Epigenetics and Epigenetics and Health DisparitiesHealth Disparities

Part II: Psychosocial FactorsPart II: Psychosocial Factors

Anita R. Webb, PhDAnita R. Webb, PhD

JPS Health NetworkJPS Health Network

Fort Worth, TexasFort Worth, Texas

Key Points: Key Points: PART I (Disease)PART I (Disease)

Gene expression can be altered by the Gene expression can be altered by the environment, including the social environment, including the social environment.environment.Alterations may be passed down to Alterations may be passed down to subsequent generations. subsequent generations. Without changes in DNA.Without changes in DNA.Epigenetics may explain some diseases.Epigenetics may explain some diseases.Burgeoning field of medicineBurgeoning field of medicine

KEY POINTSKEY POINTS

PART IIPART IIStress can affect how our genes are Stress can affect how our genes are expressed (through multiple generations).expressed (through multiple generations).

Epigenetics theory may contribute to the Epigenetics theory may contribute to the understanding of health disparities.understanding of health disparities.

Epigenetics research is suggesting how Epigenetics research is suggesting how therapies can reverse genetic damage and therapies can reverse genetic damage and diseases such as cancer.diseases such as cancer.

TOPICSTOPICS

StressStress

LonelinessLoneliness

NurturingNurturing

Childhood Adversity Childhood Adversity

TraumaTrauma

ObesityObesity

Health DisparitiesHealth Disparities

““Social Genomics”Social Genomics”

““Our interpersonal world exerts Our interpersonal world exerts biologically significant effects biologically significant effects ““On the molecular composition On the molecular composition of the human body.”of the human body.”– Hollander RS. Social genomics: Genomic Hollander RS. Social genomics: Genomic

inventions in society. Science & Eng. inventions in society. Science & Eng. 2002,8(4):485-496.2002,8(4):485-496.

Genetic inheritance is not altered.Genetic inheritance is not altered.Expression is alteredExpression is altered..

Stress and DiseaseStress and Disease

Psychosocial stress may affect basic Psychosocial stress may affect basic cellular functions and metabolism, cellular functions and metabolism, – ““Lifestyle diseases”: e.g. cardiac, diabetes Lifestyle diseases”: e.g. cardiac, diabetes

And change gene And change gene expressionexpression – Without changing DNA.Without changing DNA.– i.e. i.e. Epigenetic changesEpigenetic changes– Embryos and infants may be especially Embryos and infants may be especially

sensitivesensitive

Stress and TelomeresStress and Telomeres

Stress can accelerate Stress can accelerate telomere shorteningtelomere shortening

(protective endcaps on chromosomes).(protective endcaps on chromosomes).– Emotional stress releases cortisol.Emotional stress releases cortisol.– Cortisol can damage healthy tissue.Cortisol can damage healthy tissue.– Cell repair requires additional cell divisions.Cell repair requires additional cell divisions.– Each cell division shortens telomeres.Each cell division shortens telomeres.– So that telomeres provide less protection. So that telomeres provide less protection.

Result: Result: DNA ages more rapidlyDNA ages more rapidly..

Further Stress DamageFurther Stress Damage Immune cells patrol the bodyImmune cells patrol the body– First line of defense against infectionFirst line of defense against infection– Scan for damaged tissueScan for damaged tissue– Mount inflammatory responseMount inflammatory response

Chronic stress = Chronic inflammation = Chronic stress = Chronic inflammation = Premature telomere shortening = Risk forPremature telomere shortening = Risk for– Some types of cancerSome types of cancer– Cardiovascular diseaseCardiovascular disease– Neuro-degeneration/cognitive defectsNeuro-degeneration/cognitive defects

The Psychology of CellsThe Psychology of Cells

““Developmental Plasticity” Developmental Plasticity” – ““The environment makes its way into genes The environment makes its way into genes

and controls what your genome becomes.”and controls what your genome becomes.”

. Example: Loneliness (social . Example: Loneliness (social environment)environment)– Primes the immune systemPrimes the immune system– Activates Activates inflammatory responseinflammatory response– Can eventually lead to diseaseCan eventually lead to disease

(Azar (Azar 2011: see last slide)2011: see last slide)

Loneliness ResearchLoneliness Research

White blood cells of lonely subjects:White blood cells of lonely subjects:– 1. Over-expressed genes that resulted in 1. Over-expressed genes that resulted in

inflammationinflammation– 2. Under-expressed genes involved in 2. Under-expressed genes involved in

antibodyantibody production (lymphocytes) production (lymphocytes)Cole SW, Hawkley LC, Arevalo JM, Sung CY, Rose Cole SW, Hawkley LC, Arevalo JM, Sung CY, Rose RM, Cacioppo JT. Social regulation of gene RM, Cacioppo JT. Social regulation of gene expression in human leukocytes. expression in human leukocytes. Genome Biol. Genome Biol. 2007;8(9):R189.2007;8(9):R189.

Example: Maternal NurturingExample: Maternal Nurturing

Maternal nurturing of Maternal nurturing of rat pups rat pups promotedpromoted– DNA methylation at gene which encodes DNA methylation at gene which encodes

hippocampus glucocorticoid receptorshippocampus glucocorticoid receptors

Result: “Favorably altered emotionality”Result: “Favorably altered emotionality”– Plus rate of brain and body aging Plus rate of brain and body aging

Continued to affect pups’ stress-response Continued to affect pups’ stress-response pathway into pathway into adulthoodadulthood..

Weaver IC et al. Epigenetic programming by Weaver IC et al. Epigenetic programming by maternal behavior. Neuroscience 7, 847-54 (2004).maternal behavior. Neuroscience 7, 847-54 (2004).

Childhood AdversityChildhood Adversity

Poverty, loneliness, deprivation, neglectPoverty, loneliness, deprivation, neglect

Affect immune function at genetic levelAffect immune function at genetic level

Pro-inflammatory genes are more active Pro-inflammatory genes are more active (“ready for trouble”).(“ready for trouble”).

Creates health hazard even into adulthoodCreates health hazard even into adulthood

Regardless of adult SESRegardless of adult SES

Example: Childhood AdversityExample: Childhood Adversity

Social adversity in childhood Social adversity in childhood – ““Tunes immune system to be Tunes immune system to be vigilant forvigilant for

stressstress””– Primes immune system to use Primes immune system to use inflammatory inflammatory

response response

Increases disease riskIncreases disease risk – ““Cortisol runs rampant”Cortisol runs rampant”– ImmunosuppressiveImmunosuppressive– Health consequencesHealth consequences

(Azar)(Azar)

Chronic Stress or TraumaChronic Stress or Trauma

Since stress is associated with telomere Since stress is associated with telomere shortening in immune system cells,shortening in immune system cells,

Traumatized and chronically stressed Traumatized and chronically stressed children are at risk for:children are at risk for:– Lifelong faulty immune functionLifelong faulty immune function

Childhood adversity may contribute toChildhood adversity may contribute to– Health disparitiesHealth disparities as adults as adults

SES SES Health Disparities: Health Disparities: Mechanism?Mechanism?

Early adversity primes immune system to:Early adversity primes immune system to:

Activate Activate inflammatoryinflammatory response. response.

May May reprogramreprogram immune systemimmune system

Beginning in the wombBeginning in the womb

Increasing risk for diseaseIncreasing risk for disease

Example: GestationExample: Gestation

Conditions Conditions in the wombin the womb can affect fetus can affect fetus– Continuing well into adulthood. Continuing well into adulthood.

Example: If a pregnant woman eats poorlyExample: If a pregnant woman eats poorly– Her child will be at significantly higher riskHer child will be at significantly higher risk– For For cardiovascular diseasecardiovascular disease as an adultas an adult..

Barker DJ, Osmond C. Infant mortality, childhood Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England nutrition, and ischaemic heart disease in England and Wales. Lancet May10,1986;1(8489)1077-1081and Wales. Lancet May10,1986;1(8489)1077-1081

Mechanism? (continued)Mechanism? (continued)

Stress, poverty, traumaStress, poverty, trauma

May prematurely May prematurely age DNAage DNA

Accelerate Accelerate telomere shorteningtelomere shortening

Undermine health lifelongUndermine health lifelong

Shorten life spanShorten life span

Adult NurturanceAdult Nurturance

“Much research shows that the stresses [that] disadvantaged children undergo– Affect their physiological development,– Making them permanently vulnerable to

infection and disease.” (MIDUS: N>1200)

Buffer: Adult nurturance (attention, affection, understanding, caring, etc.)– http://www.sciencedaily.com/releases/

2011/09/110919164503.htm

Other Implications: OBESITYOther Implications: OBESITY

During times of food During times of food scarcityscarcity– Physiology becomes more efficient in storing Physiology becomes more efficient in storing

calories to protect against starvation.calories to protect against starvation.– Efficient food storageEfficient food storage mechanisms will be mechanisms will be

passed to subsequent generations.passed to subsequent generations.

If food later becomes more If food later becomes more plentifulplentiful– Descendants will be at higher risk for Descendants will be at higher risk for

obesityobesity

– Due to more efficient food storage.Due to more efficient food storage.

Epigenetic ChangesEpigenetic Changes

Can be Can be inherited inherited by multiple generationsby multiple generations– Via epigenetic marksVia epigenetic marks– But But is NOT evolutionis NOT evolution– Does NOT change DNADoes NOT change DNA

When the environmental stressor is removed, When the environmental stressor is removed, the epigenetic mark fadesthe epigenetic mark fades– DNA eventually reverts to original programming DNA eventually reverts to original programming

in a subsequent generation.in a subsequent generation.

Epigenetic TherapyEpigenetic TherapyUnlike genome, epigenome can be modifiedUnlike genome, epigenome can be modified

Therefore: Therefore: Can be Can be CORRECTEDCORRECTED

Therapy: Change cells’ instructionsTherapy: Change cells’ instructions– 1. Tell genes which play a role in disease to 1. Tell genes which play a role in disease to

“Lie dormant”.“Lie dormant”.– 2. 2. ReactivateReactivate original cell instructionsoriginal cell instructions that were that were

silenced by disease.silenced by disease.

VIA: Epigenetic MarksVIA: Epigenetic Marks

Learn how to manipulate epigenetic marksLearn how to manipulate epigenetic marks– Develop drugs that can Develop drugs that can

Silence bad genesSilence bad genes

Activate good genesActivate good genes– FDA approved epigenetic drug to treat rare FDA approved epigenetic drug to treat rare

deadly blood malignancies (MDS) (deadly blood malignancies (MDS) (20042004) )

Future targets: Cancers, schizophrenia, Future targets: Cancers, schizophrenia, autism, diabetes, Alzheimer’s autism, diabetes, Alzheimer’s

Example: Stress and the BrainExample: Stress and the Brain

Acute stress caused rapid chemical Acute stress caused rapid chemical change in rat brains.change in rat brains.

Hippocampus: MemoryHippocampus: Memory– Especially susceptible to stressEspecially susceptible to stress

Fluoxetine (Prozac) reversed some Fluoxetine (Prozac) reversed some methylation effects of chronic stress.methylation effects of chronic stress.

Hunter RG, et al. Regulation of hippocampal H3 Hunter RG, et al. Regulation of hippocampal H3 histone methylation by acute and chronic stress. histone methylation by acute and chronic stress. Natn Acad Sc. 2009;106 (49): 20912-20917.Natn Acad Sc. 2009;106 (49): 20912-20917.

Treatment Research: Treatment Research: Repairing Telomere DamageRepairing Telomere Damage

Women with cervical cancerWomen with cervical cancerTreatment: Stress managementTreatment: Stress management trainingtraining– Six sessions of telephone counselingSix sessions of telephone counseling– Reduced emotional stressReduced emotional stress

Promoted Promoted telomere repairtelomere repair and growthand growthDrury, Theall, GleasonDrury, Theall, Gleason et al. et al. Telomere length and Telomere length and early severe social deprivation: linking early early severe social deprivation: linking early adversity and cellular aging. adversity and cellular aging. Molecular Molecular PsychiatryPsychiatry, (2011) 1–9., (2011) 1–9.

Prevention ResearchPrevention Research

Women: Post-menopausal, dementia caregiversWomen: Post-menopausal, dementia caregivers

Vigorous Vigorous physical exercisephysical exercise– ‘‘‘‘Increased heart rate and/or sweating.’’Increased heart rate and/or sweating.’’– At least 14 minutes a dayAt least 14 minutes a day

Was related to longer telomeres,Was related to longer telomeres,Puterman E. et al. Power of Exercise: Buffering the Puterman E. et al. Power of Exercise: Buffering the Effect of Chronic Stress on Telomere Length. PLoS Effect of Chronic Stress on Telomere Length. PLoS One, May 2010, 5(5):e10837. One, May 2010, 5(5):e10837. e10837.doi:10.1371/journal.pone.00108372010e10837.doi:10.1371/journal.pone.00108372010

GOAL: PreventionGOAL: Prevention

Reduce/prevent inflammationReduce/prevent inflammation– InflammationInflammation damages epigenome damages epigenome– AspirinAspirin reduces inflammation reduces inflammation– Aspirin decreases risk Aspirin decreases risk

for certain cancersfor certain cancers

SUMMARY of Part IISUMMARY of Part II

– Epigenetics explores how the environment can Epigenetics explores how the environment can change gene expression.change gene expression.

– Inflammation damages the epigenome.Inflammation damages the epigenome.– The most important developmental era for the The most important developmental era for the

epigenome is during fetal development.epigenome is during fetal development.– Stress and social adversity trigger inflammatory Stress and social adversity trigger inflammatory

response, disease.response, disease.– Contributes to health disparities.Contributes to health disparities.– Rapidly growing research field.Rapidly growing research field.

Key PointsKey Points

Gene expression can be altered by the Gene expression can be altered by the environment.environment.

The alteration can be passed down to The alteration can be passed down to subsequent generations.subsequent generations.

Contributes to health disparities.Contributes to health disparities.

Suggests new therapies to reverse genetic Suggests new therapies to reverse genetic damage and disease. damage and disease.

““The The social environment social environment molds and molds and shapes the expression of our genetic shapes the expression of our genetic heritage until the genetic contribution heritage until the genetic contribution is sometimes barely evident.”is sometimes barely evident.”

“Social relationships clearly “Social relationships clearly forge our underlying biology.”forge our underlying biology.” Shelley E. Taylor, PhD. Shelley E. Taylor, PhD. The tending instinct: How nurturing is essentialThe tending instinct: How nurturing is essential to who we are and how we liveto who we are and how we live. (2002). (2002)

Recommended ReadingRecommended Reading

– Azar B. Psychology of Cells. Monitor on Azar B. Psychology of Cells. Monitor on Psychology, May 2011, 42(5):32.Psychology, May 2011, 42(5):32.

– Cloud J. Why DNA isn’t your destiny. Time Cloud J. Why DNA isn’t your destiny. Time http://www.time.com/time/magazine/article/0,9http://www.time.com/time/magazine/article/0,9171,1952313,00.html. (Jan.6,2011). 171,1952313,00.html. (Jan.6,2011).

– Hampton T. Studies probe role of telomere Hampton T. Studies probe role of telomere length. JAMA 2011,305(22):2278-2279.length. JAMA 2011,305(22):2278-2279.

– Stein R.A. Epigenetics – the link between Stein R.A. Epigenetics – the link between infectious diseases and cancer. JAMA 2011, infectious diseases and cancer. JAMA 2011, 305(4):1484-5.305(4):1484-5.