The world is in a state of rapid scientific development and innovation. The world is also experiencing increasing mortality from non-communicable chronic illnesses, increased incidence and prevalence of lifestyle disorders and increased influence of environmental stress on the ageing process. Ageing impacts the progression of certain diseases predispose individuals to other diseases and ultimately leads to death. On the other hand, diseases are predictors of mortality with or without the influence of ageing.
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Ageing is the ultimate decay of an organism’s structure and function. The mechanism through which an organism undergoes ageing is governed by a balance between cell entropy and repair of damaged cells. When cell damage/entropy exceeds the capacity of a cell to repair itself then the organism begins to age (Ho et al, 2005). Moreover, the accumulation of cellular damage over a long time decreases an organism’s ability to maintain a constant internal environment despite changes in the external environment. This deterioration of the function of homeostasis increases the organism’s susceptibility to illness and diseases and is the reason that ageing brings along with it such debilitating health concerns. On the other hand, mutations in genetic material, chromosomal abnormalities and genetic predispositions contribute to the presence of chromosomal, multifactorial, single gene, communicable and communicable diseases. Genetic predisposition, in particular works in tandem with environmental conditions to ensure some individuals are more likely than others to get infected by communicable diseases or are more likely than not to end up with a particular chronic illness or non-communicable disease. Understanding the specific mechanisms through which cells age is crucial to discovering methods through which the ageing process can be delayed or slowed down and examining the specific role of genetics in disease can assist in the development of genetic cures that will not only cure the disease in affected individuals but will also prevent the transmission of the genes that predispose individuals to the illness to subsequent generations.
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Role of Genetics In Aging And Disease Causation
Plasminogen activator inhibitor Type I targeted therapy
The gradual accumulation of DNA damage, as well as changes in DNA structure, constitutes the intrinsic changes within the cell that mediate cell senescence. DNA modifications alter the kind of proteins that will be expressed by genes and this alters the function of the cell. Moreover, specific gene encoding proteins have been identified as key mediators of cell senescence and therefore, ageing. One such gene encoding protein is Plasminogen Activator Inhibitor Type I. Increased expression of this protein is considered a guiding factor in the progression of multiple pathological conditions and is also associated with the multi-morbidity that comes with aging. Ageing is positively associated with cell senescence and is often accompanied with overexpression of PAI-I which establishes PAI-I as marker and key mediator of ageing (Douglas et al, 2017). According to Yamamoto et al, this protein increases in the different tissues within the body as human beings progress in age. Moreover specific increases in PAI-I have been found to dictate the progression of artherosclerotic conditions and thrombotic conditions seen in the elderly and in Werner’s syndrome where individuals display an accelerated ageing process. Gold stein et al observed that PAI-I levels are higher in fibroblasts derived from fetal mice than those in older mice. PAI-I is has also been shown to be elevated in chronological and stress induced aging and is a bonafide bio-maker of cell senescence. PAI-I overexpression has also been related to the incidence of obesity, and thus insulin resistance in diabetes mellitus type II, inflammation, cardiovascular disease as well as inflammatory conditions. These functions in aging and the multiple pathologies that have been linked to PAI-I overexpression have led to the consideration of the use of PAI-I inhibitors that reduce physiological levels of PAI-I and therefore act as mediators in the risk processes associated with PAI-I (Higgins, 2006).
Growth hormone targeted therapy
To understand the mechanisms through which scientists can elongate our lifespans and improve health outcomes we must first analyze the specific genes involved in longevity and protection from disease. Several studies have been conducted on dwarf mice to show the specific genetic modifications that will have to be present in order to prolong the process of ageing. One such study theorized that somatic growth and therefore ageing is mediated by the presence of circulating growth hormone which activates its receptor on a target cell and leads to the production of IGF-1 which binds to IGF-1R on a target cell and triggers the growth of that cell (Sohal & Weindruch, 1996). The role of this hormone in ageing was clear in Ames dwarf mice who showed up to 60% longevity due to being homozygous for an autosomal recessive disorder at the Prop-I gene locus which causes the absence of entire cell lineages in their anterior pituitary gland (Sornson et al, 1996).
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Cell lineages such as somatotrophs, lactotrophs and thyrotrophs were absent from these mice and this led to an inability to produce hormones such as growth hormone, prolactin and thyroid stimulating hormone (Bartke, 1964). Consequently, these mice had minimal growth and reduced body weight up to 1/3 of normal mice. Snell dwarf mouse mutation in the Pit-I gene locus also led to a deficiency in these three hormones which delayed the onset of ageing. Little mice who are homozygous for a mutation in the lit/lit locus showed growth hormone deficiency due to the absence of the receptor for the hormone (Lin et al, 1993). Growth hormone resistant knockout mice also showed significant retardation of the rate of postnatal ageing and up to 55% improvement in lifespan (Zhou et al, 1997). These experimental studies show that specific genes have a significant influence on ageing on their own by controlling the expression of specific proteins. Although therapeutic strategies to target growth hormone in humans have been limited, there is ongoing work to determine the effectiveness of protein based therapeutics, Anti-GHR antibodies and suppression of the downstream signal transduction pathway of GHR (Lu et al, 2019).
Klotho targeted therapy
Experiments such as the ones noted above form the paradigm of the scientific world and scientists are always looking for new ways to improve the human condition and ensure longevity. To do this, scientists have identified genes that control ageing specifically in humans. One such gene is the age suppressing gene known as Klotho. Klotho functions as a fibroblast growth factor 23 co-receptor required for proper phosphate hemostasis. A deficiency in Klotho results in hyperphosphatemia which leads to the development of the array of disorders associated with aging such as skin and gut abnormalities, atherosclerosis, emphysema, infertility and osteoporosis. Klotho has also been shown to be a suppressor of the downstream signaling pathway of insulin growth like hormone, although the mechanism by which it performs this function has not been elucidated (Kurosu et al, 2005). Moreover, Klotho is involved in the suppression of the Wnt signaling pathway which is involved in stem cell proliferation by binding to different types of Wnt ligands and suppressing downstream signaling and transduction. Studies involving Klotho knockout mice show that activated Wnt signaling pathway increases the cell cycle by prolonging the G2 phase which in turn increases the level of fibrogenic cytokines while overexpression of Klotho enables the cell to bypass this stage and reduce the level of fibrogenic cytokines (Satoh et al, 2012). Studies have also shown that Klotho overexpression increased the longevity of mice through its influence in the modulation of Wnt and insulin growth like hormone signalling pathways, its mediation of the processes of proliferation, senescence and oxidation (Wang & Sun, 2009) and deficiency of this gene leads to depletion of stem cells, tissue atrophy, fibrosis and cell senescence (Sun et al, 2015). There is ongoing work that is aimed at identifying small molecule modulators of Klotho in order to use recombinant Klotho proteins in gene therapeutic approaches to increase longevity.
Stem cell treatments
Stem cell are involved in organ and tissue regeneration in the body through the replacement of damaged cells. As the body ages, the magnitude of cellular damage begins to outweigh the capacity of stem cells to mediate cell entropy. This opens up an avenue for the development of anti-ageing treatments that target the stem cell directly and activate the sequences involved in regeneration. This targeted approach might improve cellular conditions by repairing the damage. Moreover, the damage to entire organs can be corrected by replacing the organs altogether. These new organs will have been grown from multipotent stem cells harvested from the umbilical cord during birth. These cells have the capacity to divide into any cell in the human body. Once, harvested, scientists can store these cells that are often discarded after birth at low temperatures and use them to grow entire organs at a later stage. This will enable the limitless replacement of any atrophied organ or tissue in the human body (Martin, 2006).
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Genetic therapy in disease treatment
Scientist could also utilize genetic therapy to treat disorders in the human body by correcting gene defects within a cell or introducing new genes to a cell. Genes can be taken through splicing and dicing through a technology known as recombinant DNA technology and defective genes removed the expression of cloned genes facilitated. Moreover, this technology can be used to eliminate defective genes from the germline to prevent these bad genes from being passed on to subsequent generations (Martin, 2006). By 2025, scientists would be able to avoid the ethical contraindications of interfering with the germline by developing an extra artificial chromosome whose gene expression can be switched on and off as the user prefers. This technology will be able to download genetic material, confer the expression of recombinant DNA and limit the expression of defective genes (Martin, 2006).
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This will be done by a process that seeks to isolate the defective gene through the construction of an entire genetic map of the individual, develop recombinant DNA and clone this DNA into the host. These cloned genes can then be expressed in preference to the defective genes (Holt et al, 2002). Scientists could also manage to cure cardiovascular diseases, cancer, develop vaccines to E. coli, HIV/AIDS and reduce the incidence of malaria in developing countries. In the case of cardiovascular disease, scientists could take advantage of the rapidly dividing state of cancerous cells and reteach the cells of the heart how to divide again. This is because the heart is composed of post-mitotic dormant cells that have ceased dividing despite still possessing the nuclear blueprint to do so. This results in the permanent damage that is witnessed after infarctions. In the case of cancer, bovine thymosine can be used to replace human thymosin which triggers the production of T cells. T cells are the major immune cells involved in the detection and control of malignant cells in the body and it is they that prevent the occurrence of cancer. As individuals progress in age, the efficiency of the thymus gland gradually decreases, this leads to a reduction in thymosin which leads to a reduction in T cell lines due to the minimized stimulation of bone marrow production by the reduced levels of the hormone. In the case of E. coli, Scientists in the United States have been studying the efficacy of utilizing plant vaccines (WHO, 2005).
This has been done by using food sources that have been ben manipulated to express the antigens of a specific disease. These food sources are then given to experimental animals or human subjects to determine their capacity to induce immune responses that will protect the subject in case of future infection. Specific studies in immunizing subjects against E. coli have been successful with 90% of subjects showing increased levels of antibody activity without any notable side effects. This kind of edible vaccine might be useful in future studies aimed at battling cholera in developing countries (WHO, 2005). In the case of HIV/AIDS, studies carried out on ‘immune’ sex workers in Nairobi-Kenya have shown promise in the development of a vaccine for HIV/AIDS. According to Kaul et al, these women showed remarkable resistance to the virus even after repeated exposure. They had no special antibodies, although some did possess a particularly robust immune system. Studies aim to determine the role of genetics in conferring immunity to these women. Scientists are optimistic that they can develop a DNA vaccine to enable immune response and reduce the rate at which HIV/AIDS is spread in developed countries and therefore reduce mortality (Kaul et al, 2000). Moreover, scientists are active in educating the public about the role of genetics in diseases such as Thalassemia, sickle cell anaemia. Tay Sach’s disease and Down syndrome and the prevention strategies they can adopt as well as available cures. These efforts in research and community education are expected to go a long way in reducing the rates of mortality from these diseases, improving the human condition in developing countries as well as increasing the longevity of life and ensuring better health outcomes globally. Moreover, the success at implementing a DNA vaccine for HIV/AIDS will ensure that the opportunistic infections that are often associated with this syndrome are completely eradicated from the majority of the population.
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Despite the striking benefits proposed by genetics and their utilization in improving longevity, specific applications have been plagued by protests labelling them as unethical and disruptive to the normal processes of life. One such strategy that involves the harvesting of pluripotent stem cells from the blastocyst to develop body tissues is highly unethical due to the belief that life starts at conception. Harvesting pluripotent stem cells after fertilization interfere with this life. Moreover, interfering with the germline may have drastic consequences to the modified individual and future generations. There is no accurate way to predict conclusively the effect that the splicing of certain genes will have on life and scientists may interfere with crucial components of the human body without intending to. One such study that, in my opinion, proves this point is the study conducted dwarf mice. Despite displaying significant longevity in life, the female mice were infertile while only a few male mice could sire offspring in spite of the presence of effective spermatogenesis. The females remained infertile due to the absence of prolactin which is responsible for supporting the corpus luteum, which produces progesterone, which is a hormone that supports pregnancy (Lin et al, 1993). If a similar genetic modification was employed on humans, it would have drastic consequences on the very existence of the human race. Moreover, a complete genetic map of an individual might reveal information to insurance companies that will facilitate discrimination based on individual susceptibility to specific illnesses that are often expensive and difficult to treat (Holt et al, 2002). It also remains undecided to whom the expensive costs of gene therapy would go to. Will government institutions cover it? Or will it be limited to the very affluent?
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Despite the ethical limitations that scientists are facing in implementing some forms of genetic engineering technology, the future life expectancy of human beings seems promising. Diseases that have been significant predictors of mortality in the modern world have been linked to genetics and this link will facilitate effective strategies to manage these illnesses. This will increase the life expectancy of human being and delay mortality. Moreover, the identification of specific genes and the proteins they code for as well as the clarification of the side effects that will be associated with knockouts, splicing, dicing and modifications will facilitate the developments of anti-ageing treatments that have a minimum capacity to cause undesired side effects. Effective anti-ageing treatments might be available to elongate our lives in the coming years. Moreover, if scientists are successful at growing organs from multipotent stem cells in the laboratory organ replacement treatments might be available in developed economies in the coming years.
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