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Molecular Mechanisms of Aging Essay Sample

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Introduction of TOPIC

The mechanisms that regulate cellular senescence, organismal ageing, and species-specific lifespan depend on a synergy of pathways that are multifactorial and extremely complex, though not yet completely understood. Recently, the development of new molecular techniques has elucidated, at least in part, the primary pathways involved in ageing. In parallel with the search to uncover the factors that control ageing is the endeavor to discover methods of extending lifespan, in hopes of living both youthfully and longer. Specifically, caloric restriction regimens and rapamycin feeding have been shown to increase lifespan in a variety of species, though other methods will be discussed as well. The illumination of ageing mechanisms side-by-side with means of extending lifespan provides a foundation from which to determine a complete multidimensional map of ageing pathways and the place of various lifespan extension methods within it. Furthermore, this information acts as a stepping stone from which to evaluate the feasibility of potential lifespan extenders and to grant recommendations for a dietary regimen bestowing a long and healthy life to its patrons. Specific Aims

The Fountain of Youth, a mystical spring that bestows youth and immortality to those who drink from it, captured the attention of Spanish Conquistadors exploring the American terrain. Though many centuries have passed, the fascination with delaying ageing and living forever has never dwindled. Today, scientists serve as contemporary conquistadors, searching for the real Fountain of Youth in the form of pharmaceuticals and health regimens that will increase lifespan, delay ageing, and decrease the onset of age-associated diseases. Before successful lifespan extension models can be implemented in humans, the following questions must be answered (Sander et al., 2008): What are the signs of human ageing? Is there a limit to the length of human life? Why does ageing occur? What are the genetic factors involved in ageing? To what extent do environmental factors influence ageing? The current study seeks to address these questions by analyzing the various theories of ageing, and relating them to each other and to means of lifespan extension. Once the current understanding of the molecular basis of ageing is established, it will be used to assess the feasibility of methodologies thought to delay death and to suggest eating habits associated with increased lifespan and healthspan. Background and Significance

What is Ageing?
Before attempting to uncover the mechanisms that guide the process of ageing, it is essential to understand what ageing actually is. Most generally, ageing is the accumulation of changes in an organism that over time leads to an increase in stress vulnerability and to a decrease in physiological homeostasis (Bowen and Atwood, 2004; Sander et al, 2008). Though the concept of age is commonly regarded as the time an organism has been alive, some believe a better functional measure is a determination of the amount of time an organism has until its death (Birren and Cunningham, 1985).

Ageing on an organismal scale is the result of the accumulation of senescence on a cellular level. Replicative senescence, or the loss of the cellular ability to divide, was first described by Dr. Leonard Hayflick upon discovering that human fibroblasts can undergo only a finite number of cell divisions (Hayflick and Moorehead, 1961). Interestingly, as the cells approached their replicative limit, their cellular structure deteriorated, they failed to produce enzymes or energy, and they accumulated a great deal of waste, all features associated with aged tissues (Hayflick and Moorehead, 1961; Ben-Porath and Weinberg, 2004). In light of this information, Hayflick believed that cellular senescence contributed immensely to ageing and could explain the death of an organism prior to the time required for all of its cells to fail to replicate (Wilson III et al, 2008).

So how does cellular senescence lead to functional decline? The answer to this question seems to be tissue specific. Fibroblasts, for instance, which are cells that provide support to epithelial tissue, produce inflammatory cytokines and destructive enzymes once they reach senescence (Krtolica et al, 2002). These cellular changes can structurally and functionally alter the tissue and provide an environment conducive for cancerous growth (Krtolica et al, 2002). Senescence and the subsequent loss of function in stem cells is also believed to play a role in human ageing (Marques et al, 2010). General Ageing Theory

Ever since Hayflick uncovered senescence on the cellular level, gerontologists have been trying to develop models to explain the mechanisms responsible for ageing on an organismal scale. These models can be split into two types: the pre-programmed, which argue that ageing is regulated by changes in gene expression, and the stochastic, which suggest that the culprit for ageing is the accumulation of macromolecular damage over time. Interestingly, ageing is determined both by stochastic damage accumulation, which leads to functional decline, and genetics, which determines the rate that such damage accumulates (Niedernhofer et al 2006).

Stochastic theories, otherwise known as wear-and-tear theories, suggest that the buildup of alterations to an organism’s macromolecular integrity eventually cause the progressive failure of the organismal system (Wilson III et al, 2008). It is thought that protein aberrations, DNA damage, mitochondrial malfunction, inflammation, and oxidative stresses can all contribute to stochastic damage accumulation, though are not mutually exclusive (Sander et al., 2008). Vijg placed some of the blame for the stochastic nature of ageing on somatic mutational events, arguing that ageing results from a decrease in the genetic integrity of an organism over time through DNA damage and mutagenesis (reviewed in Sander et al, 2008; Vijg, 2008).

This idea, known as somatic mutation theory, was further supported when it was shown that mutation rate and temperature varied inversely with the average lifespan of fruit flies, implying that increasing the expected amount of DNA damage decreases the expected lifespan of the flies (reviewed in Sander et al, 2008; Vijg, 2008). Similarly, error-catastrophe theory pinpoints the production of proteins and the replication of DNA as imperfect processes that can lead to the accumulation of flawed molecules, eventually causing disease and age-related alterations (Wilson III et al, 2008). Thus, error-catastrophe theory differs subtly from somatic mutation theory as it implies a general error in information transfer rather than damage solely to DNA (Szilard, 1959). Reliability theory, a statistical theory which argues that vital functions can be modeled as a collection of damageable elements, shows mathematically that ageing is the result of the failure of genes and their products due to accumulating damage (Laird and Sheratt, 2010).

Various theories cite flaws in mechanisms besides information transfer as causing the phenotypes associated with ageing. Cross-linkage theory, for instance, blames “cross-linking agents” for creating macromolecular covalent bridges that lead to cellular dysfunction and eventually death (Wilson III et al., 2008). Autoimmune theory, on the other hand, hypothesizes that B and T cells weaken with age, leading to a decrease in the body’s ability to fight off bacteria, viruses, and cancer cells. Weakened B and T cells decrease the capability of the body to determine self from non-self as well, leading to autoimmune disease (Wilson III et al, 2008). Note that the weakening of immune cells with age is most likely the result of the stochastic damage mechanisms mentioned above, making this theory similar to the others above. Lastly, free-radical theory, which will be discussed in detail further in the paper, hypothesizes that ageing results from the accumulation of cellular damage due to reactions with free radicals, which are reactive oxygen or nitrogen species (Harman, 1956).

Pre-programmed theories differ from the stochastic in that they blame ageing on genetic factors that produce a so-called biological clock rather than the accumulation of random damage due to imperfect systems. Genetic control theory, for instance, argues that differences in ageing are the results of interorganismal genome differences (Wilson III et al., 2008). Data in C. elegans supporting genetic control theory suggests that genotype difference can alter lifespan by a factor of 10, while in humans, twin studies showed that genetics confer a maximum of 30-40% of lifespan potential (Sander et al., 2008). One view of how these genetic differences change the timing of the biological clock is neuroendocrine theory, which suggests that the body changes levels of hormone production with age causing catastrophic physiological effects (Dilman et al, 1986). Though all of the theories mentioned cover a wide spectrum of ideology, they should be thought of as complementary as opposed to mutually exclusive. Genome Maintenance and Ageing

Genome maintenance is thought to include all mechanisms for sensing and reporting the presence of DNA damage, repairing such damage, and reconstructing the higher order structure of DNA (Vijg, 2008). Excision repair, one such maintenance mechanism, was discovered in bacteria and was used to show that organismal genomes would degrade rapidly if these systems were not in place (Setlow and Carrier, 1964). Recognition of the importance of genome maintenance prompted the idea that genes encoding DNA maintenance proteins are members of a family known as longevity genes (Sacher, 1982). So how does genome maintenance affect longevity and ageing? For one, apoptosis, senescence, and cell cycle arrest – all responses to DNA damage – are believed to lead to aging-associated tissue degradation and loss of stem cell functionality (Bell and Van Zant, 2004). These mechanisms are also imperfect, causing DNA damage to sometimes go unchecked and accumulate over time leading to changes in gene expression.

One such example is hair graying, which can be the result of the accumulation of radiation-induced DNA damage in hair follicle melanocytes (Marques et al., 2010). Furthermore, studies linking DNA damage and ageing have shown that reporter genes gather an increasing number of mutations, as well as an increasing presence of double-strand breaks, abasic lesions, and cross-linkages with age (Suh and Vijg, 2006; Mullaart et al., 1990). Interestingly, inherited disorders caused by defects in genome maintenance systems, such as Werner and Cockayne syndromes, possess phenotypes paralleling the normal ageing process (Wilson III et al., 2008). In terms of longevity, Hart and Setlow discovered a correlation between an organism’s capacity to repair DNA and its maximum lifespan, suggesting that decreasing the expected amount of lifelong accumulated DNA damage increases the expected lifespan of an organism (1974). The hominoid slowdown also supports the idea that a species’ lifespan is directly related to the efficacy of its genetic repair systems, since the rate of change in DNA sequence during primate evolution slows down as the lifespan of the species increases (reviewed in Vijg, 2008; Goodman et al., 1971).

Though there exists robust data suggesting that strengthening the effectiveness of genome maintenance lengthens lifespan, there is still a lack of conclusive evidence (Vijg, 2008). Others hypothesize that a decline in the capacity to repair DNA with age causes organismal senescence, though this is contested. Generally, studies assessing an organism’s ability to repair DNA initially expose the animal to low doses of genotoxic agents, and then measure the removal of the induced lesions (Vijg, 2008). One such study, using rodents exposed to known carcinogens, displayed slightly decreased levels of repair with age, but the changes were small (Boerrigter et al., 1995). Note, however, that even a miniscule decrease in DNA repair could cause an extreme change in the rate of mutation accumulation. Furthermore, these studies are purely correlative and future experiments that produce defects in the genome maintenance pathway and measure the subsequent change in the ageing rates are needed to determine cause and effect (Vijg, 2008). Telomeres and Ageing

Telomere shortening, another form of DNA alteration, has been implicated in both cellular and organismal senescence since the late 1980s. Structurally, telomeres make up the end

s of eukaryotic chromosomes, contain non-coding tandem repeats, such as 5’-TTAAGGG-3’ in humans,

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and can possess both single and double stranded regions (Chakhparonian and Wellinger, 2003). Without these specialized DNA structures, the genome maintenance machinery would identify chromosome ends as double stranded lesions and activate the G1 DNA checkpoint, leading to cellular senescence, thus prompting the conclusion that telomeres preserve chromosomal integrity (Shawi and Autexier, 2008).

Scientists, who understood that genome maintenance was linked to ageing, took the natural step in implicating telomeres in biological clock-like lifespan regulation and searched for evidence to support this claim. One such study, which measured cerebral matter telomeres in elderly individuals, found a direct correlation between longevity and longer telomere lengths (Nakamura, 2007). Furthermore, twin studies showed an inverse relationship between telomere length and the risk of mortality with greater telomeric differences corresponding to larger lifespan differences (Sander et al., 2008). Lastly, smokers and obese women were found to have shorter telomere lengths than non-smokers and thin women in a dose dependant manner, further supporting a role for telomeres in ageing and suggesting that environmental factors can potentially affect telomere length and lifespan (Valdes et al., 2005).

Understanding fully how telomeres relate to ageing requires elucidating their maintenance mechanisms. Most commonly, telomeres are synthesized by the reverse transcriptase known as telomerase, though normal human tissues only express telomerase in their germ line (Shawi and Autexier, 2008). Immortal tumor cells, however, have been shown to express high levels of telomerase, while paradoxically maintaining very short telomere lengths, suggesting a potential diagnostic marker for cancer (Shay and Bacchetti, 1997). More information regarding the mechanisms of telomerase and its role in lifespan extension will be provided later in the paper. Oxidative Damage and Ageing

Throughout the paper, there has been significant discussion speculating that damage accumulation to various macromolecules leads, at least in part, to organismal ageing. So what exactly creates this damage? Highly reactive oxygen and nitrogen species (ROS), known as free radicals, have been implicated in causing the much of the cellular damage accumulation seen with ageing (Harman, 1956). These molecules are byproducts of normal metabolic reactions, such as cellular respiration, and are produced mainly in mitochondria, though they are sometimes the result of exposure to external substances (Wilson III et al., 2008). The damage caused by these reactive species causes mitochondrial decay, leading to deficient energy generation, cellular dysfunction, and eventually age-associated conditions impairing the musculoskeletal, neural, and cardiovascular systems (Wilson III et al., 2008).

The past few decades have provided research supporting a role for free radicals in the ageing process. For instance, ROS production rates have been found to relate inversely to the maximal lifespan of various species (Sohal and Orr, 1992). Furthermore, flies with enhanced mitochondrial antioxidant defenses were shown to have longer life expectancies (Addabbo, 2009). Interestingly, future research hopes to focus on linking base excision repair (BER) and free radical induced ageing, since this specific maintenance pathway is thought to be responsible for correcting the majority of oxidative damage (Vijg, 2008). Progress/Preliminary Results

In parallel with the search to uncover the mechanisms controlling ageing is the quest to discover means of extending lifespan. Though methods of lifespan extension are not completely understood, recent research has led to breakthroughs in this field, especially concerning caloric restriction, resveratrol, and rapamycin, which have been shown to increase lifespan by modulating various pieces of the longevity pathway (Marques et al., 2010). This section seeks to synthesize known information regarding these drugs/techniques in hopes of providing a stepping stone from which to relate these methods to each other and to mechanisms of ageing. Caloric Restriction

Practiced for centuries by inhabitants of certain Japanese islands, caloric restriction (CR) is a dietary regimen consisting of lowered caloric intake from some baseline level in hopes of improving both healthspan and lifespan. Though much is yet to be understood, recent research has found that caloric restriction increases lifespan in a variety of high-order species and decreases the onset of age-associated diseases. Remarkably, rhesus monkeys undergoing CR were found to live significantly longer than controls and to have a reduced prevalence of cancer and diabetes, two pathologies commonly associated with ageing (Colman et al., 2009).

The long lifespan of rhesus monkeys, compared to other primates, combined with their close phylogeny to humans makes this study incredibly relevant and promising for successful CR implementation in man (Fowler et al., 2010). In fact, studies using human subjects undergoing CR for as little as a year have shown decreased risk for atherosclerosis and diabetes, as well as reduced levels of inflammation, an adaptation seen in rats and mice thought to slow the ageing process (Holloszy and Fontana, 2007). Critics of CR suggest that it lowers quality of life; however, studies in monkeys have shown no change in disposition or energy when undergoing reduced caloric intake (Cox and Mattison, 2009).

Though CR has shown significant promise as a means of extending lifespan and decreasing the incidence of age-associated pathologies, some challenges need to be met before it can be successfully implemented in humans. First is determining the most effective means of enacting the regimen, meaning what the optimal decrease in caloric intake is, and how it differs on a person-by-person basis. Along the same lines is establishing precisely when to begin CR, since studies have shown that its beneficial effects are lost when started too early in life (Messaoudi et al., 2008). Finally, elucidating the mechanism by which CR modulates ageing holds the key to its widespread implementation and opens doors for synthesizing drugs that can mimic its effects. Preliminary research has implicated the sirtuin and mTOR pathways as master regulators of ageing and as targets of CR, though this is not fully understood (Cox and Mattison, 2009) Rapamycin Feeding

Rapamycin is an immunosuppressant within the macrolide drug family and is commonly used to prevent organ rejection after transplantation. Current research, however, has suggested possible other roles for the drug by implicating it as a lifespan extender. Initially, rapamycin was found to affect the ageing process in yeast, worms, and flies (reviewed in Cox and Mattison, 2009). Recently though, researchers found that rapamycin feeding, even late in life, increases both the maximal and median lifespan of mice, extending the possibility of lifespan extension to mammals (Harrison et al., 2009).

In the Harrison study, the mice were kept in a pathogen free environment, opening the possibility that rapamycin’s lifespan extending properties may be eliminated in the presence of disease causing agents due to the drug’s immunosuppressive effects. However, the fact that rapamycin increases lifespan in the absence of pathogens suggests that it acts directly on the ageing pathway, rather than through delaying the onset of disease (Cox and Mattison, 2009). As a result, it may be necessary to find analogs to rapamycin that confer the same life extending properties, while maintaining the integrity of the immune system. Luckily, rapamycin’s mechanism of action has been studied in depth and such “rapalogs” are currently under development (reviewed in Easton and Houghton, 2006). Specifically, rapamycin inhibits the target of rapamycin (TOR), an important serine-threonine kinase known to regulate cell growth and proliferation by integrating inputs from the insulin signaling pathway (reviewed in Cox and Mattison, 2009). Future research into rapalog drug synthesis and rapamycin’s effects at varying dosages could make its use as a lifespan extending drug a reality. Other Proposed Methods of Lifespan Extension

Though caloric restriction and rapamycin feeding seem to be the primary candidates for extending lifespan in humans, other methods have shown promise as well. One idea focuses on the fact that cellular replicative senescence is modulated by telomeres. As a result, drugs that regulate either telomerase activity or transcription have been thought to be potential means of affecting ageing on an organismal scale (Blasco, 2005). Another compound, called resveratrol, which can be found in the skin of red grapes, has been shown to increase lifespan in flies and nematodes, but evidence for its therapeutic use in humans is still lacking (Marques et al., 2010). Interestingly, however, is the fact that resveratrol functions to activate the sirtuin pathway, which seems to connect its mechanism of lifespan modulation to that of CR (Baur et al., 2006). Research Proposal

Thus far, the current work has detailed the modern understanding of the ageing process and provided general information regarding methods thought to increase lifespan. So what follows next? Based on my current understanding of ageing it seems that many of the pathways share intermediates, and thus, can be connected. Consequently, in the coming months I would like to first delve deeper into the molecular mechanisms that underlie cellular and organsimal senescence, especially concerning the insulin, sirtuin, and mTOR pathways. After I have a firm grasp of these mechanisms, I will search for commonalities among them in hopes of constructing a map of ageing. Visually, I imagine a diagram of a cell with inputs and outputs coming from many different directions and converging on sites of ageing regulation, such as telomeres, genome maintenance machinery, mitochondria, etc. Though this diagram will be complex, I think it is necessary at this point to attempt to integrate the various theories of ageing. Unfortunately, in many of the papers I read, I found that the mechanisms of ageing were presented as distinct from one another, when in reality they are interconnected in a web like network. These theories, are complimentary, rather than mutually exclusive, and should be presented as they exist in nature.

In effect, this section of the paper seeks to synthesize all aspects of senescence mechanisms into an overall multidimensional model of ageing. In order to accomplish this goal, I hope to meet with leaders in the field, specifically Jan Vijg, since I think his understanding and research on the subject aligns closest with my aims. Upon meeting these experts, I will try to use their wealth of knowledge to synthesize and connect information on ageing theory, as well as ask them for feedback on my ideas. They may be able to provide me with information regarding ongoing research that has yet to be published or can critique previous papers or ideas in the field. In sum, the first half of the thesis will present a comprehensive view of ageing from which a map integrating all of its components will be constructed. After joining the pieces of the ageing puzzle in the first half of the thesis, the next half will appropriately place the various known methods of lifespan extension within it.

To accomplish this, I will first explore the mechanisms by which these regimens affect ageing and lifespan. Since these mechanisms overlap with those presented in the ageing theory section, pinpointing where these methods fit into the ageing pathways will follow smoothly. Because these drugs and techniques will be grouped based on their method of action; they will be able to be categorized mechanistically. Furthermore, these lifespan extending methods can be compared both vertically and horizontally, meaning by either acting higher or lower in a pathway or in parallel pathways. Once the various mechanisms are placed in their appropriate spots on the map of ageing, their feasibility will be assessed in terms of their potential as therapeutic lifespan extension agents in humans. In order to properly evaluate these regimens, a few factors will be considered, including: side-effects, ease of implementation, effectiveness, cost, and range of benefits.

Lastly, the work will investigate historical data of populations and their diets in search of the real-world success of different methods of lifespan extension. For instance, some cultures, specifically in remote areas of Japan, have been practicing CR for centuries and show the longest lifespan of any society on Earth. Similarly, specific regions of France consume significantly more red grapes than any other population on the planet and show a marked decrease in coronary heart disease despite eating foods rich in fats. Consequently, the research will provide suggestions for a contemporary diet with the highest chance of bestowing a long and healthy life to its patrons. Overall, the thesis will attempt to synthesize the modern conceptions of ageing, while integrating proposed methods of lifespan extension into its framework. From this will follow an evaluation of the feasibility of these regimens and recommendations for how to live both younger and longer.


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