the feasibility and potential of pharmacogenomics.

As with any gene-related technology, privacy and accuracy are also notable concerns.

In order for predictive genetic tests to improve patient care, steps must be taken to ensure the confidentiality and validity of results; false positives and negatives as well as data breaches continue to deter many clinicians from incorporating these tests into practice.

As biological advancements in pharmacogenomics are made, they will be paralleled and bolstered by technological advancements in genomic sequencing and screening. As genomic sequencing becomes a faster, more reliable, and affordable tool, pharmacogenomic therapy will be much more easily integrated into everyday clinical settings.

In just two decades, according to genome.gov, the cost of analyzing the entire human genome has plummeted from $100,000,000 to less than $1,000. Furthermore, improved screening techniques and predictive genetic tests will enable clinicians to rapidly and accurately identify genetic risk factors and variants, allowing them to prevent adverse drug reactions in patients.

Much remains to be discovered in this burgeoning field. As pharmacogenomics becomes more widely adopted and tested, flaws and inadequacies will inevitably arise. But one thing is for certain: Used in conjunction with advancements in clinical screening and genomic sequencing, pharmacogenomics will revolutionize medicine as we know it; for our nation’s rapidly expanding geriatric population, it can be the start of a more accessible, safe, and holistic healthcare system.

illustrated by varsha rajesh

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