By Nitara Wijayatilake
Growing old is inevitable. Although diet and lifestyle can impact a person’s longevity, the aging process must be considered on a cellular level. DNA damage, stem cell degeneration and telomere shortening are some of the main contributors to aging. Some cold-blooded animals experience aging differently through negligible senescence and are able to live for longer. However, the big question, could humans live longer through genetic manipulation?
If DNA becomes too damaged, cells may undergo apoptosis (programmed cell death) or enter a state called senescence where it does not divide. DNA is easily damaged during DNA replication, which is imperfect and often undergoes copying errors that lead to lesions, and due to reactive oxygen species (ROS) and other mutagens. Furthermore, senescent cells help aging as they are thought to secrete inflammatory cytokines inducing atherosclerosis, an age-related condition (The Scientist, 2015). The organelle mitochondria, responsible for the production of Adenosine Triphosphate is especially prone to genetic damage; dysfunctional mitochondria can lead to other cell and organ deteriorations (TED-Ed, 2016). Moreover, stem cell degeneration leads to a decrease in cell function, since the renewal ability of adult stem cells decreases with age, stunting their differential ability. The ‘stem cell theory of aging’, therefore, explains that the inability of pluripotent stem cells to continue in cell regeneration is due to aging. The possible mechanisms involved in this are related to DNA damage or are microenvironmental factors (hormonal or immunologic), epigenetic factors and mitochondrial dysfunction factors (Ahmed AS et al, 2017).
Interestingly, the pace of aging can be associated with the length of telomeres. Telomeres are structures of the end of chromosomes that protect the DNA from exonucleolytic degradation and are bound by telomere-binding proteins like shelterin. The enzyme telomerase extends telomeres, however, each time a cell divides, a small portion of telomeric DNA is lost. Once the length of the telomeres reaches a critical limit, the cell will either undergo apoptosis or senescence. Liver tissues in humans can lose 55 base pairs of DNA in telomeres per year. Lifestyle choices like smoking and obesity can affect the rate of telomere shortening which in turn, is associated with early onset of many age-related diseases. For instance, individuals with shorter leukocyte telomeres than the average length were considered to be three times more at risk of developing myocardial infarction (M.A.Shammas, 2011). A normal cell can on average, partake in 52 mitotic divisions. This is known as its ‘Hayflick limit’ which is the number of replications a cell can do before reaching senescence. After the Hayflick limit is reached, the cell stops replicating because the telomeres are too short to protect the chromosome (SciShow, 2012).
If telomere shortening can be targeted as the cause of aging, why can’t scientists use an increased amount of telomerase to lengthen telomeres and allow humans to live longer? It is far too risky. Cancer cells are able to access proliferative immortality as they activate the silent human TERT gene (hTERT) that codes for the enzyme telomerase (Jafri et al, 2016). These cancer cells are not subject to the Hayflick limit and can metastasise, causing damage to the body. This makes scientists cautious about the use of telomerases in trying to combat aging.
What’s fascinating is the concept of ‘negligible senescence’. Some cold-blooded animals like the Galapagos tortoises do not show reproductive decline over time and their mortality rates do not increase with maturity. These organisms show an incredible resilience to oxidative stress: the imbalance between the build-up of ROS and the body’s ability to detoxify these reactive radicals. Reactive oxygen species such as the hydroxyl radical can react with DNA and cause damage to the bonding of the molecule, driving the aging process. Animals that have negligible senescence are able to produce less reactive oxygen species and, thus, slow down aging. So how can oxidative stress be reduced? Calorie restriction has been shown to slow aging and tortoises, for instance, have a slower metabolism so need fewer calories (SciShow, 2018). According to some theories, tortoises are able to live for longer because they burn less energy and this reduces harm caused to the body because ribosomes (which synthesise proteins) can slow down and take more time to repair themselves (ScienceDaily,2017). Furthermore, tortoises can live for so long because they produce more telomerase, which means their telomeres do not shorten as quickly as in humans. An Aldabrachelys gigantea hololissa, Seychelles giant tortoise called Johnathan which hatched in 1832, is the oldest known living terrestrial animal in the world (Wikipedia, 2020).
The topic of growing old and potentially, finding a cure to old age is one of major scientific and public interest. Although changes to a person’s diet and lifestyle can prolong life, whether a safe and reasonable way to genetically modify DNA is possible, is yet to be discovered.
References:
Shammas, Masood A. “Telomeres, lifestyle, cancer, and aging.” Current opinion in clinical nutrition and metabolic care vol. 14,1 (2011): 28-34. doi:10.1097/MCO.0b013e32834121b1
The Scientist Staff (2015). “How We Age”. Available at: https://www.the-scientist.com/features/how-we-age-35872 Accessed [22/09/2020]
Monica Menesini (2016). “TED-Ed Why do our bodies age?” Available at: https://www.youtube.com/watch?v=GASaqPv0t0g Accessed [22/09/2020]
Ahmed AS, Sheng MH, Wasnik S, Baylink DJ, Lau KW. Effect of aging on stem cells. World J Exp Med. 2017 Feb 20;7(1):1-10. doi: 10.5493/wjem.v7.i1.1.
Jafri, M.A., Ansari, S.A., Alqahtani, M.H. and Shay, J.W., 2016. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome medicine, 8(1), p.69.
SciShow (2018). “How do turtles live so long?” Available at: https://www.youtube.com/watch?v=l0i7zVhxx9k Accessed [22/09/2020]
SciShow (2012). “Why We Age- And How We Can Stop It” Available at: https://www.youtube.com/watch?v=jqCo-McgHLw&t=160s Accessed [22/09/2020]
Science Daily (2017). “How eating less can slow the aging process” Available at: https://www.sciencedaily.com/releases/2017/02/170213151306.htm Accessed [22/09/2020]
Wikipedia (2020). “Johnathan (tortoise)” Available at: https://en.wikipedia.org/wiki/Jonathan_(tortoise) Accessed [22/09/2020]
Imperial Bioscience Review 