Increasing resilience to disease by increasing genomic resilience through nutritional supplementation

It is becoming clear that DNA mutations, epigenetic changes, and gene expression modulation are involved in medical disorders in general, and psychiatric disorders in particular. In addition to avoiding the offending environmental agents, what else can be done? A powerful approach in medicine is to increase resilience/immunity as a way to prevent/treat diseases.

De novo DNA mutations (micro- single nucleotide mutations , SNPs, or macro- copy-number variants, CNVs) in germinal cells may be responsible for the increased paternal and maternal age effects seen in most psychiatric disorders where modern genetic studies have been carried out to date. These parental age effects may turn out to be a widespread phenomena for psychiatric disorders and non-psychiatric disorders alike. Besides parental transmission, de novo mutations may arise in somatic cells, including neurons. Free radicals may be involved in mutation mechanisms. Free radical quenchers such as the antioxidant vitamins C, E and Selenium have a favorable risk/benefit ratio for preventive purposes. We also suggest it is of interest for the future to study their role in anxiety regulation processes.

Epigenetic changes (such as the addition or removal of methyl groups from DNA) may mediate the depressogenic effects of environmental stress and trauma on the genome. B vitamins, in addition to helping with energy metabolism, may reduce epigenetic changes and thus have an antidepressant role. We suggest it is of interest for the future to study their role in mood regulation processes.

Lastly, gene expression modulation by adverse environments and inflammation could be counteracted by omega-3 fatty acids and vitamin D3. We suggest it is of interest for the future to study their role in cognitive regulation processes.

In conclusion, at the risk of sounding like a supermarket tabloid, here are some of our biologically informed practical applications. First do no harm, so one should not exceed manufacturer and/or FDA recommended doses. It is the cumulative combination of different vitamins taken over time that may provide inter-related benefits on anxiety, mood and cognitive disorders, rather than massive acute doses of any single one of them. The earlier they are started, the better the preventative effects. A multivitamin/multimineral pill is a good starting point, along with a diverse diet rich in (organic) fruits and vegetables, and along with overall calorie restriction.

Alexander B. Niculescu, III, MD, PhD

Suicidality: a form of transient psychosis

Suicidality in a broad sense can be viewed as a self-deletion (apoptosis) of the organism due to a perception of suffering, being damaged, hopelessly/irreversibly so, and a burden to its extended kin. While there is an evolutionary rationale for such a mechanism and behavior to exist and persist in the population at large, in most cases an affective and cognitive distortion occurs, leading to psychotic thinking in the perisuicidal period- either manic/positive symptoms (delusions, paranoia), or depressed/negative symptoms (avolition, lack of interest in living). The former can be labeled as “hot” suicide (impulsive, externalizing), the later as “cold” suicide (planned, internalizing).

 Particular, psychologically and culturally influenced, forms of suicidality are: 1. passive-aggressive suicide, when the act is meant to distress or induce guilt in somebody else, 2. copycat suicides, where precedents in the environment demystify and lower the fear of committing the act in people who were vacillating, and 3. atonement suicide, prompted by overwhelming guilt at something one has done and possible ostracism consequences. The passive-aggressive suicide is more towards the psychotic side of the spectrum, whereas the atonement suicide is more towards the evolutionarily normal side of the spectrum, with copycat suicides somewhere in between.

 Identification of people at risk for hot or cold suicide due to psychiatric and medical illnesses, chronic and acute social stressors, and alcohol/drug use, can be enhanced by developing blood tests. More subtle factors such as existential crises and isolation, like for single cells, tip the balance to apoptosis. They should be probed for and included in any risk prediction score and algorithm.

Treatment should be individualized and multifaceted, based on reversing the panel of causes and risk factors each individual has. The opposites of the risk factors for suicide are protective factors for suicide, in a yin-yang fashion, and should be enhanced. For example, a strong sense of spirituality and social support may compensate for and overcome other risk factors. Medications like lithium and clozapine, that prevent cellular apoptosis by increasing BCL-2, have also been shown to prevent organismal apoptosis, i.e. suicide. Other anti-apoptotic and neurotrophic medications should be considered and studied for suicidality treatment, perhaps distinguishing between the two broad categories- hot and cold.
 
Alexander B. Niculescu, III, MD, PhD

Alzheimer (and schizophrenia) are the result of stress, plasticity and fragility

Our speculative but data-informed view: Alzheimer disease is a result of the cumulative combination of stresses on the brain in people who have increased neuronal plasticity, and reach a tipping point of neuronal fragility leading to apoptosis.

In this view, amyloid, as well as tau, are symptoms, not causes of the neuronal deterioration. In fact, they may slow down and try to mitigate neuronal apoptosis, so their therapeutic targeting is not indicated.

ApoE is involved in the increased neuronal plasticity, disconnection, remodeling and adaptation in response to stress, useful in young people with robust neurons, but detrimental in older people with fragile neurons. Free radical damage and decreased growth factor levels make neurons more fragile with age.

Evolutionarily, populations that have been subjected over the centuries to harsh and stressful environments (in Africa or other continents-genocides, pogroms, persecution) may be more susceptible to Alzheimer in old age- if they reach that age, as they do in more modern and safer societies. Individually, people with a history of exposure to major stress and who have PTSD may be at higher risk of Alzheimer in old age, even more so if accompanied by traumatic brain injury. This should become a major area or research and intervention in combat veterans, and contact-sport athletes.

How to treat Alzheimer? Target neuronal apoptosis, specifically enough that you do not increase the opposite elsewhere, which is cancer. GSK3beta and its connected biological pathways are worth exploring.

How to prevent Alzheimer? In a Mindscape fashion, addressing the three dimensions: anxiety, mood and cognition. Reduce cumulative exposure to stress (or use an anti-anxiety medication such as an SSRI), modulate neuronal plasticity through cognitive-behavioral therapy (or use a mood stabilizing medication such as lithium), decrease neuronal fragility through rich nutrients and a rich environment (or use a cognitive enhancing medication). Infection and inflammation are major stressors on the brain, so limiting them helps prevent Alzheimer. For a “primum non nocere” strategy: physical exercise, omega-3 fatty acids, antioxidants and a stimulating life. These may be our best bets- in combination.

Last but not least, in our view schizophrenia is just an accelerated early form of this whole process- indeed dementia praecox, as Emil Kraepelin has suggested. The stresses occurs earlier on, including in utero, and the neurons are more plastic and more fragile due to multiple genetic vulnerability factors. Prevention and treatment: the same, but a need to intervene very early on, in childhood,  to prevent full blown illness from developing in young adults.

Alexander B. Niculescu, III, MD, PhD

Treating Addictions: The Way of The Fist and The Palm

Addictions -and allergies- of any type can be treated by removing the stimuli (drug) and changing the receptivity of the person. As when a "kung-fu" salute ends, the fist and the palm must come apart and turn away from each other. The fist is the stimuli, and the palm is the person’s receptivity to it. “Pull the fist, turn the palm” is sage-like advice that works.

1. External trigger (The Fist): avoiding environmental exposure

1.1. Psychosocial:

Avoiding environmental/ informational/memory cues

1.2. Biological:

Avoiding slippery slope use of drug


2. Internal receptivity (The Palm): decreasing relapse risk

2.1. Psychosocial:

Increasing fear of adverse outcomes if drugs are used

Increasing support/self-esteem/importance if abstinence is practiced

Increasing desire to do good/ spirituality

2.2. Biological:

Treating withdrawal, blocking the effects of the drug

Treating other predisposing disorders (Axis I/II in psychiatry)

Increasing biological resilience: exercise, diet, meditation



 by Alexander B. Niculescu, III, MD, PhD

Aging, longevity and the mind

Aging and longevity are opposite sides of the same coin, in a Yin-Yang relationship.

There are passive and active mechanisms for aging. The passive mechanisms involve "mileage on the car" type wear and tear, free radical damage, fibrosis, necrosis. The active mechanisms involve "shutting down" due to chronic overwhelming stress, adverse environment, being damaged without hope of improvement and being a burden to extended kin. They involve active gene expression and apoptosis, triggered by anxiety, depression and their whole-body correlates. Antidepressant/antianxiety medications and therapies can have a role in mitigating these active mechanism. Modulate your Mindscape to modulate aging.

Similarly, there are passive and active mechanisms for longevity. The passive mechanisms involve "genetic lottery", inherited high levels of activity of detoxifying and free radical mopping enzymes. The active mechanisms involve "environmental choices and actions", upregulation of repair mechanisms triggered by intermittent manageable stress, such as with exercise and calorie restriction.

2010 and the decade ahead (our predictions):

1. Google will help organize access to genomic and other health information, enabling the personalized medicine revolution.

2. Envirogenomics will become a very hot scientific area- the quantitative empirical study of how the environment does (and can be used to) modulate your genome, cells, organs, brain ( as well as populations, society at large, etc.).

3. There is a geopolitical and scientific shift to the Asia-Pacific region, but the US will continue to be the top dog, due to: 1) the self-selected, resilient, entrepreneurial temperament of its population, who came here from around the world (what a gene pool!), and 2) the excellence of the US constitution and cultural framework.

Alexander B. Niculescu, III, MD, PhD