A Unified Theory of the Pathogenesis of Non-Infectious Disease

The holy grail of medicine is to develop a treatment for non-infectious diseases that’s as effective as antibiotics are for infectious diseases. The need to do so becomes more pressing every day, because if current trends continue, non-infectious diseases will account for 7 out of 10 deaths even in the developing world by 2020.1 Recent research has revealed that although there are several potential etiologies for any given instance of non-infectious disease, there is a single general pathogenesis that is applicable to many, perhaps all instances of non-infectious disease, including psychiatric disorders. In its simplest form, that pathogenesis is:

Immunological Insult →

Chronic Proinflammatory Cytokine Release ←→ Epigenetic Dysregulation →

Pathogenic Protein Synthesis and Cells →

Non-Infectious Disease Presentation.

Understanding this universally applicable pathogenesis should help invent novel cures for non-infectious diseases.

The True Root Causes of Non-Infectious Diseases

Before discussing the generalized pathogenesis of non-infectious disease, we should back up and talk about its most common root causes, or etiologies. In the general pathogenic formula, the etiology is simply described as “Immunological Insult.” The most obvious and overt kind of immunological insult is infection, and indeed people with infections are at a much higher risk of developing non-infectious diseases like cancer and depression.2 But puzzlingly, people seem to develop non-infectious diseases even in the absence of obvious and overt immunological insults like infection. Even more puzzlingly, in countries where people are exposed to a lesser diversity of pathogens (which tend to be relatively rich countries), there is a higher prevalence of non-infectious diseases like depression.3

Recent research has solved this conundrum with the “old friends” hypothesis. According to this hypothesis, chronic immunoreactivity is often caused by insufficient exposure to a group of micro- and macroorganisms in early life that are frequently referred to as humanity’s “old friends,” which coevolved with humans in a mutually dependent relationship. In human’s prehistoric past, the old friends taught the immune system to ignore harmless stimuli, rather than becoming chronically stimulated by them. Due to modern hygiene and antibiotics however, our exposure to the old friends is usually insufficient in our developing years.4 This leads to chronic and often subclinical activation of the immune system, which leads to chronic circulation of proinflammatory cytokines in the bloodstream, which leads to maladaptive epigenetic alterations to cellular genomes, which leads to the development of non-infectious disease.4

Without exposure to the old friends in early life to teach the immune system to ignore harmless stimuli, the immune system can become chronically activated by everyday psychosocial stressors, allergens, and even the body’s own cells in autoimmunity. Examples of macroorganismic old friends include the supposedly parasitic helminth worms, which have recently been used successfully to treat autoimmune diseases and immune disorders like Crohn’s disease.5

Harvill goes so far as to suggest in Cultivating Our “Frienemies”: Viewing Immunity as Microbiome Management (2013) that:

…our rapidly growing knowledge of immune interactions with our healthy microbiota, and the many benefits it confers, suggests there may be value to an alternative view: that mechanisms of defense against pathogens are one aspect of a complex system with the broader purpose of managing our healthy microbiome. From this perspective, adaptive immunity may be viewed as a flexible system for simultaneously recruiting and managing a near limitless number of potential symbionts.

Another common risk factor for triggering the pathogenesis of non-infectious disease is eating a typical western diet, which has too many Omega-6s and too few Omega-3s, too much LDL and too little HDL, too many short-acting carbohydrates like sugar, and poor nutritional value. Another is toxic exposure, such as to heavy metals, pesticides, and organic pollutants.6 7 8

What is the Pathogenesis of Non-Infectious Disease?

Immunological Insult →

Chronic Proinflammatory Cytokine Release ←→ Epigenetic Dysregulation →

Pathogenic Protein Synthesis and Cells →

Non-Infectious Disease Presentation.

Now that we’ve discussed the etiology of non-infectious disease, let’s move on to a deeper discussion of the above pathogenesis. There is ample evidence that chronic exposure to proinflammatory cytokines is associated with various non-infectious diseases, including cardiovascular disease, diabetes, metabolic syndrome, allergies, asthma, HIV, cancer, ALS, Chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, depression, Parkinson’s, chronic pain, Alzheimer’s, Hungtington’s, as well as virtually every non-infectious disease in existence.9 10 11 12 13 14 15 16 17 18 19 20 For instance, in a systematic review of cytokine patterns in cancer patients, the authors said:

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types…. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4)…

The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12—interferon-γ—HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient’s prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer.21

In these scientists’ view, cytokine cascade is an integral part of the underlying paraneoplastic systemic disease in cancer patients. The immune system becomes activated, which releases proinflammatory cytokines, which somehow participate in the pathogenesis of non-infectious disease.

So how do cytokines cause non-infectious disease? Cytokines contribute to disease pathology by epigenetic means. A smoking gun linking proinflammatory cytokines to epigenetic induction of non-infectious disease pathogenesis is found in the study Epigenetics – the Key to Understand Immune Responses in Health and Disease (2011):The intracellular signaling pathways downstream of cytokine receptors induce the expression of cell lineage–specific transcription factors, with the ability to induce chromatin remodeling within their DNA-binding regions.” For instance, “Cell lineage decision in T-helper cells is influenced by the surrounding cytokine milieu at the site of antigen encounter.” In other words, cytokines induce epigenetic chromatin remodeling.

According to Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders (2008):

“Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition….”

This study correlates cytokines with the silencing methylation of anti-inflammatory genes, a form of epigenetic chromatin remodeling and modification the last study was talking about:

DNA methylation may mediate persistent changes in gene function following chronic stress….Methylation levels were examined for association with PTSD, child abuse history, and Total Life Stress (TLS)….Global methylation was increased in subjects with PTSD….Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and Total Life Stress. Together, these results suggest that psychosocial stress may alter global and gene-specific DNA methylation patterns potentially associated with peripheral immune dysregulation.

This is how some cytokines work their pathogenic effect; they methylate and silence anti-inflammatory genes. Other cytokines acetylate and promote the transcription of proinflammatory, cytokine-synthesizing genes.

Not only can cytokines induce epigenetic alterations, conversely epigenetic alterations can trigger the synthesis of cytokines. Cytokine production by gestational tissues has been shown to be regulated by epigenetic mechanisms.23 So the causal relationship between cytokines and epigenetic alterations to the genome is bidirectional, meaning that it seems to go both ways.

What causes the epigenetic changes in cases where the chain of causality is Epigenetic Changes → Proinflammatory Cytokine Synthesis? Often, the cause is simply other cytokines of a different type. “One cytokine often influences the synthesis of other cytokines. They can produce cascades, or enhance or suppress production of other cytokines.”24 This is called a positive feedback loop induced signal cascade, which basically means the effects of a cytokine signal are often self-amplifying because they change the expression of genes in such a way that more genes are expressed that code for cytokines, or less genes are expressed that inhibit the synthesis of cytokines.

And now, a special message about cytokines and the brain from the National Institute of Health:

“Despite the brain’s status as an immune privileged site, an extensive bi-directional communication takes place between the nervous and the immune system in both health and disease. Immune cells and neuroimmune molecules such as cytokines, chemokines, and growth factors modulate brain function through multiple signaling pathways throughout the lifespan. Immunological, physiological and psychological stressors engage cytokines and other immune molecules as mediators of interactions with neuroendocrine, neuropeptide, and neurotransmitter systems. For example, brain cytokine levels increase following stress exposure, while treatments designed to alleviate stress reverse this effect.

“Neuroinflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurological disorders such as stroke, Parkinson’s and Alzheimer’s disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate CNS function in the absence of overt immunological, physiological, or psychological challenges. For example, cytokines and cytokine receptor inhibitors affect cognitive and emotional processes. Recent evidence suggests that immune molecules modulate brain systems differently across the lifespan. Cytokines and chemokines regulate neurotrophins and other molecules critical to neurodevelopmental processes, and exposure to certain neuroimmune challenges early in life affects brain development. In adults, cytokines and chemokines affect synaptic plasticity and other ongoing neural processes, which may change in aging brains. Finally, interactions of immune molecules with the hypothalamic-pituitary-gonadal system indicate that sex differences are a significant factor determining the impact of neuroimmune influences on brain function and behavior.”

Vaccinations Against the Incurable

What can be done to prevent or treat cytokine-induced non-infectious disease? Vaccinations are possible. For instance, in the fascinating study Can we vaccinate against depression?, Rook et al. state: 

Major depression is common in the context of autoimmune and inflammatory diseases and is frequently associated with persistently raised levels of proinflammatory cytokines and other markers of inflammation, even in the absence of another diagnosable immune pathology to account for these findings. Therefore immunoregulation-inducing vaccines or manipulations of the gut microbiota might prevent or treat depression. These strategies are already undergoing clinical trials for chronic inflammatory disorders, such as allergies, autoimmunity and inflammatory bowel disease. In this article, we summarize data suggesting that this approach might be effective in depression and encourage the initiation of clinical vaccination trials in this disorder.

HDACi’s Part 2

But the most exciting future treatment for non-infectious disease is by far the histone deacetylase inhibitors, or HDACi’s, which I’ve written about previously. HDACi’s specific to HDAC2 and 3 promote activating acetylation of cytoprotective and anti-inflammatory genes in most tissues, an epigenetic change that that counters cytokines’ gene-silencing effects of pathogenic methylation and deacetylation, which silences the cytokine cascade and reduces the production of proinflammatory cytokines. In “Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer,” the authors report:

This issue of Molecular Medicine contains 14 original research reports and state-of-the-art reviews on histone deacetylase inhibitors (HDACi’s), which are being studied in models of a broad range of diseases not related to the proapoptotic properties used to treat cancer. The spectrum of these diseases responsive to HDACi’s is for the most part due to several antiinflammatory properties, often observed in vitro but importantly also in animal models. One unifying property is a reduction in cytokine production as well as inhibition of cytokine postreceptor signaling.

The only unifying property of effective HDACi’s the authors consider worth mentioning is that they all reduce the production of proinflammatory cytokines.

According to Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders (2008):

“Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington’s disease, Parkinson’s disease, anxiety and mood disorders, Rubinstein-Taybi syndrome and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological and psychiatric disorders.

Some HDACs are good for certain types of cells but not for others. An example of this is HDAC1, which is neuroprotective in the brain and if you inhibit it there it causes neurodegeneration, but in the pancreases HDAC1 inhibition restores insulin sensitivity in diabetics.

In addition, it’s important to remember that HDACs are just one type of epigenetic enzymes. Here is a table of all that are currently known:

Image

Epigenetic medicine promises to be the biggest revolution in medical knowledge and practice since the invention of the antibiotic. The more people who are trying to figure out what each of the above enzymes and markers do the better. Generally speaking, HDACi’s and other epigenetic medicines are the future of neuropsychiatric medicine, and most probably of medicine in general. Just disrupt the following pathogenesis and the Nobel is yours:

Immunological Insult →

Chronic Proinflammatory Cytokine Release ←→ Epigenetic Dysregulation →

Pathogenic Protein Synthesis and Cells →

Non-Infectious Disease Presentation.

 

References

  1. Wikipedia: Non-communicable disease.
  2. Oral Cancer Risk in Relation to Sexual History and Evidence of Human Papillomavirus Infection
  3. US and France More Depressed Than Poor Countries
  4. A Darwinian View of the Hygiene or “Old Friends” Hypothesis
  5. An update on the use of helminths to treat Crohn’s and other autoimmunune diseases
  6. Association between Dietary Patterns and Depressive Symptoms Over Time: A 10-Year Follow-Up Study of the GAZEL Cohort (2008).
  7. Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial (2011).
  8. The importance of the ratio of omega-6/omega-3 essential fatty acids (2002).
  9. Chronic activation of the innate immune system may underlie the metabolic syndrome.
  10. Chronic immune activation, causes and pathogenic mechanisms in HIV infection
  11. Role of cytokines in inflammatory process in Parkinson’s disease.
  12. Peripheral cytokines profile in Parkinson’s disease.
  13. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease.
  14. Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum
  15. Huntington’s Disease Linked To Overactive Immune Response In The Brain
  16. ALS: cytokine profile in cerebrospinal fluid T-cell clones.
  17. Cytokines, allergy, and asthma.
  18. Cytokines, Inflammation and Pain
  19. Cytokines and major depression (2005).
  20. Inflammation, chronic obstructive pulmonary disease and aging
  21. Cytokines in the pathogenesis of rheumatoid arthritis
  22. Cytokine patterns in patients with cancer: a systematic review

23. Epigenetic regulation of cytokine production in human amnion and villous placenta.

24. IMMUNOLOGY – CHAPTER THIRTEEN:  CYTOKINES AND IMMUNOREGULATION

Extra Reading:

  1. Inflammation and Depression: Cause or Effect (2012).
  2. Type 2 diabetes as an inflammatory disease (2011).
  3. Neuroinflammatory Cytokines—The Common Thread in Alzheimer’s Pathogenesis (2012).
  4. Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer’s disease-related pathology (2013).
  5. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: Transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling (2002).
  6. Inflammation, Sanitation, and Consternation Loss of Contact With Coevolved, Tolerogenic Microorganisms and the Pathophysiology and Treatment of Major Depression (2010).
  7. Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression (2009).
  8. Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies (2011).

Positive Psychology’s Advice on How to Be Happy

The following is a paper I wrote in 2009 summarizing all of positive psychology’s scientific insights into how to be happy. It’s a bit long, but it’s a fairly comprehensive summary of the research into happiness as of 2009.

The How of Happiness

Whether one is informed by folk-wisdom, philosophy, religion, or (like this paper) psychology, illuminating the way to happiness is no mean feat.  The devilish details of what will make any one person happy defy prediction. Ever since our ancestors evolved self-awareness and knowledge of good and evil, each of us has stood singly responsible for striving to navigate the choices of everyday life, both large and small, so as to bring ourselves happiness. And that is as it should be, because if life came with step by step instructions it would offer us no challenge, and without challenge our lives would quickly descend into tedium. However, like physicists seeking to understand and describe the physical universe, would-be theorists of happiness have posited certain general principles of how to lead the good life. These general principles come in the form of techniques and habits of thought and action that the happiest people tend to employ, and if adopted have the potential to make anyone happier.

Through studying the dispositions of identical twins separated at birth, according to two prominent researchers in the field, Ed Diener and his son Robert Biswas-Diener, different studies have estimated that as much as 50% and as little as 22% of our happiness is determined by genetics (Biswas-Diener 149). But contrary to what the scientific vogue was for a number of years, each individual’s happiness level is not set in stone (or DNA, as the case may be). A sizable portion of our happiness is still left up to environmental influences and how we choose to think and act.

When asked what would make us happier, many of us think of changes in our circumstances: a windfall of cash or a raise, getting a romantic partner, moving someplace with a better climate, etc. According to the research however, life-circumstances such as age, ethnicity, significant events that shaped our childhoods (e.g. parental divorce or being popular), where we grew up, where we live now, how wealthy we are, etc. account for only 10% of our happiness (Lyubomirsky 41). Furthermore, research shows that attempting to become happier by changing our circumstances and accumulating possessions will probably lead to failure. This is due to a phenomenon called “hedonic adaption”. This term refers to our remarkable ability to get used to things and as time goes on, to notice them less and less, which tends to eventually neutralize the impact of circumstantial changes on our happiness. For example, imagine eating some vanilla ice cream: the first few spoonfuls are delicious, but the next few are not quite as good, and the ones after that are almost flavorless. The same thing happens when we gain a new possession, move, get a raise, or even get married: for some amount of time we get a boost in happiness from these things, but we soon adapt and return to our baseline level of happiness, our “happiness set point” as researchers call it. So the bad news is that chasing after wealth, fame, and beauty will ultimately not lead to happiness. However, the sunnier flipside of hedonic adaption is that given enough time, we adapt just as efficiently to most negative life events and circumstances as well.

So if buying that Hybrid Lexus we’ve always wanted or winning the lottery won’t lead us to lasting happiness, what will? By studying happy people, psychologists have discovered the habits of behavior and thought that lead to lasting happiness.

Cognitive Strategies

The first such habit is optimism and positive thinking. It should come as no surprise to anyone, but how we choose to think has a major impact on our quality of life. Although perhaps not quite as all-powerful a technique as some self-help gurus would have us believe, thinking positively truly does have power. As the poet Milton wrote, “The mind is its own place, and in itself, can make a heaven of Hell, a hell of Heaven.” According to Martin Seligman, a leading figure in the Positive Psychology movement, there are two axes along which to measure a thought’s relative pessimism and optimism: permanence in time and pervasiveness in space (M. E. Seligman 88). Pessimistic people believe that the causes of negative events are permanent, whereas optimistic people believe them to be temporary (e.g. “You always nag” versus “You nag when I don’t clean my room”). Conversely, pessimistic people typically think that the causes of good events are temporary, while optimists believe them to be permanent (e.g. “My lucky day” versus “I’m always lucky”). Secondly, pessimists make universal explanations for their failures (e.g. “I’m repulsive”) whereas optimists make specific ones (e.g. “I’m repulsive to him”). This localizes the negative effects of failure in optimists to the specific area in their life affected, whereas pessimists are prone to let those effects spread to other areas of their lives. As M. E. Seligman says, “Finding permanent and universal causes of good events along with temporary and specific causes for misfortune is the art of hope; finding permanent and universal causes for misfortune and temporary and specific causes of good events is the practice of despair”.

To neutralize pessimistic thinking, Seligman recommends arguing with oneself and disputing one’s negative thoughts and beliefs. “The key to disputing one’s own pessimistic thoughts is to first recognize them and then to treat them as if they were uttered by an external person, a rival whose mission in life was to make one miserable” (M. E. Seligman 93). Much of the time, negative thinking is exaggerated or simply inaccurate. Ask yourself, what evidence do I have for this belief? How do I know that I got the worst grade in the class? What grade did the person sitting next to me get? In the rare case that the negative belief is indeed accurate, ask yourself what are the consequences of this fact? Are they really as dire as all that? Is there anything you can do to help the situation? Finally, ask yourself how useful the belief is. When forced to choose between believing what you hope to be true and what you fear to be true, remember that while they both have an equal chance of being factually accurate, only one will foster happiness.

Lyubomirsky advises against another negative habit of thought called over-thinking, or “self-focused rumination” as its known in the laboratory. Although it’s often passed off as common knowledge that one should try to find relief from unhappiness by focusing inwardly and reflecting on one’s feelings and situation, studies show that this practice prolongs or even worsens a bad mood, fosters pessimism, diminishes concentration and problem-solving ability, and saps one’s will to act. As Hamlet laments, “And thus the native hue of resolution/ Is sicklied o’er with the pale cast of thought,/ And enterprises of great pith and moment/ With this regard their currents turn away,/ And lose the name of action.” To quell a negative spiral of over-thinking, Lyubomirsky suggests thinking “Stop!” or asking “Will this matter to me a year from now?”, or for full perspective “Will this matter to me on my deathbed?” She also recommends imitating what the happiest people do and distracting oneself with activity.

Lyubomirsky also cautions against judging oneself in comparison to others, a phenomenon called “social comparison”. As it turns out, the happiest people tend to judge themselves and their performance by their own internal standards and are unaffected by the relative performance of those around them. Unhappy people on the other hand are prone to anxiety and feelings of inadequecy when they see someone do something better than them. Indeed, happy people tend to rejoice in others’ successes and show concern at others’ failures and setbacks, whereas unhappy people tend to do the opposite, feeling insecure and envious at other people’s accomplishments and relieved at their failures.

Finally, one of the most powerful cognitive strategies for increasing happiness is savoring. Savoring is “the awareness of pleasure and of the deliberate conscious attention to the experience of pleasure” and “any thoughts or behaviors capable of ‘generating, intensifying, and prolonging enjoyment’” (M. E. Seligman 107) (Lyubomirsky 191). When we savor an accomplishment, the bouquet of a fine wine, or the sight of a beautiful sunset, we experience these things more fully and derive the maximum amount of pleasure and happiness from them. Savoring could come in the form of basking in praise and congratulations, expressing gratitude, marveling, luxuriating or indulging the senses, and losing oneself in the moment (M. E. Seligman 108). It’s associated with “intense and frequent happiness”, self-confidence, extroversion, satisfaction, and optimism (Lyubomirsky 192). As well as savoring the present moment, we can also savor the past and future by “reminiscing about the good old days” and “anticipating and fantasizing about upcoming positive events” (Lyubomirsky 191). According to the two leading scholars in the field of savoring, Fred B. Bryant and Joseph Veroff, some of the best ways to facilitate savoring something is sharing it with others, creating a mental picture of it, sharpening one’s perceptions of the most positive or interesting aspects of it, and letting oneself become completely absorbed in the experience of it. They also advise that one should not be afraid of taking pride in one’s accomplishments, but as is part and parcel with positive thinking and savoring, to revel in them and remind oneself how hard one’s worked to achieve them. The same is true of appreciating good news, both when it is about oneself and when it is about someone else.

Lyubomirsky also cites the importance of relishing ordinary experiences. She reports that in one study, depressed subjects who took a few minutes to relish an everyday routine that they usually hurry through, such as eating breakfast—and also wrote down “in what ways they had experienced the event differently as well as how that felt compared with the times when they rushed through it”—showed “significant increases in happiness and reductions in depression (Lyubomirsky 193). The same thing was found in a study where healthy people instructed to savor “two pleasurable experiences per day by reflecting on each for two or three minutes and trying to make the pleasure last as long and as intensely as possible” (Lyubomirsky 194). Meditating on the impermanence of something (e.g. senior year is almost over) is another excellent way of encouraging appreciation of it.

Emotional Strategies

When someone wrongs us, our first instinct as human beings is to retaliate or simply avoid the transgressor. Needless to say, both these behaviors can cause problems. They can damage our health and happiness, destroy relationships, and perhaps even harm society at large. Forgiveness can’t erase the past, but it can help us move on. Psychologist Everett L. Worthington Jr. came up with a process of forgiveness called REACH (M. E. Seligman 79). As Worthington described his process on a health website, “First you recall the hurt objectively, without blame and self-victimization. Then you empathize by trying to imagine the viewpoint of the person who wronged one. The altruistic part involves getting people to think about a time they were forgiven and how that felt. When it’s time to commit to forgiveness, people usually say, not yet, but when they finally do, they must then hold on to forgiveness.”

We all have occasion to feel anger along with its many variations (impatience, annoyance, rage) on a daily basis, and not just when we have a major trespass to forgive. Over a century ago, Freud theorized that suppressing anger was unhealthy and ultimately futile as it was bound to resurface in some other, often undesirable way. However, research points to just the opposite conclusion: that anger and its expression are bad for one’s physical and psychological health (and often one’s interpersonal relationships to boot), and that if left alone, anger will simply dissipate. As the Dalai Lama said when asked by reporters if he wasn’t ever angry at the Chinese, “They stole my country. Why should I let them steal my mind?” (Levine 5).

Of course, this Zen-like injunction to simply let one’s anger flow away when something makes it rear its ugly head should not be heeded instead of taking action to solve one’s problems, but in concert with doing so. These two styles of dealing with anger belong to the more general coping-strategies of “emotion-focused coping” and “problem-focused coping”, both of which are vitally important for dealing with stress, hardship and trauma. In emotion-focused coping, one seeks to combat negative emotion directly by accepting the situation with serenity, positively reinterpreting it (perhaps even construing benefit in it), and distracting oneself with other things like exercise, the beauty of nature, or the pleasant company of friends (Lyubomirsky 153). On the other hand, problem-focused coping is where one does something about it, as Hamlet put it: “to take arms against a sea of troubles, / and by opposing end them.” Here are some examples Lyubomirsky provides of “how people describe themselves when using problem-focused coping:

  • I concentrate my efforts on doing something about it.
  • I do what has to be done, one step at a time.
  • I try to come up with a strategy about what to do.
  • I make a plan of action.
  • I put aside other activities in order to concentrate on this.
  • I try to get advice from someone about what to do”

Practicing gratitude is another important happiness boosting strategy. According to Lyubomirsky, one characteristic of the happiest people is that “they are comfortable expressing gratitude for all they have”. Practicing gratitude focuses our thinking on everything that’s right with our lives and the world around us. In one study, participants who were asked to write down five things they were grateful for once a week for ten weeks in a row tended to feel more optimistic and more satisfied with their lives. Writing a letter of gratitude to someone important in one’s life is another powerful method for boosting happiness, and delivering the letter in person and reading it aloud is even more potent. Similarly, studies done with both students and adults with chronic illnesses have shown that on days that they “strive to express their gratitude, they also experience more positive emotions (that is, feelings like interest, excitement, joy, and pride) and are more likely to report helping someone, to feel connected with others, and even to catch more hours of quality sleep”. Additionally, several other studies have shown that consistently grateful people are relatively happier, more energetic, more hopeful and likely to report experiencing more frequent positive emotions, as well as less prone to depression, anxiety, loneliness, envy, and neuroses (Lyubomirsky 90). However, it’s difficult to say to what extent gratitude fosters these characteristics, and to what extent those good characteristics simply cause people to be grateful. Either way though, it’s undeniable that counting one’s blessings on a regular basis is a boon to happiness.

Goal-Centered Strategies

One of the most important elements of happiness is striving for personally meaningful goals. Researcher has found that people who actively pursue their dreams are much happier than those who don’t, and the process of pursuing a goal is just as important for happiness as its attainment (Lyubomirsky 206). Working to accomplish goals gives us a feeling of purpose, control, competency, and self-esteem. According to Lyubomirsky, goals with certain characteristics will make us happier than those without them. Ideally, pursuits should be inherently rewarding, authentic to our interests and values, as well as flexible and non-conflicting with our other goals. Additionally, goals that involve approaching a desirable outcome are better than those that involve avoiding a negative one. Research also shows that the psychological benefits accrued from working towards changing our circumstance (e.g. moving into a new apartment) fade quickly once we accomplish our goal due to hedonic adaption. However, goals that are activity-based boost our well-being for much longer. People are most likely to achieve their goals and attain the maximum enjoyment from the process by starting with a dream, breaking it down into baby step sub-goals, identifying and preparing for any potential challenges or setbacks that might make one want to quit, and finally executing the plan.

Social Strategies

Social relationships are a key element of happiness. Two of the most vital needs of human beings are to love and be loved, and to satisfy them we need other people. No man is an island, even shy introverts: one study revealed that both extroverts and introverts experienced a boost in positive mood when around other people (Biswas-Diener 52). According to Lyubomirsky, “The happier a person is, the more likely he or she is to have a large circle of friends or companions, a romantic partner, and ample social support. The happier the person, the more likely she is to be married and to have a fulfilling and long-lasting marriage. The happier the person, the more likely she is to be satisfied with her family life and social activities, to consider her partner her “great love,” and to receive emotional and tangible support from friends, supervisors, and coworkers” (Lyubomirsky 138). People with strong social support are better able to cope with stress and trauma, have better health, and live longer. Indeed, researchers have found that while no one variable can account for happiness, good social relations were necessary for happiness to be possible (E. D. Seligman).

Another excellent way to boost happiness is doing kind things for others. The 14th Dalai Lama said “kindness is my religion”. There are of course limits to what science can measure; no one, for example, has yet come up with a study empirically examining the benefits of leading a life dedicated to service to others, and no one is likely to. So the full benefits of kindness and service may be beyond what science can prove. Nevertheless, psychologists have reached some solid conclusions about kindness on a more everyday scale. First, “doing acts of kindness on a regular basis makes people happy for an extended period”, but this is only true if the would-be altruist is allowed to vary the act of kindness he or she performs (Lyubomirsky 129). According to Lyubomirsky, the long term benefits of consistently doing kind things for others are seeing others in a more positive light, greater integration into one’s social community, increased ability to be grateful, relief from guilt and distress at the plight of whoever one is helping as well as from self-focused rumination and self-consciousness, an increased sense of purpose in life, and in general a much more positive opinion of oneself as someone who is kind and compassionate (Lyubomirsky 130).

Happiness Now

There are many experiences that can make us happy in the present moment, but one of the most universal and satisfying is the experience of flow, also referred to colloquially as being “in the zone”, “on the ball”, and “in the groove” (Flow: Wikipedia). “Flow” is the name psychologist Mihaly Csikszentmihalyi gave to a curious phenomenon he discovered while studying painters and their creative process whereby they would often ignore discomfiture and even pain so as to not have to stop painting, yet once their work was finished, they lost all interest in the product, suggesting that it was the process of creation rather than its fruits that gave them happiness. There are several components of flow. To start, there must be clear goals to the activity and immediate feedback on one’s performance. One’s attention must be wholly absorbed in the activity. As one masters new skills, the difficulty of an activity must also increase for it to continue producing flow. The trick is to find the sweet spot between too little challenge, which will surely cause boredom, and too much challenge, which will lead to anxiety and frustration. When in flow, time can seem to stop, slow down, or speed up. Emotions, self-consciousness, and thoughts of the past and future are temporarily extinguished. As Csikszentmihalyi’s initial research with painters in flow suggests, being in flow does not necessarily imply comfort or pleasure; in fact, flow activities can be quite stressful and discomforting. However, they more than make up for it by being deeply enjoyable and satisfying. They’re so intrinsically rewarding that they can even be addictive. Indeed, Csikszentmihalyi points to how flow is a natural high that merges our experience with our actions and environment, leaving no attention to attend to anything else.

Many activities can allow us to experience flow. Of course, the more rewarding the activity and the more closely it attains the guidelines set forth in the previous paragraph, the more successful it will be. Some of the most flow-inducing hobbies and professions Csikszentmihalyi mentions are rock climbing, chess playing, and performing surgery. But virtually any activity can be retooled into a flow activity. Lyubomirsky gives the example of someone who came up with a mini-flow activity for while he was driving. In it, he would tap his fingers on the steering wheel in synchrony with a rhythm or riff in the music he was listening to. Some activities are certainly more conducive to flow than others, but in truth, whether we experience flow from moment to moment is completely up to how we choose to order our consciousness. Even if outer activity is impossible or undesirable, perhaps because of being in a prison cell or dentist’s office, one can still do flow activities in one’s head. Some examples are silently reciting poetry, fantasizing, maintaining a running dialogue in which one tries to make as many jokes and interesting observations about the environment as one can, and composing funny limericks. The possibilities are endless.

Many of us like to spend our free time doing relaxing, low-challenge activities like watching TV; however, in a fascinating survey, Csikszentmihalyi showed that the group of workers under study actually found their work much more rewarding than their leisure time. This is because work typically provided them with more opportunities for flow than their relaxing yet relatively boring leisure activities. Perhaps one prescription for the epidemic of depression that has swept industrialized nations in the past sixty years is to start to see work as a vital and enjoyable part of a happy life, and to see leisure time at least partially as an opportunity to engage in freely chosen challenging activities that allow us to experience flow.

And there you have it, the habits of thought and behavior that science tells us help bring about happiness. Although a certain portion of our happiness can be accounted for by genetics and our circumstances, much of our happiness is in our hands. By regularly working to cultivate optimism and positive thinking, counting our blessings, avoiding over-thinking and social comparison, practicing forgiveness, controlling our anger, coping effectively, savoring life’s pleasures, immersing ourselves in flow, striving to complete our goals, and nurturing our social relationships, we have the power to become lastingly happy. No body of scientific literature, nor any ideology, philosophy, or religion, can tell us precisely how to lead a good life, nor do the work of living our lives for us. However, we may glean some wisdom from examining psychology’s general principles of living well. And ultimately, what is happiness if not striving with wisdom as the guide?

Works Cited

Biswas-Diener, Ed Diener and Robert. Happiness: Unlocking the Mysteries of Psychological Wealth. Blackwell Publishing, 2008.

Csikszentmihalyi, Mihaly. Flow: The Psychology of Optimal Experience. New York: Harper Perrenial, 1990.

Flow: Wikipedia. 09 01 2009 <http://en.wikipedia.org/wiki/Flow_(psychology)&gt;.

Levine, Marvin. The Positive Psychology of Buddhism and Yoga. Mahwah, New Jersey: Lawrence Erblbaum Associates, 2000.

Lyubomirsky, Sonja. The How Of Happiness. New York: The Penguin Press, 2008.

Seligman, Ed Diener & Martin E.P. “Very Happy People.” Psychological Science (2002).

Seligman, Martin E. P. Authentic Happiness. New York, London, Toronto, Syndey: Free Press, 2002.

WebMD. 1 1 2009 <http://www.webmd.com/balance/guide/forgive-forget?page=2&gt;.

No Longer Phineas Gage: How to Improve Memory, Planning, Self-Control, Conscientiousness, Executive function, and Get Control of Your Life.

Everyone who’s ever taken a neuroscience course knows about Phineas Gage. For those of us who haven’t, all you need to know is that he was a nineteenth century railroad construction foreman who, in a freak accident, got a large iron rod driven through his head, destroying most of his brain’s left frontal lobe. Remarkably, he survived. Here is one researcher’s account of how Gage was changed after his injury:

“The equilibrium or balance, so to speak, between his intellectual faculties and animal propensities, seems to have been destroyed. He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operations, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passions of a strong man. Previous to his injury, although untrained in the schools, he possessed a well-balanced mind, and was looked upon by those who knew him as a shrewd, smart businessman, very energetic and persistent in executing all his plans of operation. In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was “no longer Gage”.”

Accounts of his post-injury neuropsychiatric symptoms have taken on mythic proportions over the years, and are probably often quite exaggerated. Nevertheless, based on what we know of the functions of the frontal lobes today, it would make sense that many of the changes described, though perhaps exaggerated, are probably pretty solidly based in fact.

The frontal lobes contain the prefrontal cortex, the area of the brain that is evolutionarily the newest and the one that makes us most human. From Wikipedia:

The prefrontal cortex (PFC) is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.

This brain region has been implicated in planning complex cognitive behavior, personality expression, decision making, and moderating social behavior.[1] The basic activity of this brain region is considered to be orchestration of thoughts and actions in accordance with internal goals.[2]

The most typical psychological term for functions carried out by the prefrontal cortex area is executive function. Executive function relates to abilities to differentiate among conflicting thoughts, determine good and bad, better and best, same and different, future consequences of current activities, working toward a defined goal, prediction of outcomes, expectation based on actions, and social “control” (the ability to suppress urges that, if not suppressed, could lead to socially unacceptable outcomes).

Many authors have indicated an integral link between a person’s personality and the functions of the prefrontal cortex.[3]

Probably the best way I’ve ever heard of summing up the role of the prefrontal cortex is to imagine that the whole brain is an orchestra, and all the various regions musicians in it, except for the prefrontal cortex, which is the conductor. The conductor makes sure that all the musicians are playing the same piece of music in harmony and synchronicity.

Have you ever wondered how meditation exerts positive effects on the brain and personality of practitioners? It does so because the act of meditating requires intense activation of the prefrontal cortex, which “conducts” the rest of the brain to work in a way that doesn’t come to it easily. Just like a muscle, the prefrontal cortex becomes stronger from this intense usage and the more you meditate, the stronger your prefrontal cortex becomes. This results in improvements in many areas of neuropsychiatric functioning, including reductions in the symptoms of ADHD, depression, pain, anxiety, and stress, as well as increases in self-control and good mood.1 2 3 4 5 6 7

Meditation is arguably the ultimate neuropsychiatric treatment. However, many people aren’t psychologically prepared to invest the necessary time into practicing it often enough to see significant results (which seems to be meditating for fifteen minutes a day for two weeks). For those of us with limited time and/or patience, there are other ways to improve the functioning of our prefrontal cortex. Several dopaminergic and noradrenergic antidepressant and ADHD medications stimulate the prefrontal cortex to some extent, but they do so weakly, and they non-selectively stimulate subcortical areas as well. There are a few exceptions to this rule though. The best I’ve found so far is a pharmaceutical drug called guanfacine.

Guanfacine is a noradrenergic agonist (meaning that it mimics norepineprhrine, a neurotransmitter that regulates alertness, attention, etc.) that stimulates the alpha-2A receptors in the prefrontal cortex with a high degree of selectivity.8 It is designed to ameliorate the prefrontal cortex dysfunction typically seen in people with ADHD or ADD. The title of the 1998 study that persuaded me to try guanfacine was: “Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans”. The authors concluded: “The 29 μg/kg dose of guanfacine improved spatial working memory and planning. It is possible that the greater selectivity of guanfacine for α2A-adrenoceptor subtype may underlie its differences from clonidine.” I’m a big proponent of anything that selectively stimulates the prefrontal cortex, so I thought I’d give it a try.

I started taking about 2.9mg of guanfacine day three days ago, and the change in my behavior has been fairly dramatic. I’ve been planning a lot more since I started taking it, to the point that my girlfriend complained today that I’m planning too much, a criticism which I assure you has never been leveled at me in my entire life. I’ve also found myself being more helpful around the house, having more self-control, and being more productive. I attribute the fact that I started this blog yesterday to the effects of guanfacine.

So, if you have a disorder like ADD, ADHD, or depression in which the prefrontal cortex isn’t being stimulated enough, or if you just feel like you could use some help with planning, short term memory, and other higher cognitive functions, I highly recommend trying guanfacine and seeing if it works for you.

References:

1: ADHD, Brain Functioning, and Transcendental Meditation Practice (2011).

2: Mindfulness meditation counteracts self-control depletion (2012).

3: The effectiveness of a stress coping program based on mindfulness meditation on the stress, anxiety, and depression experienced by nursing students in Korea (2009).

4: How Does Mindfulness Reduce Anxiety, Depression, and Stress? An Exploratory Examination of Change Processes in Wait-List Controlled Mindfulness Meditation Training (2013).

5: Mindfulness-Based Stress Reduction, Mindfulness-Based Cognitive Therapy, and Zen Meditation for Depression, Anxiety, Pain, and Psychological Distress (2012).

6: The Effect of Mindfulness-Based Therapy on Anxiety and Depression: A Meta-Analytic Review (2010).

7: Loving-kindness and compassion meditation: Potential for psychological interventions (2011).

8: Pharmacological and therapeutic directions in ADHD: Specificity in the PFC (2007).

How to Cure Alzheimer’s, Dementia, Depression, Parkinson’s, Cardiovascular Disease, Diabetes, and Cancer, all while Boosting your Intelligence, Memory, and Ability to Learn with Epigenetics: HDAC is the one.

If something sounds too good to be true, it usually is. But sometimes it isn’t. The most exciting exception to this rule of thumb I’ve ever seen is the potential of novel selective HDAC2 and HDAC3 inhibitors to cure neurodegenerative diseases including Alzheimer’s, depression, Parkinson’s, as well as boost the intelligence, memory, and ability to learn of “healthy” neurotypical humans. Other HDAC inhibitors can also cure or at least reduce the symptoms of cancer, diabetes, heart disease, and virtually every other chronic disease.

Don’t Get Your DNA in a Bunch

First, some background. Within every cell in our body, the strands of our DNA are wound up into a ball called chromatin by proteins called histones. Which genes on the DNA are expressed and translated into proteins is determined by how tightly the histones coil the DNA. The more tightly the DNA is coiled by the histones, the fewer genes will be physically exposed to DNA polymerase; those genes that are coiled up and hidden from DNA polymerase will not be expressed and translated into protein.

The Epigenetic Miracle Cure

The family of enzymes that controls how tightly the histones coil DNA is called the histone deacetylases, or HDACs. The more HDACs you have in your cells, the more tightly the DNA will be coiled around the histones and the fewer genes will be expressed. Why might this become a problem? Well, the most obvious example is if an HDAC silences a gene that induces apoptosis (healthy cell death), cell differentiation, or some other important gene controlling the cell cycle, which gives you cancer. And indeed, HDAC inhibitors that shrink tumors have been on the market for years now, most prominently for hematological cancers like refractory T-cell lymphoma.1 2 3

More recently, scientists have been discovering that inhibiting the various HDACs can do a lot more than just shrink cancer tumors. According to one study, “HDACs are implicated as a regulator in various pathological heart diseases such as fibrosis, arrhythmia, ischemic heart diseases, and heart failure.”4 According to another,“Surprisingly, HDAC inhibitors have also been shown to be efficacious in preclinical models of heart failure.”5  

HDAC inhibitors also show a lot of promise forimproving insulin sensitivity in patients with diabetes mellitus or obesity.6 7

HDAC inhibitors also have the potential to treat autoimmune and transplantation related disorders, as well as any kind of inflammatory disease (which most chronic diseases are).8 9

Just in case you weren’t already convinced that HDAC inhibitors are the most awesome thing since the invention of antibiotics, it gets even better. HDAC inhibitors have also proven effective at treating neurodegenerative diseases like Alzheimer’s, dementia, Parkinson’s, Huntington’s, and depression.10

So what’s the catch? Why isn’t there already an HDAC inhibitor panacea drug for all that ails you on the market? Well, the problem is that there are at least eighteen different kinds of HDACs, which are grouped into four different classes. Some HDACs do good things, and only a small minority of them seems to be responsible for disease.11

The good news is that we now know which ones are the bad guys and which are the good. HDAC3 appears to cause over seventeen inherited neurodegenerative diseases, including Huntington’s.12 HDAC6 is implicated in the pathogenesis of Alzheimer’s, Parkinson’s, ALS, FTLD, and CMT.13 HDAC2 is the principal villain behind diabetes, inflammation, depression, Alzheimer’s, and dementia.14 15 16 17 18 Perhaps most excitingly, not only does inhibiting HDAC2 and HDAC3 reverse these diseases, it also has the potential in healthy humans to enhance neuroplasticity and improve the ability to remember, form new memories, and learn, making it the ultimate nootropic or “smart-drug”.19

Unfortunately, the only HDAC inhibitors on the market today are woefully non-specific, meaning that they inhibit several kinds of HDACs, the good and the bad. That doesn’t mean specific inhibitors of HDAC2 and HDAC3 don’t exist though. It just means they’re stuck in the research phase.20 However, a patent entitled “INHIBITION OF HDAC2 TO PROMOTE MEMORY” detailing exactly how to make your very own HDAC2 inhibitor is freely available online here. I’ve got a 93 year old uncle with dementia who’s quality of life and happiness would be greatly increased by taking an HDAC2 inhibitor to whom I’d like to offer the option, so if you are or know a chemist capable of synthesizing this compound, please let me know.

Over the Counter HDAC Inhibitors

Worth mentioning is that curcumin, the active compound found in the spice turmeric, has been found to reduce inflammation, prevent stress induced damage to various organs, inhibit tumor growth in cancer, reduce depression and seizures, and improve memory and learning. 21 22 23 24 25 26 27 28 29 It is a non-specific HDAC inhibitor that is easily and reasonably cheaply available over the counter. It’s probably not as effective as future specific HDAC2 and 3 inhibitors, but it won’t hurt you either—in fact it will probably help significantly with a variety of diseases—and it’s the easiest to get next best thing for now.

References:

1: HDAC inhibitors in cancer care (2010).

2: HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications.

3: Curbing autophagy and histone deacetylases to kill cancer cells

4: Roles and Targets of Class I and IIa Histone Deacetylases in Cardiac Hypertrophy (2010).

5: Therapeutic Potential for HDAC Inhibitors in the Heart (2012).

6: Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-β1-induced renal injury (2009).

7: Improving Insulin Sensitivity With HDAC Inhibitor (2012).

8: Rationale for HDAC inhibitor therapy in autoimmunity and transplantation (2011).

9: Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells.

10: Multiple roles of HDAC inhibition in neurodegenerative conditions (2009).

11: HDAC inhibitors and neurodegeneration: at the edge between protection and damage.

12: Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions

13: HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

14: HDAC2 negatively regulates memory formation and synaptic plasticity (2009).

15: Antidepressant actions of histone deacetylase inhibitors (2009).

16: Affective disorders: Antidepressant action through gene regulation (2009).

17: Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation (2013).

18: Reversing Alzheimer’s gene ‘blockade’ can restore memory, other cognitive functions: Neuroscientists show that HDAC2 enzyme could be a good target for new drugs (2012).

19: Learning and memory: HDAC2 is the one (2009).

20: Novel histone deacetylase (HDAC) inhibitors with improved selectivity for HDAC2 and 3 protect against neural cell death (2011).

21: Curcumin improves learning and memory ability and its neuroprotective mechanism in mice.

22: Mechanisms of cancer chemoprevention by curcumin (2001).

23: Inhibitory effects of curcumin on tumorigenesis in mice (1997).

24: Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin (1998).

25: Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow (2009).

26: Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostatis (2001).

27: Curcumin ameliorates memory deficits via neuronal nitric oxide synthase in aged mice (2013).

28: A pyrazole derivative of curcumin enhances memory (2010).

29: Ameliorative effect of Curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice (2013).