Developmental Biology - Research Paper Example

? Aging: effect of genes, epigenetics and environment The purpose of this research paper is to develop an in-depth knowledge about the process of aging in terms of how it is affected by genetic and epigenetic factors as well as the environment. Aging is defined as the progressive changes that occur within organisms related to the passage of time. This process is regulated by genetic and epigenetic factors while it is modulated by environmental factors such as stress, exposure to ultraviolet radiation and environmental pollution. A gene is defined as a basic unit of heredity. These are self-replicating, DNA structures that are responsible for the presence of certain traits. Epigenetic factors refer to changes other than the changes at the level of DNA that lead to changes in heredity. These include DNA methylation which is present in all known vertebrates. This paper aims to study recent literature and studies that have been produced in order to find out the factors that affect aging. For this purpose, literature dated after 2006 has been used in order to ensure that the information is as recent as possible. This study will be useful in developing a better understanding of a vital part of developmental biology that is aging. INTRODUCTION Human race has always been fascinated by the idea of eternal youthfulness and functionality. The physiological and psychological changes that occur with age have always haunted humans and as a result, a lot of time, money and effort have gone into discovering the reasons behind aging in order to avoid the effects of growing age. With the advent of newer technologies, scientists have come to see aging as a process that occurs at the molecular level that eventually shows its effect at the level of the organ and later the whole organism. Some of the physiological changes that occur with age include decreased activity of neurotransmitters, a fall in sensory acuity and perception and a reduction in circulatory capacity. These changes lead to the loss of functionality that is associated with aging at the level of an organism. At the level of the organ, these changes occur due to the inability of the existing cells to replace the dying or damaged cells in order to maintain function. Thus, we see several diseases that pertain to specific organs and are closely related to increasing age. The inability to replace the older cells with new ones is a loss of functionality at the cellular level. The biochemical machinery within a cell enables the cell to replicate adequately so that the number of functional cells is always enough to maintain the health of an organ. However, with age, changes within this machinery shift the balance such that the process slows down gradually affecting the organ hence the organism (Morimoto and Cuervo). Therefore, the real key to unlocking the secret behind aging lies in the factors that affect the cellular machinery. Whether it is the change in DNA, a change in gene expression or a change in the environment of the organism which eventually penetrates his system that regulates aging and to what extent is a question that has been investigated extensively in recent past. This research paper takes a detailed look at such investigations in an attempt to understand how aging is affected by genetic, epigenetic or environmental factors. Aging: effect of genes, epigenetics and environment Genes and aging The field of biological aging has been exploring the effect of genes on aging with a view of not only attaining the capability to slow or stop the process of aging but also to stop the development of several disease that have very strong links with increasing age. However, most of these investigations have been carried out on worms, rodents and drosophila on the basis that not only are they easily accessible but also because certain studies suggest that worms, yeast and people have common genes for aging (Callaway). In 2008, scientists from Eovtos Lorand University, Hungary, conducted a research on nematodes, Caenorhabditis elegans, that were deficient for BEC-1 gene, that is bec1(-), and compared them with bec1(+) nematodes on the basis of their lifespan. The bec1(+) nematodes were found to have a longer lifespan than bec(-) nematodes. Similarly they compared the lifespan of nematodes in which the igg-1 and atg-18 had been knocked off to nematodes that were genotypically normal and the similar results were obtained. The normal nematodes had longer lifespan. Bec-1 plays a critical role in development while igg-1 and atg-18 play a critical role in autophagy. Together these genes regulate the net extent of cellular autophagy and seem to have increased the lifespan of the nematodes. In order to ensure that this fall in lifespan was due to aging and not some other disease, the lipofuscin contents of the cells from the mutant nematodes were compared to that of normal nematodes and the result was an obvious raise. The researchers concluded that inactivation of autophagy gene led to decreased lifespan and characteristic changes of aging (Toth, Sigmond and Borsos). Similarly the Raf/MEK/ERK and P13K/PTEN/Akt/mTOR pathways are being investigated for their role in aging as the dysregulation of these pathways is associated with uncontrolled cellular proliferation and reduced sensitivity to apoptosis-inducing agents. Both of these lead to cancers and aging and ability to control the regulation of this pathway can lead to a therapeutic breakthrough in the management of diseases associated with aging (Steelman, Chappell and Abrams). The role of sirtuin gene (SIRT1) is being seen as a potential breakthrough in the prevention of diseases related to aging. Sirtuins are proteins that are linked to mitochondrial biology which is said to be a key player in the process of aging. In a study conducted in order to find out this link, the conclusion drawn was that while science is still a long way from using sirtuins to prevent diseases of aging, the potential for this is huge as this is a class of proteins that is amenable to drugs and regulation of this protein at the genetic level must be explored (Westphal, Dipp and Guarente). A study conducted to address the hypothesis that the intrinsic properties of oligodendrocytes are modified by age and result in memory loss was conducted in 2008 and showed that aged oligodendrocytes displayed decreased histone methylation and increased acetylation resulting in changes in gene expression such as re-expression of bHLH inhibitors (ld4 and Hes5) and precursor markers (Sox2) (Shen, Liu and Li). Thus genes and epigenetics work together and bring about the characteristic changes in memory due to increasing age. Similarly, studies have been conducted in trying to find out the mechanism through which a restricted calorie intake delays mortality and the onset of age-related diseases. One such study concluded that this occurs via the sirtuin pathway which affects apoptosis and cellular bioenergetics (Couteur, Sinclair and Cogger). This is an example of how genes and environmental factors co-ordinate and bring about aging. Epigenetics and aging Epigenetic factor are gaining importance in the research about aging because at this point, scientists are miles away from discovering any way of reversing the genetic changes that are associated with aging. On the other hand, changes brought about by epigenetic factors are potentially reversible. There are certain conditions that have to be considered when assessing the role of epigenetics in the process of aging. First of all, these epigenetic changes must be specific to the process of aging and secondly, they must have functional association with the aging phenotype (Calvaneze, Lara and Kahn). Only when an epigenetic change fulfills these criteria, can it be considered to play a role in the process of aging. While conducting a research on investigating the link between aberrant DNA methylation and hepatocellular carcinoma (HCC), the researchers found out that aberrant methylation was a part of normal aging process as well as chronic liver inflammation. They also found out that aberrant methylation in the promoter areas of tumor suppressor gene led to the development of cancers. Thus, aberrant methylation is an epigenetic factor that is a part of normal aging process and can lead to the initiation and progression of hepatocellular carcinoma (Nishida, Nagasaka and Nishimura). Moreover, the effect if this factor is enhanced by co-existing infection. For this purpose, 176 liver tissues were taken out of which 77 were pairs of normal and diseased tissue taken from known cases of HCC while 22 were taken from healthy individuals. Their methylation quantification was done using COBRA and the results showed that aberrant methylation is not only a causative factor of HCC but is also an epigenetic factor for aging. Slowing down this process can lead to prevention from liver, colon and lung cancer. The role of epigenetic changes in reproduction has been a subject of study due to the possibility of transgenerational epigenetic effects. Certain studies suggest that in utero and neonatal exposure to certain toxins such as endocrine-disrupting chemicals (EDCs), can affect female reproductive function in adulthood. These toxins work via DNA methylation, histone modification and non-coding RNA, all of which are epigenetic factors. EDCs can affect the ovaries and cause transgenerational epigenetic effects by modifying the epigenetic mechanisms in the oocyte (Zama and Uzumcu). EDCs include fairly common compounds like methoxychlor and bisphenol A and whether exposure to these substances has a cumulative effect on reproduction as a person ages is yet to be discovered. However, when a reproductive assessment of aging mouse oocytes was done at the McGill University Health Center Research Institute, the results were different. Young and aged female mice were mated with males of same age and several aspects of their pregnancy and subsequent offspring were assessed. A group of genes (Snrpn, kcnq1ot1,U2af1-rs1,Peg-1,lgf2r and H19) were observed for changes in methylation in order to assess changes in epigenetic mechanisms. This was done through Restriction Landmark Genome Scanning and while it was noted that there were differences in placental morphology, resorption sites and morphological abnormalities related to the difference in maternal age, there was no significant age-related changes in methylation of the above genes in the placenta or the embryo (Lopes, Fortier and Darricarrere). Therefore, the role of epigenetic mechanisms in the reproductive ability of an aging subject is not clear as yet. Environment and aging Environmental factors have an important role to play in the study of aging. Whether elimination of certain factors or addition of certain factors can lead to longevity in lifespan and improved quality of life is a question that is asked by common man. Therefore, study of these factors is very important. A study was conducted on rhesus monkeys at Wisconsin National Primate Research Centre. This longitudinal study spanned over 20 years and the adult monkeys were divided into two groups. One was put on calorie restriction but not malnutrition while the other was given control feeding. Comparison of the two groups gave the result that 80% of the calorize-restricted monkeys survived till the end of the 20 year period while 50% of the control monkeys survived for the same time. Moreover, the calorie-restricted monkeys showed a delay in the age-related pathologies (Colman, Anderson and Johnson). Oxidative stress has been implicated in the development of age-related organ dysfunction. It can develop as a result of ionizing radiation, air pollution, metals, pesticides and smoking. This oxidative stress consists of generation of radical oxygen superoxides and is counteracted by isoforms of superoxide dismutase (SOD) in healthy young adults. With age the activity of SOD decreases and oxidative stress leads to epigenetic modifications that are associated with aging. In a study conducted to investigate the role of oxidative stress and AT1 receptors on cerebral vascular dysfunction with aging, three groups of mice divided according to their ages into young, old and very old were studied. Acetylcholine was introduced into the basilar arteries of each mouse allowing a buildup of oxidative stress and assessed for dilation. Measurements showed that compared to the young rats, the old rats and the older rats showed a dilation of less than 60% and 90% respectively. When treated with tempol, a superoxide scavenger, the older mice showed almost complete restoration (Modrick, Didion and Sigmund). This shows that aging is linked to a high degree of endothelial dysfunction in cerebral artery and that this dysfunction is facilitated by radical oxygen superoxides. However another study was done in 2008 on a pool of Caenorhabditis elegans. The sod genes, which are responsible for synthesis and release of SOD, in this pool had been manipulated in order to closely monitor the effect of oxidative stress on lifespan of the nematode. Surprisingly, the sod gene manipulation had little or no effect on the longevity of the nematode’s lifespan implying that the superoxide radicle might not be playing a character as important in aging as it is thought to play. CONCLUSION Aging is a multidimensional and a multifactorial process. The aim of this research paper was to obtain in-depth knowledge about the multi-factorial nature of aging. These factors include genes, epigenetic factors and environmental factors and an attempt has been made to study literature pertaining to each of these types of factors. Genes play the most important part in the process of aging. The effect of genes on aging is not only important from a scientific point of view but also from a therapeutic point of view. All the other factors eventually lead to the regulation of genes and it is the genetic changes that lead to the cumulative effect of increasing age. This is very important particularly in the light of diseases that are associated with aging and the rapidly expanding aged population of the world. Genetic promotion of cellular development and proliferation through BEC1 and regulation of autophagy through igg-1 and atg-18 are impaired with the passage of time leading to the development of lipofuscin granules. A dysregulation in the Raf/MEK/ERK and P13K/PTEN/Akt/mTOR pathways is also being investigated as it is said to desensitize the cells to apoptosis-inducing agents. Both of these mechanisms allow the buildup of substances that are characterized by aging and further studies need to be undertaken on whether both these mechanisms play a role in the diseases that are associated with aging. Further studies on sirtuins are important in this aspect as they are potentially modifiable effectors of mitochondrial biology and can be used to prevent diseases of aging. Aberrant methylation and histone modification are two epigenetic pathways that modulate aging. Studies have shown that aberrant methylation is a part of normal aging and can lead to the development of cancers of liver, lung and colon. The possibility of the effects of epigenetic changes transcending across a generation via reproduction, particularly with respect to aging oocytes is unclear but definitely present. Epigenetic factors are often the bridge between the genetic and environmental causes of aging. Environmental factors explored in the paper were diet and oxidative stress. A restriction of caloric intake while avoiding malnutrition not only increases the lifespan but also delays the onset of age-related changes. On the other hand, oxidative stress promotes aging. An example is the effect of smoking on the vascular system but recent studies imply that the role of oxidative stress is not as critical as was considered in the past. It can be concluded from the information in the paper that aging is regulated by genes and modulated by epigenetic and environmental factors. Works Cited Callaway, Ewen. "Comon age: worms, yeast and people share genes for aging." Science News (2009): 164. Calvaneze, Vincenzo, et al. "The role of epigenetics in aging and age-related diseases." Ageing Research Reviews (2009): 268-276. Colman, Ricki, et al. "Caloric restriction delays disease onset and mortality in rhesus monkeys ." Science (2009): 201-204. Couteur, David, David Sinclair and David Cogger. "The aging liver and the effects of effects of long-term caloric restriction." Everitt, AV. Calorie restriction, aging and longevity. Sydney: Springer Media, 2010. 191-216. Lopes, Flavia, et al. "Reproductive and epigenetic outcomes associated with aging mouse oocytes." Human Molecular Genetics (2009): 2032-2044. Modrick, Mary, et al. "Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging." American Journal of Physiology (2009). Morimoto, Richard and Ana Cuervo. "Protein Homeostasis and Aging: Taking Care of Proteins to the Cradle to the Grave." The Journals of Gerontology (2009): 167-170. Nishida, Naoshi, et al. "Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis and hepatocellular carcinoma." Hepatology (2008): 908-918. Shen, Siming, et al. "Epigenetic memory loss in aging oligodendrocytes in the corpus callosum." Neurobiology of Aging (2008): 452-463. Steelman, LS, et al. "Roles of the Raf/MEK/ERK and P13K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging ." Aging (2011): 192-222. Toth, Marton, et al. Longevity pathways converge on autophagy genesto regulate lifespan in Caenorhabditis elegans. Budapest: Landes Bioscience, 2008. Westphal, C.H, M.A Dipp and L Guarente. "A therapeutic role of sirtuins in aging?" Trends in Biochemical Sciences (2007): 555-560. Zama, Aparna and Mehmet Uzumcu. "Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective." Frontiers in Neuroendocrinology October 2010: 420-439. Read More