Elixir of Immortality

Is it possible to prolong our life and reverse aging?

by Emily Ng

Does the elixir of immortality exist in the world? Is it a potion concocted by mercury and sulphur? Or the water from the fountain of life? For centuries, people have been seeking ways to prolong their lives — from spiritual rituals to making potions from different combinations of ingredients. Witches in the western culture were believed to harness their magical power to make the mythical potion whereas in ancient China, alchemists spent day and night to concoct the elixir of immortality using cinnabar, gold, mercury, and sulphur (Winterhalter, 2018). Ironically, many of the elixir seekers died after drinking the mythical potion when elixirs were meant to extend their lifespan and grant them eternal life. They did not realise they had made a deadly poison that shortened people’s lifespan and made them age faster due to harmful chemicals present in the potion. As technology advanced, people started to look for scientific methods to prolong our lives by understanding how and why we age. This led to the emergence of modern innovations such as epigenetic engineering to stop us from aging rather than hunting for the elixir blindly.

to dysregulation of our body maintenance, repair and defence system (b) Error theory hypothesises that random cellular changes mean our body loses the ability to repair DNA damage and the accumulation of cross-linked proteins destroy cells and slow down biological functions (c) Genetic theory proposes our lifespan is determined by the genes inherited from our parents as telomeres located at the end of chromosomes determine the lifespan of a cell (Healthline, 2021). These DNA shorten as we grow up, and eventually the cell ceases to divide without losing the important parts of the DNA. There are also other theories proposed such as programmed senescence theory which involves the cell cycle and stem cell theory that suggests body stem cells lose their cell differentiation ability to replace old and damaged cells. It has always been believed that aging is caused by a combination of biological and environmental factors but until recently, a leading scientist and professor in the genetics field from Harvard Medical School, Dr David. A. Sinclair, stated that aging is a treatable disease that can be cured by epigenetic engineering, so reverse aging may no longer be a dream (Deac, 2022).

Epigenetic engineering and regenerative medicine

Understanding how and why we age

Aging is an inevitable part of human life due to declining of the normal functioning of our cells over time. We experience two types of aging — intrinsic and extrinsic aging. Intrinsic aging refers to ‘a genetically predetermined process that naturally occurs’ (Healthline, 2021) which is determined by an individual’s genetic clock that varies from one another. On the other hand, extrinsic aging refers to environmental stressors (surroundings and lifestyle) such as air pollution, radiation, stress level, smoking and malnutrition affecting cellular functions that cause aging. There are lots of prominent theories to explain the biological factors that lead to aging: (a) Programmed theory suggests everyone has a predetermined lifespan as specific genes are turned on and off over time that may lead

Epigenetic engineering is a type of genetic engineering that manipulates and modifies the epigenome (the operating system of a cell which consists of chemical compounds that modify or mark the genome to instruct gene expression) without causing any permanent changes in the DNA sequence (Genome.gov, 2019). Dr Sinclair analogised human body as the hardware and epigenome as the software: if the software breaks down, we can simply reboot the whole system (hardware) using a backup copy of the software that contains all the original information so that the cell can function normally again with a restored ability to read instructions correctly (LaMotte, 2023). To illustrate the existence of the rejuvenation switch, Dr Sinclair and his team used ICE (inducible changes to the epigenome) to mimic the natural process of epigenetic modification experienced in everyday life such as exposure to sunlight and chemical substances (The Scientist Magazine, n.d.). ICE involves introducing temporary breaks in DNA non-coding regions to alter the way DNA folds without altering DNA coding regions that may trigger mutation. Initially, epigenetic factors (proteins that help regulate gene expression) moved to the breaks to repair DNA and returned to their original positions afterwards.Yet, after some time, the factors became distracted and did not find their way back to their original positions, ending up with the epigenome becoming jumbled up and led to cellular malfunction as the genes could not be expressed accurately anymore. As the team compared ICE mice and controlled mice after 6 months, it was found that ICE mice had much more biomarkers that indicate aging and appear to be older in phenotype such as grey hair and muscle weakness which resembled old wild mice that made them look and act old. Many methyl groups were lost across the genome in ICE mice, indicating their biological age was older than the controlled mice of the same chronological age. Then, the team tried to reverse aging in mice by gene therapy — insertion of three (Oct4, Sox2, and Klf4) of the four Yamanaka factors (a group of transcription factors capable of turning adult cells back to induced pluripotent stem cells) (Yamanaka factors, n.d.) into ICE mice to activate the genes responsible for the development of embryonic stem cells to rewind mature, old cells back to their earlier youthful stage. As a result, the ICE mice’s tissues and organs became young and healthy again (about 50-75% of the original age).

Implications of epigenetic engineering

Dr Sinclair’s study supports the idea that epigenome plays an important role in aging and that epigenetic engineering is a possible way to reverse aging. It works by installing an epigenetic program in the body to reboot the corrupted system that can stimulate body cells to restore all the information lost in order to return to their youthful state. It also employs regenerative medicine which utilises Yamanaka genes to create induced stem cells which can be de-differentiated into young pluripotent stem cells and differentiate into specific cells again. Despite the success in lab mice, will it be the same when applying epigenetic technology to humans? There are also other issues regarding epigenome engineering: how long can the reprogrammed cells sustain at the young age? Can the body epigenetic system be rebooted again and again without any side effects? Further experiments are required to answer these questions to support epigenetic treatment application on humans.

Anti-aging drug

A pill that can extend our lifespan? It may sound absurd as it only exists in fairy tale or myth, but recent studies suggest it may actually exist — Rapamycin, an immunosuppressant and cell growth inhibitor used in cancer therapy and organ transplantation. Dr Paula Juricic, who works at the Max Planck Institute for Biology of Aging, conducted a study to find out the anti-aging property of rapamycin by testing on fruit flies and mice (www.medicalnewstoday.com, 2022). The drug was given to fruit flies for two weeks that appeared to protect them from age-related pathogens in the intestine that helped extend their lifespan. A group of three-month-old mice were also given the drug treatment for three months and they experienced similar benefits of increased pathogenic resistance in the intestine, especially when they reached middle age. To investigate the optimum dosage and period of time the drug should be prescribed, scientists tested the effect of small doses of rapamycin on a group of twentymonth-old mice (equivalent to sixty-year-old humans) for three months.

Interestingly, the mice lived on average for an extra two months and some even lived up to nearly four years more (equivalent to 140-year-old humans) rather than dying at about thirty months old. Scientists then searched for the operating system of rapamycin and came up with two possible explanations — autophagy and improving DNA storage. Rapamycin can trigger autophagy, which is a recycling system of the cell that breaks down dysfunctional and misbehaving organelles and proteins to save energy in order to keep the cell alive and assemble new cellular components (www.lifespan.io, n.d.). The research also shows that rapamycin can increase the number of histone proteins wrapped around DNA in gut cells, leading to less exposure of DNA to outside environment. This reduces the number of genes contributed to aging to be expressed and thus increases lifespan. The reverse of age-related loss can also be done by inhibiting mTOR pathway (a regulator of anabolic metabolism) by rapamycin as lower activity of mTOR can lengthen lifespan based on the test results on mice, yeast and flies (www.lifespan.io, n.d.).