By: Eric Sun
Aging. To some, this word symbolizes equality, wisdom, and progress; to others, this word represents weakness, disease, and death. To me, aging has taken on a mixed meaning. When I was a small child, I remember lying awake in bed and counting my heartbeats as if the thumping in my chest was also the ticking of my biological clock. I imagined that each person was given a certain number of heartbeats in a lifetime. Aging, to my young mind, was simply the slow and eventual countdown of these limited heartbeats. Although not many people will admit it, the fear of aging and death is extremely common (1). Throughout history, our fascination with mortality has contributed to the rise and spread of religions and legends. Since then, scientific research has begun to shed light on one of life’s greatest mysteries.
Aging Research in History
During the late Middle Ages, alchemy was a booming practice. The holy grail of alchemy was procurement of the fabled philosopher’s stone—a stone that had the ability to extend the life of its wielder indefinitely (1). Despite numerous efforts, there are no records of any successful attempts at synthesizing the object. The philosopher’s stone was not the only fabled anti-aging object. After the discovery of the Americas, there was growing interest in the possibility of uncovering the fountain of youth in this uncharted territory. In 1513, the conquistador Juan Ponce de León set out on a quest to find the fabled fountain, which ultimately ended in failure (1).
In the following decades, the interest in anti-aging ‘research’ faded along with its associated myths. In fact, aging research was under the public radar from the Renaissance until the 1940s when James Birren produced a theory involving what he called the “tertiary, secondary, and primary processes of aging” (1). Birren developed the field of gerontology, which is the study of aging, and expanded it firstly socially and secondly scientifically. At this time, aging research was widely considered a pseudoscience—a label that was not helped by the unscientific blood and serum transfusions championed by charlatans as anti-aging treatments. Ironically, a recent study reported that old mice that received plasma transfusions from younger mice were physiologically healthier, although this has yet to be validated in humans and although it was quite clear that these results were unknown in the early 1900s (2). Under Birren’s lead, the scientific stigma surrounding aging began to dissipate as more scientists were attracted to this young and growing field of research.
Notable Advances
In the following years, aging research underwent a series of profound, exciting breakthroughs. Perhaps the most famous discovery was that of the telomere. Telomeres are the repeating DNA sequences at the end of each of the chromosomes. Through the DNA replication mechanism, the telomeres deteriorate after each cycle of replication and the chromosomes become shorter. Although telomeres themselves do not appear to have any significant function outside of protecting other DNA sequences from degradation, when a cell exhausts its telomeres, each successive division results in deterioration of essential genes and deleterious effects that often result in cellular death (3).
The first indication of telomeres came in 1962 through Leonard Hayflick’s discovery of the limit on somatic cell replication. Hayflick, considered by many to be the father of modern aging research, carried out a groundbreaking experiment that indicated that somatic cells could only divide a finite number of times (1). At the time, it was widely accepted that cell lineages were immortal and that each body cell was capable of an indefinite number of divisions. It was only until several other scientists replicated Hayflick’s result that the socalled Hayflick limit became largely accepted by the scientific community. This limit to cellular division was typically 50-54 divisions for human somatic cells (1). In the 1970s, Jack Szostak discovered the existence of telomeres at the end of chromosomes, which explained the Hayflick limit phenomenon (3). If cell replication was restricted by the length of the telomere, and the telomere was of a finite length, then surely cell lineages are finite. Szostak garnered a Nobel Prize for his work. Soon after the discovery of telomeres, the enzyme that extends telomeres on chromosomes, telomerase, was discovered. In recent years, overexpression of telomerase has been linked to the vicious proliferation and immortality of cancer cells (3). Telomeres serve as the switch for immortality—at least on a cellular level.
An often overlooked, but perhaps even greater breakthrough was the development of several notable theories of aging. Imagine an organism as a car. Cars, no matter how well kept or maintained, begin to lose function with time. At first, there may be a few scratches to the windshield, buildup in the exhaust pipe, and worn-out tires. These are minor issues that can be amended relatively easily. Then, the engine starts to malfunction, the wires begin to rust, and the car becomes unsalvageable. Like a car, the organism has many parts that are being used daily. Similarly, an organism can break down through continuous wear and tear. This seemingly obvious idea has been revolutionary in the field of aging research. Contrary to other theories that proposed that humans were genetically programmed to age, the cumulative damage theory presented aging as a random process (1). As such, it may be reasonable to conclude that aging is the byproduct of environmental effects. Surely, this would mean that after centuries of medical advancement, which included vaccines, antibiotics, and surgery among its ranks, humans have been able to increase their life spans considerably. Yet, despite significant increases in life expectancy, meaning more humans are realizing the full extent of their maximum lifespans, the actual human lifespan has stayed relatively the same (3). A more recent theory proposed that the maximum lifespan is determined genetically and that environmental factors can only contribute to expedited biological aging. Given the saturation of human population survival curves, this theory is especially convincing (3).
As a corollary to the cumulative damage theory of aging, aging is regarded as a holistic process—a process that is affected by a multitude of genes and environmental factors. One suspected contributor to the aging process is free radical damage.1 Free radicals are molecules that harbor a single, unpaired valence electron and induce oxidative damage in cellular machinery. Free radicals are byproducts of cellular respiration and can damage DNA. In particular, mtDNA (mitochondrial DNA) is at risk of oxidative damage due to both its proximity to free radical formation, as cellular respiration occurs in mitochondria, and significantly lower levels of DNA repair. The free radical theory of aging has become especially popular in the health industry where antioxidants, compounds that neutralize free radicals, have become synonymous with anti-aging treatments.3 The effectiveness of antioxidant consumption in retarding aging has not been validated. Other notable candidates for contributing to aging include protein aggregation, cross linkage, and induced apoptosis (1).
In order to discern other contributing factors, several longitudinal studies on aging have been implemented. Longitudinal studies offer one major advantage over the cross-sectional studies traditionally employed in medical research in that they allow scientists to track an individual’s health as they grow older. The Baltimore Longitudinal Study of Aging (BLSA) is the most prominent of these studies and was started in 1958 by Nathan Shock, a pioneer in the field of aging research, along with over 1,000 participants (4). Since then, several other studies have taken root including The SardiNIA Project executed by the National Institute on Aging that includes 6,100 participants from the island of Sardinia off the coast of Italy (3). Armed with the powerful tools of bioinformatics, these studies have become potential windows from which to understand the intricacies of human aging.
Aging Research Today
Aging research has gained steady momentum in recent years. In fact, one of the most famous aging experiments was conducted in 1993 by Cynthia Kenyon, a professor at UCSF and now vice president at Calico. Kenyon discovered that mutations in the daf-2 and daf- 16 genes doubled the lifespan of C. elegans, a model organism. Her future work saw increasingly lengthened lifespans from modulating these two gene (5). The search for homologous counterparts in humans is ongoing. A recent subset of aging research has focused on life extension treatments in more complex model organisms such as D. melanogaster, lab mice, and Rhesus monkeys (1).
Recently, other molecular mechanisms have been implicated with aging. These include reservatrol, sirtuins, and rapamycin. Reservatrol, a compound commonly found in red wines, activates sirtuin deacetylases, which extend the lifespan of lower organisms and may also be involved in human aging (6). Reservatrol has also been related to cardioprotective benefits. Discovery of these mechanisms and possible relations to aging have been led by pioneers such as David Sinclair of Harvard Medical School. Treatments involving rapamycin, an immunosuppressant, have increased the longevity of mice (7). The search for contributing molecular factors of aging is an active and promising facet of aging research.
In the past decade, the advent of computational tools for large-scale data analysis has revealed fascinating insights into aging. Computational biology and bioinformatics have expedited the search for biomarkers of aging. Traditionally, pulse wave velocity and telomere length served as the gold standards of biological age measurement, but only explained a fraction of individual variance in aging (3). Recent research has implicated a litany of cardiovascular traits, physical and mental characteristics, and genetic mutations as potential biomarkers. In 2014, Steve Horvath, a professor at UCLA, developed a method for deriving an estimate of biological age (DNAm) from DNA methylation patterns, which was highly correlated with chronological age and seemed to explain several tendencies in both aging and disease (8). There is ongoing research in detection of a central aging signal that explains most physiological causes of aging.
Aging research has garnered considerable public spotlight in the past several years. Aubrey de Grey, a computer scientist turned biologist and founder of the SENS foundation, gave an extremely well-received TED talk on a strategy that he has proposed to tackle the obstacle of aging. The strategy involves partitioning the aging process into several major factors: aggregates, cellular senescence and growth, cross linkage, and mutations. By targeting medical advancements in each field separately, the problem becomes more manageable and the human lifespan could potentially be elongated in small increments over a long period of breakthroughs (9). Other social movements such as transhumanism have highlighted the potential of anti-aging treatments in the near future. Transhumanism embraces emerging technologies and their potential in bettering the human body or quality of life—including extension of the healthy lifespan (9).
Controversies
Since the age of alchemy, aging research has been a field brewing with controversy. Today, there are two major concerns with developments in aging research and rejuvenation technology. First, critics of anti-aging research are concerned with the very real possibility of overpopulation. The current age distribution of ages in the United States is a micro-example of what an ageless population might entail. There are already concerns that the aging Baby Boomers generation may overburden the healthcare and Social Security systems. Imagine this same effect but with continuous, cumulative addition to the old end of the age spectrum. Critics espousing this belief, however, do not take into consideration what current aging research implies about future anti-aging therapies. Nearly all current testing in model organisms has indicated that anti-aging treatments tend to promote extended, healthy aging. That is, the relative age of individuals would simply be stretched across a longer temporal span. Individuals under treatment who are chronologically 70 years old may instead be 50 years old biologically. As such, fears of skewing towards an elderly population are largely unfounded in a relative world. Additionally, longer healthy life spans would entail greater productivity from an individual over their lifetime (9).
Other opponents of aging research cite religious and ethical concerns (10). After all, if we are extending our lifespans beyond their natural limit, are we not playing God? There is no simple solution to address these concerns. There will always be advocates and critics of aging research and scientists should be attentive to these ethical concerns as they continue to pursue this line of research. In the end, if an anti-aging treatment is procured, it is only an additional opportunity that has been extended and would be by no means obligatory.
The Path Ahead
Aging research is an exciting and growing field. Developments in our understanding of the fundamental aging process are likely to proffer increased insight in related research areas such as cancer, diabetes, and Alzheimer’s research. Aging is still a relatively underpopulated field of research and looks to benefit from the recent explosion of biotechnology and big data-aided research (11). In the coming decades, one can expect to see greater innovation and progress in aging research. Perhaps one day, even the fabled philosopher’s stone or fountain of youth may manifest as a product of this push for greater understanding.
Eric Sun ‘20 is a freshman in Hollis Hall.
WORKS CITED
[1] Hayflick, L. How and Why We Age; Ballantine Books: New York, 1996.
[2] Scudellari, M. Nature 2015, 517, 426-429.
[3] Austad, S. Why We Age, 1st ed.; Wiley: Hoboken, NJ, 1999.
[4] Shock, N. et al. Normal Human Aging: The Baltimore Longitudinal Study of Aging; NIH-84-2450; NIH: Washington, D.C., 1984.
[5] Kenyon, C., et al. Nature 1993, 366, 461- 464.
[6] Baur, J. A.; Sinclair, D. A. Nat. Rev. Drug Discov. 2006, 5, 493-506.
[7] Wilkinson, J.E., et al. Aging Cell 2012, 4, 675-682.
[8] Horvath, S. Genome Biology 2013, 14, R115.
[9] de Grey, A.; Rae, M. Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging, 1st ed.; St. Martin’s Press: New York, 2007.
[10] Green, B. Radical Life Extension: An Ethical Analysis. Santa Clara University [Online], February 27, 2017. http://www.scu.edu/ethics/all-about-ethics/radical-life-extension/ (accessed Mar. 26, 2017).
[11] Arking, R. Biology of Aging: Observations and Principles, 2nd ed.; Oxford University Press: Oxford, U.K., 2006.