Karun Nair ’16 and Jalal Taleb ’18
Soon after her 68th birthday, my grandmother in Beirut, Lebanon became increasingly worried about her memory, wondering if she could have the beginnings of dementia.
Although she seemed to have no more difficulty than the rest of her friends and our family of similar age, in remembering events, names and places, her primary-care physician suggested that, given her level of concern and that of my family, she should have things checked out. You know, just to be safe.
So she consulted a specialist at American University of Beirut Hospital System (pictured above), and had a full-blown neuropsychological assessment — two days of tests of her cognitive abilities. The dozen measures included I.Q. and memory scales, auditory learning and animal naming tests, an oral word association test, a connect-the-dots trail-making test, and a test of her ability to copy complex figures. Explaining to her these examinations even served as a larger challenge, with her limited medical knowledge and huge concerns regarding her mental health.
The result, fortunately: reassurance and relief. Everything was in the normal range for her age, and she registered as superior on the ability to perform tasks and solve problems. Although a red flag initially, she took the initiative to sharpen her cognitive abilities, whether it be through reading, engaging in philanthropic work, and maintaining physical activity.
Fears about memory issues, commonplace among those of us who often misplace our cellphones and mix up the names of our children, are likely to skyrocket as baby boomers move into their 70s, 80s and beyond. Many may be unwilling to wait to have their memories tested until symptoms develop that could herald encroaching dementia or Alzheimer’s disease, like finding one’s glasses in the refrigerator, getting lost on a familiar route or being unable to follow directions or normal conversation. Now, more than ever, these issues are surfacing across clinics, research, and in appointments between primary-care physicians and their elderly patients. In this podcast, we will take you on a journey through fascinating discoveries made in a in a growing field of genetics known as neuroepigenetics. These underlying genetic mechanisms have paved the way for better understanding age-related diseases of the brain, making room for potential drug pathways to combat many of these complications. We will also tackle opinions regarding policy that will be crucial in combating age-related brain disease.
Memory is perhaps the most intimate of our personal possessions, the loss of which can pose extremely distressing for elderly individuals who are most susceptible. The quintessential question for neuroscientists and doctors therefore becomes: how does the process of memory-making change as we grow older? While we commonly associate aging with a natural decline of cognitive ability, the development of age-related neurological diseases is a topic that has confounded researchers for decades. Recently, promise has been seen in a rapidly growing field: neuroepigenetics, which aims to explore the connection between nature and nurture— the relationship between our brain, our genetic information, and how the environment interplays between the two.
To better understand this, we should first consider DNA as the text of an instruction manual that explains our body composition. Epigenetics is as if somebody has taken a package of highlighters and used various colors to annotate different parts of the text that need to be read the most carefully – whether it be memory genes, or genetic material necessary for a particular behavior. To analogize this further, I may use a pink highlighter to mark parts of the text that need to be read the most carefully, and a blue highlighter that may be less important. We will refer to these different highlighted areas as epigenetic “marks,” each mark telling the machinery in our body what type of traits should be expressed. These “marks” on the DNA can be tagged with tiny chemical molecules, and in the case of the studies that will be discussed, this chemical marker is called an acetyl group. There are proteins in the body that serve as machinery to find these acetyl groups, the pink highlighted areas, bind to them and turn these genes on. These fascinating proteins that have the ability to identify these markers are called histones (Top left). Amazingly, these histones will wrap themselves around the highlighted DNA marks. With histone proteins now wrapped around the DNA, there are other “tags” that can bind to some locations on the histone and loosen its tight wrap around the DNA – when this is loosened, the DNA is exposed and can be turned on. Modifications that relax the histones can make the DNA accessible to proteins that “read” genes. We can analogize this mechanism to the pink highlighter telling the cells in our body “hey, this is important!” This is the mechanism of the acetyl group; however, there are other chemical groups, “tags,” that can do the very opposite, which has the opposite effect on turning on DNA…turning genes off. If histones squeeze DNA tightly, the DNA cannot be “read” by the cell. Comically, we can think of histones like the sauce and meatballs of our favorite spaghetti. They coat it and twist it and straighten it. What the histones do to the DNA structure depends on how they are modified – and this mechanism is crucial in our brain’s evolution. (The figure to the right gives insight to this mechanism further, with a similar analogy).
Across our body, the text has different patterns of pink and blue highlighters in different types of cells – for example, the cells of our liver will not read the instruction manual the same way the cells in our brain do. Indeed, when some of these highlighted regions are activated, the highlighting is also copied, at times through generations, just like a photocopier. We will discuss how this photocopying occurs in the brain, and how the highlighting of some text in the instruction manual of our brain is crucial in the development of neurological disease.
At the beginning of life, the instruction manual making up the genetic material of our brain is shaped by environmental forces, such as maternal care or drug use, which deeply affects whether each chapter is highlighted – the understanding of this phenomenon is fairly recent, and demonstrates how far we have advanced in the field of genetics. In biological terms, these “tags” on the chapters are called epigenetic marks, and they control how and which genes—i.e. highlighted marks—are read – this codes for a specific traits behaviorally, developmentally, and beyond; this is the phenomenon of gene expression.
At first, these highlighted tags of the instruction manual were thought to be permanent. Fascinatingly, many scientists, including Dr. Marsha Penner of the University of Arizona, have challenged this view, instead arguing that these marks are transient. When we previously thought these marks were established earlier in life, Dr. Penner has found that some of these are continuously changing alongside the experiences of our everyday life. Now, why does this matter for the aging brain? Dr. Penner’s work has found that the aged brain demonstrates several different tags as time goes on, some of these genes coding for age-related cognitive impairments. The question becomes, how can we identify these changes early, maybe to reverse them with day-to-day habits (left) and with recent developments in medicine, is there a way to target these marks with drugs?
There are different types of marks, as mentioned previously, we will focus on histone acetylation – remember, the protein and chemical group associated with the highlighter telling the cell “Hey, this is important!” As we know, the acetyl group, “tag,” allows the highlighted text to be more feasibly identified by the cell, turning on particular genes and keeping others off. New research from the lab of Dr. Nilkantha Sen in the Department of Neuroscience and Regenerative Medicine of Augusta University is interested in how aging is linked to these specific types of tags. He describes how a decrease in histone acetylation – i.e the wrapping of the histone stays tight rather than loosening – causes impairments in long-term memory, which has been observed in experimental studies on aging8. A decrease in histone acetylation means that the highlighted areas of genes for long-term memory is harder to access – these areas, therefore, are more rigorous to identify and turn on. In other words, the highlighter may have worn away, and these imperative genes for long-term memory can no longer be found. There is a protein that will, at times, perform this catastrophic task – they are able to remove our chemical groups, “tags,” such as acetyl. These antagonists of the story to our acetyl protagonists are called histone deacetylases. They do, at times, stop the expression of important genes for memory and cognition; the question is, can we inhibit these inhibitors? Fortunately, scientists are chasing this question successfully.
There are substances undergoing development that can stop the action of histone deacetylases… these are known as histone deacetylase (HDAC) inhibitors (mechanism: Right4). What do these inhibitors do? Well, for starters, they have the potential to save important genes, such as those for memory, from being turned off. Maybe, just maybe, they have the ability to apply the highlighter once more to the most important part of our brain’s instruction manual, preserving some of the most precious cognitive genes. These inhibitors are now being used therapeutically, tackling age-related cognitive decline.
Dr. Jonathan Levenson of the Baylor College of Medicine is one of many researchers today that is interested in the relationship between histone structure and memory, and his findings have supported the idea that these HDAC inhibitors described above can work to treat cognitive impairments. Dr. Levenson’s has found that changes in the codes of our brain’s DNA manual, are highly involved in one’s ability to form long-term memories7. Therefore, the process of aging may be the culprit responsible for highlighter disappearance from our manual. Indeed, with aging comes great wisdom, but this wisdom can only be maintained and strengthened for all aging people if scientists and physicians can identify the changes to our highlighted marks early, and fascinatingly, target them with newly-developed drugs.
While more research certainly needs to be conducted in regards to clinical usage of these potential drugs, there is certainly room for non-interventional methods in preventing loss of cognition – methods that do not require drugs, but instead, are composed of day-to-day activities that can keep our manual in good condition. In her own study of HDAC inhibitors, Dr. Angila Sewal, a post-doctoral fellow at UCLA, found that personal experience, both past and ongoing, is integral in how a subject responds to this type of therapy. Dr. Sewal suggests that maintaining a high level of activity – i.e reading, exercise, eating healthy – as we age can help as we strive to remain self-sufficient9. Epigenetics is inherently connected to the present discussion on nature versus nurture, and if anything, its study shows us that both DNA and our environment contribute to who we are and how we function – and our ever-changing environment is linked to our ever-changing genetic manual.
Indeed, slowing the biological processes of aging in people is not only a plausible target for science and public health communities, but it is a necessity of a rapidly aging world, where an insatiable desire for longer life drives our health-care system. One of the most imperative health care ideas that should be scaled up is certainly this process of slowing aging, which is in itself a challenge for scientists and physicians globally.
To overcome this challenge, leading scientists, students, and nonprofit organizations worldwide have developed plans to combat age-related disease and reducing healthcare costs by developing and distributing innovative therapeutic interventions that will delay the biological effects of aging. As the population of the United States continues to age, with the Center for Disease Control and Prevention projection of 1/5 of the population exceeding 65 years old by 2030 (~65 million people), the incidence of age-related neurological disorders continue to increase. With this information in mind, The United States Senate has developed a committee on aging, so it is clearly becoming an issue of public policy. In the private sector, even, Google has launched Calico, an enterprise directed at extending life span, and has hired top pharmaceutical and biotechnology experts to spearhead the search for a drug to retard aging.
It is important that our aging population continues to immerse in learning complex new tasks like quilting, crocheting or digital photography — seeking to improve cognitive performance. First and foremost, be physically active. Second, prevent or control cardiovascular risk factors, including high blood pressure, smoking, obesity and diabetes. What is good for the heart also appears to be good for the brain. And importantly, engage your brain. Even if you missed out on a good education early in life, it is not too late to engage in intellectually stimulating activities, including taking courses online or at a local college, reading books, participating in discussion groups, and attending lectures and other cultural activities. By taking these precautions, similar to those my grandma has taken, and when considering the genetic effects on age-related disease, we will, together, combat Alzheimer’s and other age-related diseases.
- Ed Sheeran – Afire Love
- Introductory Monologue (Audio File): http://memories.myajc.com/
- American University of Beirut Medical Center: http://english.al-akhbar.com/node/17592
- “HDAC Inhibitors and Novel Therapeutics – Granule Cell and Pyramidal Neuron”
J. David Sweatt (Epigenetic Regulation in the Nervous System, pg 224)
- CH Arrowsmith, C Bountra, PV Fish, et al. Epigenetic Protein Families: A New Frontier for Drug Discovery Nature Reviews Drug Discovery 11, 384-400 (May 2012)
- JJ McIntyre, MA Bozzo, et al. Combination therapy with valproic acid in cancer: Initial clinical approach Drugs Fut 2007, 32 (1): 45
- “Part 3 – Epigenetics.” 2ndAct Health Testing Services. Web. 22 Apr. 2016.
- Lu T , Pan Y , Kao SY , et al. Gene regulation and DNA damage in the ageing human brain . Nature . 2004 ; 429 ( 6994 ) : 883 – 891
- Penner MR , Roth TL , Barnes CA , Sweatt JD . An epigenetic hypothesis of aging-related cognitive dysfunction . Front Aging Neurosci . 2010 ; 2 : 9.
- Levenson JM , O’Riordan KJ , Brown KD , Trinh MA , Molfese DL , Sweatt JD . Regulation of histone acetylation during memory formation in the hippocampus . J Biol Chem . 2004 ; 279 ( 39 ) : 40545 – 40559
- Sen, Nilkantha. “Epigenetic Regulation of Memory by Acetylation and Methylation of Chromatin: Implications in Neurological Disorders, Aging, and Addiction.” Neuromol Med NeuroMolecular Medicine 17.2 (2014): 97-110.
- Sewal, A. S., H. Patzke, E. J. Perez, P. Park, E. Lehrmann, Y. Zhang, K. G. Becker, B. R. Fletcher, J. M. Long, and P. R. Rapp. “Experience Modulates the Effects of Histone Deacetylase Inhibitors on Gene and Protein Expression in the Hippocampus: Impaired Plasticity in Aging.” Journal of Neuroscience 35.33 (2015): 11729-1742. Web.