By Lukasz Jaros

Over the past century, the average human lifespan has increased from 45 years to almost 80 years. In large part, this is the direct result of the invention of vaccines, antivirals, and antibiotics.1 The threat of outside agents to health has decreased significantly. Now, scientists have turned to the human body to tackle the remaining barriers to extending human life. As it turns out, the very essence of life, DNA, can also facilitate illness and death, as damage to DNA can occur as an individual ages. The new treatment that is being developed to address this issue is gene therapy. However, to prove its worth, gene therapy cannot simply treat against the progress of degradation in the human body; it must also reverse it. If humans attain immortality, the inevitable questions becomes, “Should we live forever?”

To understand how scientists are undertaking the monumental task of extending life, one must first understand the mechanism of aging and death. Dr. Valter Longo and his team at the University of South California are making steady progress in this direction. In 1996, Dr. Longo described how, much like the combustion reaction damages the engine of a car over time, mitochondria (which supply every cell in our body with energy) wear down due to the energy-releasing reactions occurring within them.2 These chemical processes can cause similar damage to DNA, whether inside the mitochondria or elsewhere in the cell. This corruption of cellular structures represents the main cause of bodily decay and aging. Throughout the past decade, Dr. Longo and his team have isolated 2 genes (RAS2 and SCH9) and two genetic pathways (IGF-1 and PKA) responsible for aging.3 By excising these genes and restricting caloric intake, they have increased the lifespan of yeast tenfold and doubled the lifespan of mice.4

In 2008, Dr. Longo explained in The Journal of Cell Biology how “the deletion of SCH9 [and RAS2]…protects against age-dependent defects…by inhibiting error-prone recombination and preventing DNA damage and dedifferentiation, [which is a specialized cell’s regression to a more embryonic, unspecialized form].”3 In effect, the deletion reduced the risk of harmful DNA mutations by keeping the cell in the G0 phase, a specialized, non-dividing, resting state that resists environmental stresses and reduces risk of cancer. Meanwhile, the low calorie diet enhanced the effect by favoring these non-dividing cells and acting on the natural inhibitory pathways that prevent cellular division under unfavorable conditions. Finally, the absence of IGF-1 and PKA pathways repress metabolic activity in mitochondria, further decreasing their degradation.5

In 2011, Dr. Longo collaborated with a team of endocrinologists from Ecuador to demonstrate that human populations with deficiencies in expression of the genes IGF-1, RAS, PKA, and SCH9 displayed a delayed onset of aging in addition to a very low incidence of cancer and diabetes.6 Theoretically, scientists could significantly delay aging in humans by excising these genes. However, these deficiencies are also associated with stunted growth.6 Scientists must first develop techniques to turn the genetic expression on and off before moving on with developmental issues.

Currently, Dr. Christopher Voigt and his research team at the Massachusetts Institute of Technology are attempting to solve this very issue. In 2005, the team developed techniques to bestow bacteria with new abilities to sense their environment.7 As proof of their concept, they inserted genes into E. coli (which normally live in the light-deficient environment of the large intestine) in order to allow the bacterium to react to light stimulus. This experiment demonstrated the ability to genetically engineer a desired genetic response to a designated stimulus.

In the past five years, the team has further expanded this genetic control to operate in more complex functions.8  By placing different promoters (regions of DNA that initiate transcription of specific genes) and repressors (DNA-binding proteins that prevent transcription of a particular gene) on select sites in the bacterial DNA and then spatially arranging them in a particular fashion, Dr. Voigt’s team programmed the bacteria to give certain outputs in the presence of a series of specific environmental triggers.  Consequently, these extensively modified bacteria could sense and react to changes in light, temperature, acidity, and the concentration of specific compounds in a carefully designed manner.2 In fact, Dr. Voigt’s team has already modified E. coli to invade cancer cells (in vitro) and release cytotoxic chemicals while leaving normal-functioning cells alone.9 This success suggests that programmed bacteria may be used in the future to deliver anything from cancer treatments to genetic modifiers. The diversity of treatments that could be delivered in this manner provides an important advantage in extending the human lifespan.  Nonetheless, further research on the effectiveness and potential side effects is still required before programmable bacterium can be utilized as a vector in human patients.

Dr. Aubrey de Grey, a theorist and geneticist, has proposed an additional approach to the problem of aging. He alleges that the accumulation of compounds in the body that cannot be broken down by enzymatic activity can generate the aging effect.10 This “junk” exists both within the cell and in the extracellular matrix. Several other conditions associated with aging, such as macular degeneration, atherosclerosis, and Alzheimer’s, arise from a buildup of harmful proteins in or near cells, compromising their structural integrity and proper function.11

Dr. de Grey’s pursuit of a treatment has led his team to the most unlikely of places: the graveyard. As it turns out, the solution to aging may be found in the processes occurring postmortem.2 After an individual dies, insects, bacteria, and other decomposers break down cells and tissue, including the compounds that the body was incapable of digesting. If scientists can discover exactly which enzymes and genes are employed in the digestion of those compounds, then perhaps they can formulate the rejuvenating medicine that Dr. de Grey envisions.2

While the hunt for specific compounds and genes continues, the mere prospect of viable rejuvenation has excited many scientists. While other treatments must be utilized while a patient is relatively young, an injection of Dr. de Grey’s microbial enzymes could remove the harmful clutter and permit the body to repair damage independent of age.2 Consequently, the aging process could be halted, allowing humans to remain 25 years old forever.

Despite these promising projects, gene therapy must overcome several obstacles before it can become a viable anti-aging treatment. Current delivery systems consist of other viruses or bacteria.12 However, these often incite an immune response that destroys them and the designed genes that they carry. Thus, even if the initial dose achieves a certain degree of success, the triggered immune response could diminish the effectiveness of subsequent treatment.12 This presents a major predicament because current gene therapies are short-lived and require multiple applications to affect the scores of cells in the body.12 The only other options, injecting either naked DNA or DNA protected by a protein complex, are even more likely to trigger an immune response, as the body has evolved highly specialized defenses to destroy foreign genetic material.12

Even if scientists do overcome these setbacks, another hurdle lies within the cell. Gene therapy is ideal when only one gene is involved. However, inserting multiple genes simultaneously can have serious consequences. For example, the probability of inserting a promoter or repressor into the wrong section of DNA and inducing the formation of tumors increases when more genes are involved.12  Unfortunately, the anti-aging medicines devised by scientists such as Dr. Voigt and Dr. Longo do involve several genes and genetic pathways. Nonetheless, medicines that will help us achieve immortality are still in the early stages, and it is possible that multiple research teams are working on gene therapy projects will aid in resolving its problems.

If immortality crosses over into the realm of reality, humans will have to answer the question, “Should people live forever?” After all, many areas around the world already struggle with overpopulation and the problems with pollution that accompany it. Consequently, immortality may necessitate laws barring conception in an effort to curb a rising population. Also, the technology may be expensive at first, further dividing society according to wealth and promoting inequality.

Perhaps the biggest obstacle standing in the way of gene therapies becoming commonplace in the medical market is that they can be viewed as incursions against the philosophy of human life. The ethical dilemmas surrounding the introduction of anti-aging technologies are largely centered upon the potential progression towards achieving immortality in humans.  Human societies operate under the belief that life has value because it is finite. People are motivated to work hard to fulfill both personal and professional goals before their time runs out. Relationships matter more as people know that time with one another is relatively limited. However, immortality could radically alter such a belief system. As extended families could come to include many more generations, the traditional family structure might be threatened by a lifespan extension. The job market could be drastically changed by a much higher retirement age, which would inevitably require governments to restructure their methods for allocating limited resources. The possible outcomes are endless and largely unpredictable.

All of these ethical and social issues present a substantial barrier to introducing immortality drugs. However, the issue of whether or not immortality therapies should ever be utilized will not be so easily decided. After all, the human instinct causes us to desire prolonged life and the prospect of conquering death seems irresistible. If these therapies are indeed introduced to the general public, their implications for humanity will be unprecedented. ■ MD

References

1. Sonnega, A. (2006). The Future of Human Life Expectancy. Retrieved from Population Reference Bureau website: http://www.prb.org/pdf06/NIA_FutureofLifeExpectancy.pdf

2. Through the Wormhole: Can We Live Forever? : Videos : Science Channel [Video file]. (2011, July 27). Retrieved from http://www.sciencechannel.com/tv-shows/through-the-wormhole/videos/can-we-live-forever.html

3. Madia, F., Gattazzo, C., Wei, M., Fabrizio, P., Burhans, W. C., Weinberger, M., . . . Longo, V. D. (2008). Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. Journal of Cell Biology, 180(1), 67-81. doi:10.1083/jcb.200707154

4. Kaczor, T., & Longo, V. (2012, April 3). Caloric Restriction and Fasting in Disease Prevention and Treatment – Natural Medicine Journal: The Official Journal of the American Association of Naturopathic Physicians. Retrieved March 14, 2013, from http://www.naturalmedicinejournal.com/article_content.asp?article=312

5. Yorimitsu, T., Zaman, S., Broach, J. R., & Klionsky, D. J. (2007). Protein Kinase A and Sch9 Cooperatively Regulate Induction of Autophagy in Saccharomyces cerevisiae. Molecular Biology of The Cell, 18(10), 4180-4189. doi:10.1091/mbc.E07-05-0485

6. Taubes, G. (2013, March 27). Rare Form of Dwarfism May Protect Against Diabetes Cancer. Discover. Retrieved from http://http://discovermagazine.com/2013/april/19-double-edged-genes#.Ux4NM1xS_nY

7. Anderson, J. C., Clarke, E. J., Arkin, A. P., & Voigt, C. A. (2006). Environmentally Controlled Invasion of Cancer Cells by Engineered Bacteria. Journal of Molecular Biology, 355(4), 619-627. doi:10.1016/j.jmb.2005.10.076

8. Tamsir, A., Tabor, J. J., & Voigt, C. A. (2011). Robust multicellular computing using genetically encoded NOR gates and chemical `wires’. Nature, 469(7329), 212-215. doi:10.1038/nature09565

9. Voigt, C. A., & Clancy, K. (2010). Programming cells: towards an automated ‘Genetic Compiler’. Current Opinion in Biotechnology, 21(4), 572-581. doi: 10.1016/j.copbio.2010.07.005

10. Nuland, S. (2005, February 1). Do You Want to Live Forever? | MIT Technology Review. Retrieved March 14, 2013, from http://www.technologyreview.com/featuredstory/403654/do-you-want-to-live-forever/

11. SENS Research Foundation (2013). Aging as We’ve Known It | SENS Research Foundation. Retrieved March 14, 2013, from http://sens.org/research/aging-as-weve-known-it

12. University of Utah Health Sciences (n.d.). Challenges in Gene Therapy? Retrieved March 10, 2013, from http://learn.genetics.utah.edu/content/genetherapy/gtchallenges/

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