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Sunday, November 28, 2021

Memory and aging

From Wikipedia, the free encyclopedia
 

Age-related memory loss, sometimes described as "normal aging" (also spelled "ageing" in British English), is qualitatively different from memory loss associated with types of dementia such as Alzheimer's disease, and is believed to have a different brain mechanism.

Mild cognitive impairment

Mild cognitive impairment (MCI) is a condition in which people face memory problems more often than that of the average person their age. These symptoms, however, do not prevent them from carrying out normal activities and are not as severe as the symptoms for Alzheimer's disease (AD). Symptoms often include misplacing items, forgetting events or appointments, and having trouble finding words.

According to recent research, MCI is seen as the transitional state between cognitive changes of normal aging and Alzheimer's disease. Several studies have indicated that individuals with MCI are at an increased risk for developing AD, ranging from one percent to twenty-five percent per year; in one study twenty-four percent of MCI patients progressed to AD in two years and twenty percent more over three years, whereas another study indicated that the progression of MCI subjects was fifty-five percent in four and a half years. Some patients with MCI, however, never progress to AD.

Studies have also indicated patterns that are found in both MCI and AD. Much like patients with Alzheimer's disease, those suffering from mild cognitive impairment have difficulty accurately defining words and using them appropriately in sentences when asked. While MCI patients had a lower performance in this task than the control group, AD patients performed worse overall. The abilities of MCI patients stood out, however, due to the ability to provide examples to make up for their difficulties. AD patients failed to use any compensatory strategies and therefore exhibited the difference in use of episodic memory and executive functioning.

Normal aging

Normal aging is associated with a decline in various memory abilities in many cognitive tasks; the phenomenon is known as age-related memory impairment (AMI) or age-associated memory impairment (AAMI). The ability to encode new memories of events or facts and working memory shows decline in both cross-sectional and longitudinal studies. Studies comparing the effects of aging on episodic memory, semantic memory, short-term memory and priming find that episodic memory is especially impaired in normal aging; some types of short-term memory are also impaired. The deficits may be related to impairments seen in the ability to refresh recently processed information.

Source information is one type of episodic memory that suffers with old age; this kind of knowledge includes where and when the person learned the information. Knowing the source and context of information can be extremely important in daily decision-making, so this is one way in which memory decline can affect the lives of the elderly. Therefore, reliance on political stereotypes is one way to use their knowledge about the sources when making judgments, and the use of metacognitive knowledge gains importance. This deficit may be related to declines in the ability to bind information together in memory during encoding and retrieve those associations at a later time.

Throughout the many years of studying the progression of aging and memory, it has been hard to distinguish an exact link between the two. Many studies have tested psychologists theories throughout the years and they have found solid evidence that supports older adults having a harder time recalling contextual information while the more familiar or automatic information typically stays well preserved throughout the aging process (Light, 2000). Also, there is an increase of irrelevant information as one ages which can lead to an elderly person believing false information since they are often in a state of confusion.

Episodic memory is supported by networks spanning frontal, temporal, and parietal lobes. The interconnections in the lobes are presumed to enable distinct aspects of memory, whereas the effects of gray matter lesions have been extensively studied, less is known about the interconnecting fiber tracts. In aging, degradation of white matter structure has emerged as an important general factor, further focusing attention on the critical white matter connections.

Exercise affects many people young and old. For the young, if exercise is introduced it can form a constructive habit that can be instilled throughout adulthood. For the elderly, especially those with Alzheimer's or other diseases that affect the memory, when the brain is introduced to exercise the hippocampus is likely to retain its size and improve its memory.

It is also possible that the years of education a person has had and the amount of attention they received as a child might be a variable closely related to the links of aging and memory. There is a positive correlation between early life education and memory gains in older age. This effect is especially significant in women.

In particular, associative learning, which is another type of episodic memory, is vulnerable to the effects of aging, and this has been demonstrated across various study paradigms. This has been explained by the Associative Deficit Hypothesis (ADH), which states that aging is associated with a deficiency in creating and retrieving links between single units of information. This can include knowledge about context, events or items. The ability to bind pieces of information together with their episodic context in a coherent whole has been reduced in the elderly population. Furthermore, the older adults' performances in free recall involved temporal contiguity to a lesser extent than for younger people, indicating that associations regarding contiguity become weaker with age.

Several reasons have been speculated as to why older adults use less effective encoding and retrieval strategies as they age. The first is the "disuse" view, which states that memory strategies are used less by older adults as they move further away from the educational system. Second is the "diminished attentional capacity" hypothesis, which means that older people engage less in self-initiated encoding due to reduced attentional capacity. The third reason is the "memory self-efficacy," which indicates that older people do not have confidence in their own memory performances, leading to poor consequences. It is known that patients with Alzheimer's disease and patients with semantic dementia both exhibit difficulty in tasks that involve picture naming and category fluency. This is tied to damage to their semantic network, which stores knowledge of meanings and understandings.

One phenomenon, known as "Senior Moments", is a memory deficit that appears to have a biological cause. When an older adult is interrupted while completing a task, it is likely that the original task at hand can be forgotten. Studies have shown that the brain of an older adult does not have the ability to re-engage after an interruption and continues to focus on the particular interruption unlike that of a younger brain. This inability to multi-task is normal with aging and is expected to become more apparent with the increase of older generations remaining in the work field.

A biological explanation for memory deficits in aging includes a postmortem examination of five brains of elderly people with better memory than average. These people are called the "super aged," and it was found that these individuals had fewer fiber-like tangles of tau protein than in typical elderly brains. However, a similar amount of amyloid plaque was found.

More recent research has extended established findings of age related decline in executive functioning, by examining related cognitive processes that underlie healthy older adults' sequential performance. Sequential performance refers to the execution of a series steps needed to complete a routine, such as the steps required to make a cup of coffee or drive a car. An important part of healthy aging involves older adults' use of memory and inhibitory processes to carry out daily activities in a fixed order without forgetting the sequence of steps that were just completed while remembering the next step in the sequence. A study from 2009 examined how young and older adults differ in the underlying representation of a sequence of tasks and their efficiency at retrieving the information needed to complete their routine. Findings from this study revealed that when older and young adults had to remember a sequence of eight animal images arranged in a fixed order, both age groups spontaneously used the organizational strategy of chunking to facilitate retrieval of information. However, older adults were slower at accessing each chunk compared to younger adults, and were better able to benefit from the use of memory aids, such as verbal rehearsal to remember the order of the fixed sequence. Results from this study suggest that there are age differences in memory and inhibitory processes that affect people's sequence of actions and the use of memory aids could facilitate the retrieval of information in older age.

Causes

The causes for memory issues and aging is still unclear, even after the many theories have been tested. There has yet to be a distinct link between the two because it is hard to determine exactly how each aspect of aging effects the memory and aging process. However, it is known that the brain shrinks with age due to the expansion of ventricles causing there to be little room in the head. Unfortunately, it is hard to provide a solid link between the shrinking brain and memory loss due to not knowing exactly which area of the brain has shrunk and what the importance of that area truly is in the aging process (Baddeley, Anderson, & Eysenck, 2015) Attempting to recall information or a situation that has happened can be very difficult since different pieces of information of an event are stored in different areas. During recall of an event, the various pieces of information are pieced back together again and any missing information is filled up by our brains, unconsciously which can account for ourselves receiving and believing false information (Swaab, 2014).

Memory lapses can be both aggravating and frustrating but they are due to the overwhelming number of information that is being taken in by the brain. Issues in memory can also be linked to several common physical and psychological causes, such as: anxiety, dehydration, depression, infections, medication side effects, poor nutrition, vitamin B12 deficiency, psychological stress, substance abuse, chronic alcoholism, thyroid imbalances, and blood clots in the brain. Taking care of your body and mind with appropriate medication, doctoral check-ups, and daily mental and physical exercise can prevent some of these memory issues.

Some memory issues are due to stress, anxiety, or depression. A traumatic life event, such as the death of a spouse, can lead to changes in lifestyle and can leave an elderly person feeling unsure of themselves, sad, and lonely. Dealing with such drastic life changes can therefore leave some people confused or forgetful. While in some cases these feelings may fade, it is important to take these emotional problems seriously. By emotionally supporting a struggling relative and seeking help from a doctor or counselor, the forgetfulness can be improved.

Memory loss can come from different situations of trauma including accidents, head-injuries and even from situations of abuse in the past. Sometimes the memories of traumas can last a lifetime and other times they can be forgotten, intentionally or not, and the causes are highly debated throughout psychology. There is a possibility that the damage to the brain makes it harder for a person to encode and process information that should be stored in long-term memory (Nairne, 2000). There is support for environmental cues being helpful in recovery and retrieval of information, meaning that there is enough significance to the cue that it brings back the memory.

Theories

Tests and data show that as people age, the contiguity effect, which is stimuli that occur close together in the associated time, starts to weaken. This is supported by the associative deficit theory of memory, which access the memory performance of an elder person and is attributed to their difficulty in creating and retaining cohesive episodes. The supporting research in this test, after controlling for sex, education, and other health-related issues, show that greater age was associated with lower hit and greater false alarm rates, and also a more liberal bias response on recognition tests.

Older people have a higher tendency to make outside intrusions during a memory test. This can be attributed to the inhibition effect. Inhibition caused participants to take longer time in recalling or recognizing an item, and also subjected the participants to make more frequent errors. For instance, in a study using metaphors as the test subject, older participants rejected correct metaphors more often than literally false statements.

Working memory, which as previously stated is a memory system that stores and manipulates information as we complete cognitive tasks, demonstrates great declines during the aging process. There have been various theories offered to explain why these changes may occur, which include fewer attentional resources, slower speed of processing, less capacity to hold information, and lack of inhibitory control. All of these theories offer strong arguments, and it is likely that the decline in working memory is due to the problems cited in all of these areas.

Some theorists argue that the capacity of working memory decreases as we age, and we are able to hold less information. In this theory, declines in working memory are described as the result of limiting the amount of information an individual can simultaneously keep active, so that a higher degree of integration and manipulation of information is not possible because the products of earlier memory processing are forgotten before the subsequent products.

Another theory that is being examined to explain age related declines in working memory is that there is a limit in attentional resources seen as we age. This means that older individuals are less capable of dividing their attention between two tasks, and thus tasks with higher attentional demands are more difficult to complete due to a reduction in mental energy. Tasks that are simple and more automatic, however, see fewer declines as we age. Working memory tasks often involve divided attention, thus they are more likely to strain the limited resources of aging individuals.

Speed of processing is another theory that has been raised to explain working memory deficits. As a result of various studies he has completed examining this topic, Salthouse argues that as we age our speed of processing information decreases significantly. It is this decrease in processing speed that is then responsible for our inability to use working memory efficiently as we age. The younger persons brain is able to obtain and process information at a quicker rate which allows for subsequent integration and manipulation needed to complete the cognitive task at hand. As this processing slows, cognitive tasks that rely on quick processing speed then become more difficult.

Finally, the theory of inhibitory control has been offered to account for decline seen in working memory. This theory examines the idea that older adults are unable to suppress irrelevant information in working memory, and thus the capacity for relevant information is subsequently limited. Less space for new stimuli due may attribute to the declines seen in an individual's working memory as they age.

As we age, deficits are seen in the ability to integrate, manipulate, and reorganize the contents of working memory in order to complete higher level cognitive tasks such as problem solving, decision making, goal setting, and planning. More research must be completed in order to determine what the exact cause of these age-related deficits in working memory are. It is likely that attention, processing speed, capacity reduction, and inhibitory control may all play a role in these age-related deficits. The brain regions that are active during working memory tasks are also being evaluated, and research has shown that different parts of the brain are activated during working memory in younger adults as compared to older adults. This suggests that younger and older adults are performing these tasks differently.

Types of studies

There are two different methods for studying the ways aging and memory effect each other which are cross-sectional and longitudinal. Both methods have been used multiple times in the past, but they both have advantages and disadvantages. Cross-sectional studies include testing different groups of people at different ages on a single occasion. This is where most of the evidence for studies including memory and aging come from. The disadvantage of cross-sectional studies is not being able to compare current data to previous data, or make a prediction about the future data. Longitudinal studies include testing the same group of participants the same number of times, over many years which are carefully selected in order to reflect upon a full range of a population (Ronnlund, Nyberg, Backman, & Nilsson; Ronnlund & Nilsson, 2006). The advantage to longitudinal studies include being able to see the effects that aging has on performance for each participant and even being able to distinguish early signs of memory related diseases. However, this type of study can be very costly and timely which might make it more likely to have participants drop out over the course of the study. (Baddeley, Anderson, & Eysenck, 2015).

Mechanism research

A deficiency of the RbAp48 protein has been associated with age-related memory loss.

In 2010, experiments that have tested for the significance of under-performance of memory for an older adult group as compared to a young adult group, hypothesized that the deficit in associate memory due to age can be linked with a physical deficit. This deficit can be explained by the inefficient processing in the medial-temporal regions. This region is important in episodic memory, which is one of the two types of long-term human memory, and it contains the hippocampi, which are crucial in creating memorial association between items.

Age-related memory loss is believed to originate in the dentate gyrus, whereas Alzheimer's is believed to originate in the entorhinal cortex.

During normal aging, oxidative DNA damage in the brain accumulates in the promoters of genes involved in learning and memory, as well as in genes involved in neuronal survival. Oxidative DNA damage includes DNA single-strand breaks which can give rise to DNA double-strand breaks (DSBs). DSBs accumulate in neurons and astrocytes of the hippocampus and frontal cortex at early stages and during the progression to Alzheimer’s disease, a process that could be an important driver of neurodegeneration and cognitive decline.

Prevention and treatment

Various actions have been suggested to prevent memory loss or even improve memory.

The Mayo Clinic has suggested seven steps: stay mentally active, socialize regularly, get organized, eat a healthy diet, include physical activity in your daily routine, and manage chronic conditions. Because some of the causes of memory loss include medications, stress, depression, heart disease, excessive alcohol use, thyroid problems, vitamin B12 deficiency, not drinking enough water, and not eating nutritiously, fixing those problems could be a simple, effective way to slow down dementia. Some say that exercise is the best way to prevent memory problems, because that would increase blood flow to the brain and perhaps help new brain cells grow.

The treatment will depend on the cause of memory loss, but various drugs to treat Alzheimer's disease have been suggested in recent years. There are four drugs currently approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's, and they all act on the cholinergic system: Donepezil, Galantamine, Rivastigmine, and Tacrine. Although these medications are not the cure for Alzheimer's, symptoms may be reduced for up to eighteen months for mild or moderate dementia. These drugs do not forestall the ultimate decline to full Alzheimer's.

Also, modality is important in determining the strength of the memory. For instance, auditory creates stronger memory abilities than visual. This is shown by the higher recency and primacy effects of an auditory recall test compared to that of a visual test. Research has shown that auditory training, through instrumental musical activity or practice, can help preserve memory abilities as one ages. Specifically, in Hanna-Pladdy and McKay's experiment, they tested and found that the number of years of musical training, all things equal, leads to a better performance in non-verbal memory and increases the life span on cognition abilities in one's advanced years.

Caregiving

By keeping the patient active, focusing on their positive abilities, and avoiding stress, these tasks can easily be accomplished. Routines for bathing and dressing must be organized in a way so that the individual still feels a sense of independence. Simple approaches such as finding clothes with large buttons, elastic waist bands, or Velcro straps can ease the struggles of getting dressed in the morning. Further, finances should be managed or have a trusted individual appointed to manage them. Changing passwords to prevent over-use and involving a trusted family member or friend in managing accounts can prevent financial issues. When household chores begin to pile up, find ways to break down large tasks into small, manageable steps that can be rewarded. Finally, talking with and visiting a family member or friend with memory issues is very important. Using a respectful and simple approach, talking one-on-one can ease the pain of social isolation and bring much mental stimulation. Many people who experience memory loss and other cognitive impairments can have changes in behaviors that are challenging to deal with for care givers. See also Caregiver stress. To help caregivers should learn different ways to communicate and to deescalate possibly aggressive situations. Because decision making skills can be impaired, it can be beneficial to give simple commands instead of asking multiple questions. See also Caring for People with Dementia. Caregiving can be a physically, mentally, and emotionally taxing job to take on. A caregiver also needs to remember to care for themselves, taking breaks, finding time to themselves and possibly joining a support group are a few ways to avoid burnout.

Domains of memory spared vs. affected

In contrast, implicit, or procedural memory, typically shows no decline with age. Other types of short-term memory show little decline, and semantic knowledge (e.g. vocabulary) actually improves with age. In addition, the enhancement seen in memory for emotional events is also maintained with age.

Losing working memory has been cited as being the primary reason for a decline in a variety of cognitive tasks due to aging. These tasks include long-term memory, problem solving, decision making, and language. Working memory involves the manipulation of information that is being obtained, and then using this information to complete a task. For example, the ability of one to recite numbers they have just been given backwards requires working memory, rather than just simple rehearsal of the numbers which would require only short-term memory. One's ability to tap into one's working memory declines as the aging process progresses. It has been seen that the more complex a task is, the more difficulty the aging person has with completing this task. Active reorganization and manipulation of information becomes increasingly harder as adults age. When an older individual is completing a task, such as having a conversation or doing work, they are using their working memory to help them complete this task. As they age, their ability to multi-task seems to decline; thus after an interruption it is often more difficult for an aging individual to successfully finish the task at hand. Additionally, working memory plays a role in the comprehension and production of speech. There is often a decline in sentence comprehension and sentence production as individuals age. Rather than linking this decline directly to deficits in linguistic ability, it is actually deficits in working memory that contribute to these decreasing language skills.

Qualitative changes

Most research on memory and aging has focused on how older adults perform worse at a particular memory task. However, researchers have also discovered that simply saying that older adults are doing the same thing, only less of it, is not always accurate. In some cases, older adults seem to be using different strategies than younger adults. For example, brain imaging studies have revealed that older adults are more likely to use both hemispheres when completing memory tasks than younger adults. In addition, older adults sometimes show a positivity effect when remembering information, which seems to be a result of the increased focus on regulating emotion seen with age. For instance, eye tracking reveals that older adults showed preferential looking toward happy faces and away from sad faces.

 

Biogerontology

From Wikipedia, the free encyclopedia
 
The hand of an older adult

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick has said that the natural average lifespan for a human is around 92 years and, if humans do not invent new approaches to treat aging, they will be stuck with this lifespan. James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000. Many surveyed biogerontologists have predicted life expectancies of more than three centuries for people born after the year 2100. Other scientists, more controversially, suggest the possibility of unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age". The idea of this approach is to use presently available technology to extend lifespans of currently living humans long enough for future technological progress to resolve any remaining aging-related issues. This concept has been referred to as longevity escape velocity.

Biomedical gerontology, also known as experimental gerontology and life extension, is a sub-discipline of biogerontology endeavoring to slow, prevent, and even reverse aging in both humans and animals.

Approaches to aging

Wrinkled skin on the face is a characteristic feature of old people

Biogerontologists vary in the degree to which they focus on the study of the aging process as a means of mitigating the diseases of aging, or as a method for extending lifespan. A relatively new interdisciplinary field called geroscience focuses on preventing diseases of aging and prolonging the 'healthspan' over which an individual lives without serious illness. The approach of biogerontologists is that aging is disease per se and should be treated directly, with the ultimate goal of having the probability of individual dying be independent of their age (if external factors are held constant). This is in contrast to the opinion that maximum life span can not, or should not, be altered.

Biogerontology should not be confused with geriatrics, which is a field of medicine that studying the treatment of existing disease in aging people, rather than the treatment of aging itself.

There are numerous theories of aging, and no one theory has been entirely accepted. At their extremes, the wide spectrum of aging theories can be categorized into programmed theories - which imply that aging follows a biological timetable, and error theories - which suggest aging occurs due to cumulative damage experienced by organisms.

Stochastic theories

Stochastic theories of aging are theories suggesting that aging is caused by small changes in the body over time and the body's failure to restore the system and mend the damages to the body. Cells and tissues are injured due to the accumulation of damage over time resulting in the diminished functioning of organs. The notion of accumulated damage was first introduced in 1882 by biologist Dr. August Weismann as the "wear and tear" theory.

Wear and tear theories

Wear and tear theories of aging began to be introduced yet in 19th century. They suggest that as an individual ages, body parts such as cells and organs wear out from continued use. Wearing of the body can be attributable to internal or external causes that eventually lead to an accumulation of insults which surpasses the capacity for repair. Due to these internal and external insults, cells lose their ability to regenerate, which ultimately leads to mechanical and chemical exhaustion. Some insults include chemicals in the air, food, or smoke. Other insults may be things such as viruses, trauma, free radicals, cross-linking, and high body temperature.

Accumulation

Accumulation theories of aging suggest that aging is bodily decline that results from an accumulation of elements, whether introduced to the body from the environment or resulting from cell metabolism.

Mutation accumulation theory

Mutation accumulation theory was first proposed by Peter Medawar in 1952 as an evolutionary explanation for biological ageing and the associated decline in fitness that accompanies it. The theory explains that, in the case where harmful mutations are only expressed later in life, when reproduction has ceased and future survival is increasingly unlikely, then these mutations are likely to be unknowingly passed on to future generations. In this situation the force of natural selection will be weak, and so insufficient to consistently eliminate these mutations. Medawar posited that over time these mutations would accumulate due to genetic drift and lead to the evolution of what is now referred to as ageing.

Free radical theory

Free radicals are reactive molecules produced by cellular and environmental processes, and can damage the elements of the cell such as the cell membrane and DNA and cause irreversible damage. The free-radical theory of aging proposes that this damage cumulatively degrades the biological function of cells and impacts the process of aging. The idea that free radicals are toxic agents was first proposed by Rebeca Gerschman and colleagues in 1945, but came to prominence in 1956, when Denham Harman proposed the free-radical theory of aging and even demonstrated that free radical reactions contribute to the degradation of biological systems. Oxidative damage of many types accumulate with age, such as oxidative stress that oxygen-free radicals, because the free radical theory of aging argues that aging results from the damage generated by reactive oxygen species (ROS). ROS are small, highly reactive, oxygen-containing molecules that can damage a complex of cellular components such as fat, proteins, or from DNA; they are naturally generated in small amounts during the body's metabolic reactions. These conditions become more common as humans grow older and include diseases related to aging, such as dementia, cancer and heart disease. Amount of free radicals in the cell can be reduced with help of antioxidants. But there's a problem that some free radicals are used by organism as signal molecules, and too active general reduction of free radicals causes to organism more harm than good. Some time ago idea of slowing aging using antioxidants were very popular but now high doses of antioxidants are considered harmful. At present some scientists try to invent approaches of local suppression of free radicals only in certain places of cells. Efficiency of such approach remains to be unclear, research is ongoing.

DNA damage theories

DNA damage has been one of the major causes in diseases related to aging. The stability of the genome is defined by the cells machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. One hypothesis proposed by physicist Gioacchino Failla in 1958 is that damage accumulation to the DNA causes aging. The hypothesis was developed soon by physicist Leó Szilárd. This theory has changed over the years as new research has discovered new types of DNA damage and mutations, and several theories of aging argue that DNA damage with or without mutations causes aging.

DNA damage is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of standard base pairs. The theory that DNA damage is the primary cause of aging is based, in part, on evidence in human and mouse that inherited deficiencies in DNA repair genes often cause accelerated aging. There is also substantial evidence that DNA damage accumulates with age in mammalian tissues, such as those of the brain, muscle, liver and kidney (see DNA damage theory of aging and DNA damage (naturally occurring)). One expectation of the theory (that DNA damage is the primary cause of aging) is that among species with differing maximum life spans, the capacity to repair DNA damage should correlate with lifespan. The first experimental test of this idea was by Hart and Setlow who measured the capacity of cells from seven different mammalian species to carry out DNA repair. They found that nucleotide excision repair capability increased systematically with species longevity. This correlation was striking and stimulated a series of 11 additional experiments in different laboratories over succeeding years on the relationship of nucleotide excision repair and life span in mammalian species (reviewed by Bernstein and Bernstein). In general, the findings of these studies indicated a good correlation between nucleotide excision repair capacity and life span. Further support for the theory that DNA damage is the primary cause of aging comes from study of Poly ADP ribose polymerases (PARPs). PARPs are enzymes that are activated by DNA strand breaks and play a role in DNA base excision repair. Burkle et al. reviewed evidence that PARPs, and especially PARP-1, are involved in maintaining mammalian longevity. The life span of 13 mammalian species correlated with poly(ADP ribosyl)ation capability measured in mononuclear cells. Furthermore, lymphoblastoid cell lines from peripheral blood lymphocytes of humans over age 100 had a significantly higher poly(ADP-ribosyl)ation capability than control cell lines from younger individuals.

Cross-linking theory

The cross-linking theory proposes that advanced glycation end-products (stable bonds formed by the binding of glucose to proteins) and other aberrant cross-links accumulating in aging tissues is the cause of aging. The crosslinking of proteins disables their biological functions. The hardening of the connective tissue, kidney diseases, and enlargement of the heart are connected to the cross-linking of proteins. Crosslinking of DNA can induce replication errors, and this leads to deformed cells and increases the risk of cancer.

Genetic

Genetic theories of aging propose that aging is programmed within each individual's genes. According to this theory, genes dictate cellular longevity. Programmed cell death, or apoptosis, is determined by a "biological clock" via genetic information in the nucleus of the cell. Genes responsible for apoptosis provide an explanation for cell death, but are less applicable to death of an entire organism. An increase in cellular apoptosis may correlate to aging, but is not a 'cause of death'. Environmental factors and genetic mutations can influence gene expression and accelerate aging.

More recently epigenetics have been explored as a contributing factor. The epigenetic clock, which relatively objectively measures the biological age of cells, are useful tool for testing different anti-aging approaches. The most famous epigenetic clock is Horvath's clock, but now already more accurate analogues have appeared.

General imbalance

General imbalance theories of aging suggest that body systems, such as the endocrine, nervous, and immune systems, gradually decline and ultimately fail to function. The rate of failure varies system by system.

Immunological theory

The immunological theory of aging suggests that the immune system weakens as an organism ages. This makes the organism unable to fight infections and less able to destroy old and neoplastic cells. This leads to aging and will eventually lead to death. This theory of aging was developed by Roy Walford in 1969. According to Walford, incorrect immunological procedures are the cause of the process of aging.

DNA repair-deficiency disorder

From Wikipedia, the free encyclopedia
 
DNA repair-deficiency disorder
SpecialtyEndocrinology 

A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.

DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both.

DNA repair defects and accelerated aging

DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely. Because the accelerated aging diseases display different aspects of aging, but never every aspect, they are often called segmental progerias by biogerontologists.

Human disorders with accelerated aging

Examples

Some examples of DNA repair defects causing progeroid syndromes in humans or mice are shown in Table 1.

Table 1. DNA repair proteins that, when deficient, cause features of accelerated aging (segmental progeria).
Protein Pathway Description
ATR Nucleotide excision repair deletion of ATR in adult mice leads to a number of disorders including hair loss and graying, kyphosis, osteoporosis, premature involution of the thymus, fibrosis of the heart and kidney and decreased spermatogenesis
DNA-PKcs Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; higher level of DNA damage persistence
ERCC1 Nucleotide excision repair, Interstrand cross link repair deficient transcription coupled NER with time-dependent accumulation of transcription-blocking damages; mouse life span reduced from 2.5 years to 5 months;) Ercc1−/− mice are leukopenic and thrombocytopenic, and there is extensive adipose transformation of the bone marrow, hallmark features of normal aging in mice
ERCC2 (XPD) Nucleotide excision repair (also transcription as part of TFIIH) some mutations in ERCC2 cause Cockayne syndrome in which patients have segmental progeria with reduced stature, mental retardation, cachexia (loss of subcutaneous fat tissue), sensorineural deafness, retinal degeneration, and calcification of the central nervous system; other mutations in ERCC2 cause trichothiodystrophy in which patients have segmental progeria with brittle hair, short stature, progressive cognitive impairment and abnormal face shape; still other mutations in ERCC2 cause xeroderma pigmentosum (without a progeroid syndrome) and with extreme sun-mediated skin cancer predisposition
ERCC4 (XPF) Nucleotide excision repair, Interstrand cross link repair, Single-strand annealing, Microhomology-mediated end joining mutations in ERCC4 cause symptoms of accelerated aging that affect the neurologic, hepatobiliary, musculoskeletal, and hematopoietic systems, and cause an old, wizened appearance, loss of subcutaneous fat, liver dysfunction, vision and hearing loss, chronic kidney disease, muscle wasting, osteopenia, kyphosis and cerebral atrophy
ERCC5 (XPG) Nucleotide excision repair, Homologous recombinational repair, Base excision repair mice with deficient ERCC5 show loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months
ERCC6 (Cockayne syndrome B or CS-B) Nucleotide excision repair [especially transcription coupled repair (TC-NER) and interstrand crosslink repair] premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines
ERCC8 (Cockayne syndrome A or CS-A) Nucleotide excision repair [especially transcription coupled repair (TC-NER) and interstrand crosslink repair] premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines
GTF2H5 (TTDA) Nucleotide excision repair deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein with retarded repair of 6-4-photoproducts
Ku70 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; persistent foci of DNA double-strand break repair proteins
Ku80 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; defective repair of spontaneous DNA damage
Lamin A Non-homologous end joining, Homologous recombination increased DNA damage and chromosome aberrations; progeria; aspects of premature aging; altered expression of numerous DNA repair factors
NRMT1 Nucleotide excision repair mutation in NRMT1 causes decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration
RECQL4 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining mutations in RECQL4 cause Rothmund-Thomson syndrome, with alopecia, sparse eye brows and lashes, cataracts and osteoporosis
SIRT6 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining  SIRT6-deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging-associated degenerative processes
SIRT7 Non-homologous end joining mice defective in SIRT7 show phenotypic and molecular signs of accelerated aging such as premature pronounced curvature of the spine, reduced life span, and reduced non-homologous end joining
Werner syndrome helicase Homologous recombination, Non-homologous end joining, Base excision repair, Replication arrest recovery shorter lifespan, earlier onset of aging related pathologies, genome instability
ZMPSTE24 Homologous recombination lack of Zmpste24 prevents lamin A formation and causes progeroid phenotypes in mice and humans, increased DNA damage and chromosome aberrations, sensitivity to DNA-damaging agents and deficiency in homologous recombination

DNA repair defects distinguished from "accelerated aging"

Most of the DNA repair deficiency diseases show varying degrees of "accelerated aging" or cancer (often some of both). But elimination of any gene essential for base excision repair kills the embryo—it is too lethal to display symptoms (much less symptoms of cancer or "accelerated aging"). Rothmund-Thomson syndrome and xeroderma pigmentosum display symptoms dominated by vulnerability to cancer, whereas progeria and Werner syndrome show the most features of "accelerated aging". Hereditary nonpolyposis colorectal cancer (HNPCC) is very often caused by a defective MSH2 gene leading to defective mismatch repair, but displays no symptoms of "accelerated aging". On the other hand, Cockayne Syndrome and trichothiodystrophy show mainly features of accelerated aging, but apparently without an increased risk of cancer. Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging". (Also see the "DNA damage theory of aging" for a discussion of the evidence that DNA damage is the primary underlying cause of aging.)

Debate concerning "accelerated aging"

Some biogerontologists question that such a thing as "accelerated aging" actually exists, at least partly on the grounds that all of the so-called accelerated aging diseases are segmental progerias. Many disease conditions such as diabetes, high blood pressure, etc., are associated with increased mortality. Without reliable biomarkers of aging it is hard to support the claim that a disease condition represents more than accelerated mortality.

Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage. The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging". Such conditions, it is argued, are readily distinguishable from genetic diseases associated with increased mortality, but not associated with an aging phenotype, such as cystic fibrosis and sickle cell anemia. It is further argued that segmental aging phenotype is a natural part of aging insofar as genetic variation leads to some people being more disposed than others to aging-associated diseases such as cancer and Alzheimer's disease.

DNA repair defects and increased cancer risk

Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer. When a mutation is present in a DNA repair gene, the repair gene will either not be expressed or be expressed in an altered form. Then the repair function will likely be deficient, and, as a consequence, damages will tend to accumulate. Such DNA damages can cause errors during DNA synthesis leading to mutations, some of which may give rise to cancer. Germ-line DNA repair mutations that increase the risk of cancer are listed in the Table.

Inherited DNA repair gene mutations that increase cancer risk
DNA repair gene Protein Repair pathways affected Cancers with increased risk
breast cancer 1 & 2 BRCA1 BRCA2 HRR of double strand breaks and daughter strand gaps breast, ovarian 
ataxia telangiectasia mutated ATM Different mutations in ATM reduce HRR, SSA or NHEJ  leukemia, lymphoma, breast 
Nijmegen breakage syndrome NBS (NBN) NHEJ  lymphoid cancers 
MRE11A MRE11 HRR and NHEJ  breast 
Bloom syndrome BLM (helicase) HRR  leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stomach, tonsil, larynx, uterus 
WRN WRN HRR, NHEJ, long patch BER  soft tissue sarcoma, colorectal, skin, thyroid, pancreas 
RECQL4 RECQ4 Helicase likely active in HRR  basal cell carcinoma, squamous cell carcinoma, intraepidermal carcinoma 
Fanconi anemia genes FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N FANCA etc. HRR and TLS  leukemia, liver tumors, solid tumors many areas 
XPC, XPE (DDB2) XPC, XPE Global genomic NER, repairs damage in both transcribed and untranscribed DNA  skin cancer (melanoma and non-melanoma)
XPA, XPB, XPD, XPF, XPG XPA XPB XPD XPF XPG Transcription coupled NER repairs the transcribed strands of transcriptionally active genes  skin cancer (melanoma and non-melanoma) 
XPV (also called polymerase H) XPV (POLH) Translesion synthesis (TLS)  skin cancers (basal cell, squamous cell, melanoma) 
mutS (E. coli) homolog 2, mutS (E. coli) homolog 6, mutL (E. coli) homolog 1,

postmeiotic segregation increased 2 (S. cerevisiae)

MSH2 MSH6 MLH1 PMS2 MMR  colorectal, endometrial 
mutY homolog (E. coli) MUTYH BER of A paired with 8-oxo-dG  colon 
TP53 P53 Direct role in HRR, BER, NER and acts in DNA damage response for those pathways and for NHEJ and MMR  sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas 
NTHL1 NTHL1 BER for Tg, FapyG, 5-hC, 5-hU in dsDNA Colon cancer, endometrial cancer, duodenal cancer, basal-cell carcinoma

 

Cancer epigenetics

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Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, or even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. Several medications which have epigenetic impact are now used in several of these diseases.

Epigenetics patterns in a normal and cancer cells
 
Epigenetic alterations in tumour progression

Mechanisms

DNA methylation

A DNA molecule fragment that is methylated at two cytosines

In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity. Typically, this methylation only occurs at cytosines that are located 5' to guanosine in the CpG dinucleotides of higher order eukaryotes. However, epigenetic DNA methylation differs between normal cells and tumor cells in humans. The "normal" CpG methylation profile is often inverted in cells that become tumorigenic. In normal cells, CpG islands preceding gene promoters are generally unmethylated, and tend to be transcriptionally active, while other individual CpG dinucleotides throughout the genome tend to be methylated. However, in cancer cells, CpG islands preceding tumor suppressor gene promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic repeat sequences is often decreased.

Hypermethylation of tumor suppressor gene promoter regions can result in silencing of those genes. This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis. The addition of methyl groups to cytosines causes the DNA to coil tightly around the histone proteins, resulting in DNA that can not undergo transcription (transcriptionally silenced DNA). Genes commonly found to be transcriptionally silenced due to promoter hypermethylation include: Cyclin-dependent kinase inhibitor p16, a cell-cycle inhibitor; MGMT, a DNA repair gene; APC, a cell cycle regulator; MLH1, a DNA-repair gene; and BRCA1, another DNA-repair gene. Indeed, cancer cells can become addicted to the transcriptional silencing, due to promoter hypermethylation, of some key tumor suppressor genes, a process known as epigenetic addiction.

Hypomethylation of CpG dinucleotides in other parts of the genome leads to chromosome instability due to mechanisms such as loss of imprinting and reactivation of transposable elements. Loss of imprinting of insulin-like growth factor gene (IGF2) increases risk of colorectal cancer and is associated with Beckwith-Wiedemann syndrome which significantly increases the risk of cancer for newborns. In healthy cells, CpG dinucleotides of lower densities are found within coding and non-coding intergenic regions. Expression of some repetitive sequences and meiotic recombination at centromeres are repressed through methylation 

The entire genome of a cancerous cell contains significantly less methylcytosine than the genome of a healthy cell. In fact, cancer cell genomes have 20-50% less methylation at individual CpG dinucleotides across the genome. CpG islands found in promoter regions are usually protected from DNA methylation. In cancer cells CpG islands are hypomethylated  The regions flanking CpG islands called CpG island shores are where most DNA methylation occurs in the CpG dinucleotide context. Cancer cells are deferentially methylated at CpG island shores. In cancer cells, hypermethylation in the CpG island shores move into CpG islands, or hypomethylation of CpG islands move into CpG island shores eliminating sharp epigenetic boundaries between these genetic elements. In cancer cells "global hypomethylation" due to disruption in DNA methyltransferases (DNMTs) may promote mitotic recombination and chromosome rearrangement, ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis.

CpG island methylation is important in regulation of gene expression, yet cytosine methylation can lead directly to destabilizing genetic mutations and a precancerous cellular state. Methylated cytosines make hydrolysis of the amine group and spontaneous conversion to thymine more favorable. They can cause aberrant recruitment of chromatin proteins. Cytosine methylations change the amount of UV light absorption of the nucleotide base, creating pyrimidine dimers. When mutation results in loss of heterozygosity at tumor suppressor gene sites, these genes may become inactive. Single base pair mutations during replication can also have detrimental effects.

Histone modification

Eukaryotic DNA has a complex structure. It is generally wrapped around special proteins called histones to form a structure called a nucleosome. A nucleosome consists of 2 sets of 4 histones: H2A, H2B, H3, and H4. Additionally, histone H1 contributes to DNA packaging outside of the nucleosome. Certain histone modifying enzymes can add or remove functional groups to the histones, and these modifications influence the level of transcription of the genes wrapped around those histones and the level of DNA replication. Histone modification profiles of healthy and cancerous cells tend to differ.

In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of histone H4 (decreased H4ac and H4me3). Additionally, mouse models have shown that a decrease in histone H4R3 asymmetric dimethylation (H4R3me2a) of the p19ARF promoter is correlated with more advanced cases of tumorigenesis and metastasis. In mouse models, the loss of histone H4 acetylation and trimethylation increases as tumor growth continues. Loss of histone H4 Lysine 16 acetylation (H4K16ac), which is a mark of aging at the telomeres, specifically loses its acetylation. Some scientists hope this particular loss of histone acetylation might be battled with a histone deacetylase (HDAC) inhibitor specific for SIRT1, an HDAC specific for H4K16.

Other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (H3K4me3), and increased monomethylation of histone H3 Lysine 9 (H3K9me) and trimethylation of histone H3 Lysine 27 (H3K27me3). These histone modifications can silence tumor suppressor genes despite the drop in methylation of the gene's CpG island (an event that normally activates genes).

Some research has focused on blocking the action of BRD4 on acetylated histones, which has been shown to increase the expression of the Myc protein, implicated in several cancers. The development process of the drug to bind to BRD4 is noteworthy for the collaborative, open approach the team is taking.

The tumor suppressor gene p53 regulates DNA repair and can induce apoptosis in dysregulated cells. E Soto-Reyes and F Recillas-Targa elucidated the importance of the CTCF protein in regulating p53 expression. CTCF, or CCCTC binding factor, is a zinc finger protein that insulates the p53 promoter from accumulating repressive histone marks. In certain types of cancer cells, the CTCF protein does not bind normally, and the p53 promoter accumulates repressive histone marks, causing p53 expression to decrease.

Mutations in the epigenetic machinery itself may occur as well, potentially responsible for the changing epigenetic profiles of cancerous cells. The histone variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering chromatin structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is detected in many cancers and is significantly associated with cellular proliferation and genomic instability. Histone variant macroH2A1 is important in the pathogenesis of many types of cancers, for instance in hepatocellular carcinoma. Other mechanisms include a decrease in H4K16ac may be caused by either a decrease in activity of a histone acetyltransferases (HATs) or an increase in deacetylation by SIRT1. Likewise, an inactivating frameshift mutation in HDAC2, a histone deacetylase that acts on many histone-tail lysines, has been associated with cancers showing altered histone acetylation patterns. These findings indicate a promising mechanism for altering epigenetic profiles through enzymatic inhibition or enhancement.

DNA damage, caused by UV light, ionizing radiation, environmental toxins, and metabolic chemicals, can also lead to genomic instability and cancer. The DNA damage response to double strand DNA breaks (DSB) is mediated in part by histone modifications. At a DSB, MRE11-RAD50-NBS1 (MRN) protein complex recruits ataxia telangiectasia mutated (ATM) kinase which phosphorylates Serine 129 of Histone 2A. MDC1, mediator of DNA damage checkpoint 1, binds to the phosphopeptide, and phosphorylation of H2AX may spread by a positive feedback loop of MRN-ATM recruitment and phosphorylation. TIP60 acetylates the γH2AX, which is then polyubiquitylated. RAP80, a subunit of the DNA repair breast cancer type 1 susceptibility protein complex (BRCA1-A), binds ubiquitin attached to histones. BRCA1-A activity arrests the cell cycle at the G2/M checkpoint, allowing time for DNA repair, or apoptosis may be initiated.

MicroRNA gene silencing

In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes. Some miRNAs also undergo methylation-associated silencing in cancer cells. Let-7 and miR15/16 play important roles in down-regulating RAS and BCL2 oncogenes, and their silencing occurs in cancer cells. Decreased expression of miR-125b1, a miRNA that functions as a tumor suppressor, was observed in prostate, ovarian, breast and glial cell cancers. In vitro experiments have shown that miR-125b1 targets two genes, HER2/neu and ESR1, that are linked to breast cancer. DNA methylation, specifically hypermethylation, is one of the main ways that the miR-125b1 is epigenetically silenced. In patients with breast cancer, hypermethylation of CpG islands located proximal to the transcription start site was observed. Loss of CTCF binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with DNA methylation and miR-125b1 silencing. Mechanistically, CTCF may function as a boundary element to stop the spread of DNA methylation. Results from experiments conducted by Soto-Reyes et al. indicate a negative effect of methylation on the function and expression of miR-125b1. Therefore, they concluded that DNA methylation has a part in silencing the gene. Furthermore, some miRNA's are epigenetically silenced early on in breast cancer, and therefore these miRNA's could potentially be useful as tumor markers. The epigenetic silencing of miRNA genes by aberrant DNA methylation is a frequent event in cancer cells; almost one third of miRNA promoters active in normal mammary cells were found hypermethylated in breast cancer cells - that is a several fold greater proportion than is usually observed for protein coding genes.

Metabolic recoding of epigenetics in cancer

Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. The accumulation of certain metabolites in cancer can target epigenetic enzymes to globally alter the epigenetic landscape. Cancer-related metabolic changes lead to locus-specific recoding of epigenetic marks. Cancer epigenetics can be precisely reprogramed by cellular metabolism through 1) dose-responsive modulation of cancer epigenetics by metabolites; 2) sequence-specific recruitment of metabolic enzymes; and 3) targeting of epigenetic enzymes by nutritional signals.

MicroRNA and DNA repair

DNA damage appears to be the primary underlying cause of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage can increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage can also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms).

Germ line mutations in DNA repair genes cause only 2–5% of colon cancer cases. However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal factor for these cancers.

Over-expression of certain miRNAs may directly reduce expression of specific DNA repair proteins. Wan et al. referred to 6 DNA repair genes that are directly targeted by the miRNAs indicated in parentheses: ATM (miR-421), RAD52 (miR-210, miR-373), RAD23B (miR-373), MSH2 (miR-21), BRCA1 (miR-182) and P53 (miR-504, miR-125b). More recently, Tessitore et al. listed further DNA repair genes that are directly targeted by additional miRNAs, including ATM (miR-18a, miR-101), DNA-PK (miR-101), ATR (miR-185), Wip1 (miR-16), MLH1, MSH2 and MSH6 (miR-155), ERCC3 and ERCC4 (miR-192) and UNG2 (mir-16, miR-34c and miR-199a). Of these miRNAs, miR-16, miR-18a, miR-21, miR-34c, miR-125b, miR-101, miR-155, miR-182, miR-185 and miR-192 are among those identified by Schnekenburger and Diederich as over-expressed in colon cancer through epigenetic hypomethylation. Over expression of any one of these miRNAs can cause reduced expression of its target DNA repair gene.

Up to 15% of the MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression. However, the majority of 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1 were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene.

In 28% of glioblastomas, the MGMT DNA repair protein is deficient but the MGMT promoter is not methylated. In the glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3’UTR (the three prime untranslated region of MGMT mRNA). Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor. In 29–66% of glioblastomas, DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT.

High mobility group A (HMGA) proteins, characterized by an AT-hook, are small, nonhistone, chromatin-associated proteins that can modulate transcription. MicroRNAs control the expression of HMGA proteins, and these proteins (HMGA1 and HMGA2) are architectural chromatin transcription-controlling elements. Palmieri et al. showed that, in normal tissues, HGMA1 and HMGA2 genes are targeted (and thus strongly reduced in expression) by miR-15, miR-16, miR-26a, miR-196a2 and Let-7a.

HMGA expression is almost undetectable in differentiated adult tissues but is elevated in many cancers. HGMA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed AT hooks, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinoma, show a strong increase of HMGA1a and HMGA1b proteins. Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is not only associated with cancers, but that the HMGA1 gene can act as an oncogene to cause cancer. Baldassarre et al., showed that HMGA1 protein binds to the promoter region of DNA repair gene BRCA1 and inhibits BRCA1 promoter activity. They also showed that while only 11% of breast tumors had hypermethylation of the BRCA1 gene, 82% of aggressive breast cancers have low BRCA1 protein expression, and most of these reductions were due to chromatin remodeling by high levels of HMGA1 protein.

HMGA2 protein specifically targets the promoter of ERCC1, thus reducing expression of this DNA repair gene. ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is unknown).

Palmieri et al. showed that each of the miRNAs that target HMGA genes are drastically reduced in almost all human pituitary adenomas studied, when compared with the normal pituitary gland. Consistent with the down-regulation of these HMGA-targeting miRNAs, an increase in the HMGA1 and HMGA2-specific mRNAs was observed. Three of these microRNAs (miR-16, miR-196a and Let-7a) have methylated promoters and therefore low expression in colon cancer. For two of these, miR-15 and miR-16, the coding regions are epigenetically silenced in cancer due to histone deacetylase activity. When these microRNAs are expressed at a low level, then HMGA1 and HMGA2 proteins are expressed at a high level. HMGA1 and HMGA2 target (reduce expression of) BRCA1 and ERCC1 DNA repair genes. Thus DNA repair can be reduced, likely contributing to cancer progression.

DNA repair pathways

A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error prone microhomology-mediated end joining pathway with increased expression in various cancers.

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.

Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two broad experimental survey articles also document most of these epigenetic DNA repair deficiencies in cancers.

Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see translesion synthesis) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.

The two gray-highlighted genes RAD51 and BRCA2, are required for homologous recombinational repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on RAD51 and BRCA2, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself.

Cyan-highlighted genes are in the microhomology-mediated end joining (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5-25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway. FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung. PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer, BRCA-mutated ovarian cancer, and BRCA-mutated serous ovarian cancer. Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in blue.

Frequencies of epimutations in DNA repair genes

Deficiencies in DNA repair proteins that function in accurate DNA repair pathways increase the risk of mutation. Mutation rates are strongly increased in cells with mutations in DNA mismatch repair or in homologous recombinational repair (HRR). Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see DNA repair defects and increased cancer risk).

In sporadic cancers, a deficiency in DNA repair is occasionally found to be due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 protein was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.

Epigenetic defects in DNA repair genes are frequent in cancers. In the table, multiple cancers were evaluated for reduced or absent expression of the DNA repair gene of interest, and the frequency shown is the frequency with which the cancers had an epigenetic deficiency of gene expression. Such epigenetic deficiencies likely arise early in carcinogenesis, since they are also frequently found (though at somewhat lower frequency) in the field defect surrounding the cancer from which the cancer likely arose (see Table).

Frequency of epigenetic reduction in DNA repair gene expression in sporadic cancers and in adjacent field defects
Cancer Gene Frequency in Cancer Frequency in Field Defect
Colorectal MGMT 46% 34%
Colorectal MGMT 47% 11%
Colorectal MGMT 70% 60%
Colorectal MSH2 13% 5%
Colorectal ERCC1 100% 40%
Colorectal PMS2 88% 50%
Colorectal XPF 55% 40%
Head and Neck MGMT 54% 38%
Head and Neck MLH1 33% 25%
Head and Neck MLH1 31% 20%
Stomach MGMT 88% 78%
Stomach MLH1 73% 20%
Esophagus MLH1 77%–100% 23%–79%

It appears that cancers may frequently be initiated by an epigenetic reduction in expression of one or more DNA repair enzymes. Reduced DNA repair likely allows accumulation of DNA damages. Error prone translesion synthesis past some of these DNA damages may give rise to a mutation with a selective advantage. A clonal patch with a selective advantage may grow and out-compete neighboring cells, forming a field defect. While there is no obvious selective advantage for a cell to have reduced DNA repair, the epimutation of the DNA repair gene may be carried along as a passenger when the cells with the selectively advantageous mutation are replicated. In the cells carrying both the epimutation of the DNA repair gene and the mutation with the selective advantage, further DNA damages will accumulate, and these could, in turn, give rise to further mutations with still greater selective advantages. Epigenetic defects in DNA repair may thus contribute to the characteristic high frequency of mutations in the genomes of cancers, and cause their carcinogenic progression.

Cancers have high levels of genome instability, associated with a high frequency of mutations. A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to carcinogenesis. On the basis of whole genome sequencing, cancers are found to have thousands to hundreds of thousands of mutations in their whole genomes. (Also see Mutation frequencies in cancers.) By comparison, the mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation. In the protein coding regions of the genome, there are only about 0.35 mutations between parent/child generations (less than one mutated protein per generation). Whole genome sequencing in blood cells for a pair of identical twin 100-year-old centenarians only found 8 somatic differences, though somatic variation occurring in less than 20% of blood cells would be undetected.

While DNA damages may give rise to mutations through error prone translesion synthesis, DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes. The DNA damages that accumulate due to epigenetic DNA repair defects can be a source of the increased epigenetic alterations found in many genes in cancers. In an early study, looking at a limited set of transcriptional promoters, Fernandez et al. examined the DNA methylation profiles of 855 primary tumors. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG sites evaluated) showed differential DNA methylation. Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there is a high level of epigenetic promoter methylation alterations in tumors. Some of these epigenetic alterations may contribute to cancer progression.

Epigenetic carcinogens

A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence. However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist. FDA label information for Vidaza, a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.

Cancer subtypes

Skin cancer

Melanoma is a deadly skin cancer that originates from melanocytes. Several epigenetic alterations are known to play a role in the transition of melanocytes to melanoma cells. This includes DNA methylation that can be inherited without making changes to the DNA sequence, as well as silencing the tumor suppressor genes in the epidermis that have been exposed to UV radiation for periods of time. The silencing of tumor suppressor genes leads to photocarcinogenesis which is associated to epigenetic alterations in DNA methylation, DNA methyltransferases, and histone acetylation. These alterations are the consequence of deregulation of their corresponding enzymes. Several histone methyltransferases and demethylases are among these enzymes.

Prostate cancer

Prostate cancer kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone. Prostate cancer is the second leading cause of cancer-caused fatalities in men, and within a man's lifetime, one in six men will have the disease. Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer, and have been seen in genes involved in hormonal response. More than 90% of prostate cancers show gene silencing by CpG island hypermethylation of the GSTP1 gene promoter, which protects prostate cells from genomic damage that is caused by different oxidants or carcinogens. Real-time methylation-specific polymerase chain reaction (PCR) suggests that many other genes are also hypermethylated. Gene expression in the prostate may be modulated by nutrition and lifestyle changes.

Cervical cancer

The second most common malignant tumor in women is invasive cervical cancer (ICC) and more than 50% of all invasive cervical cancer (ICC) is caused by oncongenic human papillomavirus 16 (HPV16). Furthermore, cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16. As in many cases, the causative factor for cancer does not always take a direct route from infection to the development of cancer. Genomic methylation patterns have been associated with invasive cervical cancer. Within the HPV16L1 region, 14 tested CpG sites have significantly higher methylation in CIN3+ than in HPV16 genomes of women without CIN3. Only 2/16 CpG sites tested in HPV16 upstream regulatory region were found to have association with increased methylation in CIN3+. This suggests that the direct route from infection to cancer is sometimes detoured to a precancerous state in cervix intraepithelial neoplasia. Additionally, increased CpG site methylation was found in low levels in most of the five host nuclear genes studied, including 5/5 TERT, 1/4 DAPK1, 2/5 RARB, MAL, and CADM1. Furthermore, 1/3 of CpG sites in mitochondrial DNA were associated with increased methylation in CIN3+. Thus, a correlation exists between CIN3+ and increased methylation of CpG sites in the HPV16 L1 open reading frame. This could be a potential biomarker for future screens of cancerous and precancerous cervical disease.

Leukemia

Recent studies have shown that the mixed-lineage leukemia (MLL) gene causes leukemia by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control. Mutations in MLL block the correct regulatory regions in leukemia associated translocations or insertions causing malignant transformation controlled by HOX genes. This is what leads to the increase in white blood cells. Leukemia related genes are managed by the same pathways that control epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. It was indicated that infections, electromagnetic fields and increased birth weight can contribute to being the causes of leukemia.

Sarcoma

There are about 15,000 new cases of sarcoma in the US each year, and about 6,200 people were projected to die of sarcoma in the US in 2014. Sarcomas comprise a large number of rare, histogenetically heterogeneous mesenchymal tumors that, for example, include chondrosarcoma, Ewing's sarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, synovial sarcoma, and (alveolar and embryonal) rhabdomyosarcoma. Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. These include APC, CDKN1A, CDKN2A, CDKN2B, Ezrin, FGFR1, GADD45A, MGMT, STK3, STK4, PTEN, RASSF1A, WIF1, as well as several miRNAs. Expression of epigenetic modifiers such as that of the BMI1 component of the PRC1 complex is deregulated in chondrosarcoma, Ewing's sarcoma, and osteosarcoma, and expression of the EZH2 component of the PRC2 complex is altered in Ewing's sarcoma and rhabdomyosarcoma. Similarly, expression of another epigenetic modifier, the LSD1 histone demethylase, is increased in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Drug targeting and inhibition of EZH2 in Ewing's sarcoma, or of LSD1 in several sarcomas, inhibits tumor cell growth in these sarcomas.

Identification methods

Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team. Recently, however, scientists have been moving toward a more genomic approach to determine an entire genomic profile for cancerous versus healthy cells.

Popular approaches for measuring CpG methylation in cells include:

Since bisulfite sequencing is considered the gold standard for measuring CpG methylation, when one of the other methods is used, results are usually confirmed using bisulfite sequencing[1]. Popular approaches for determining histone modification profiles in cancerous versus healthy cells include:

Diagnosis and prognosis

Researchers are hoping to identify specific epigenetic profiles of various types and subtypes of cancer with the goal of using these profiles as tools to diagnose individuals more specifically and accurately. Since epigenetic profiles change, scientists would like to use the different epigenomic profiles to determine the stage of development or level of aggressiveness of a particular cancer in patients. For example, hypermethylation of the genes coding for Death-Associated Protein Kinase (DAPK), p16, and Epithelial Membrane Protein 3 (EMP3) have been linked to more aggressive forms of lung, colorectal, and brain cancers. This type of knowledge can affect the way that doctors will diagnose and choose to treat their patients.

Another factor that will influence the treatment of patients is knowing how well they will respond to certain treatments. Personalized epigenomic profiles of cancerous cells can provide insight into this field. For example, MGMT is an enzyme that reverses the addition of alkyl groups to the nucleotide guanine. Alkylating guanine, however, is the mechanism by which several chemotherapeutic drugs act in order to disrupt DNA and cause cell death. Therefore, if the gene encoding MGMT in cancer cells is hypermethylated and in effect silenced or repressed, the chemotherapeutic drugs that act by methylating guanine will be more effective than in cancer cells that have a functional MGMT enzyme.

Epigenetic biomarkers can also be utilized as tools for molecular prognosis. In primary tumor and mediastinal lymph node biopsy samples, hypermethylation of both CDKN2A and CDH13 serves as the marker for increased risk of faster cancer relapse and higher death rate of patients.

Treatment

Epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones plays a role in the formation and progression of cancer. Pharmaceuticals that reverse epigenetic changes might have a role in a variety of cancers.

Recently, it is evidently known that associations between specific cancer histotypes and epigenetic changes can facilitate the development of novel epi-drugs. Drug development has focused mainly on modifying DNA methyltransferase, histone acetyltransferase (HAT) and histone deacetylase (HDAC).

Drugs that specifically target the inverted methylation pattern of cancerous cells include the DNA methyltransferase inhibitors azacitidine and decitabine. These hypomethylating agents are used to treat myelodysplastic syndrome, a blood cancer produced by abnormal bone marrow stem cells. These agents inhibit all three types of active DNA methyltransferases, and had been thought to be highly toxic, but proved to be effective when used in low dosage, reducing progression of myelodysplastic syndrome to leukemia.

Histone deacetylase (HDAC) inhibitors show efficacy in treatment of T cell lymphoma. two HDAC inhibitors, vorinostat and romidepsin, have been approved by the Food and Drug Administration. However, since these HDAC inhibitors alter the acetylation state of many proteins in addition to the histone of interest, knowledge of the underlying mechanism at the molecular level of patient response is required to enhance the efficiency of using such inhibitors as treatment. Treatment with HDAC inhibitors has been found to promote gene reactivation after DNA methyl-transferases inhibitors have repressed transcription. Panobinostat is approved for certain situations in myeloma.

Other pharmaceutical targets in research are histone lysine methyltransferases (KMT) and protein arginine methyltransferases (PRMT). Preclinical study has suggested that lunasin may have potentially beneficial epigenetic effects.

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