1. Epigenetics and Health Disparities Part II: Psychosocial Factors Anita R. Webb, PhD JPS Health Network Fort Worth, Texas

2. Key Points: PART I (Disease) Gene expression can be altered by the environment, including the social environment. Alterations may be passed down to subsequent generations. Without changes in DNA. Epigenetics may explain some diseases. Burgeoning field of medicine

3. KEY POINTS PART II Stress can affect how our genes are expressed (through multiple generations). Epigenetics theory may contribute to the understanding of health disparities. Epigenetics research is suggesting how therapies can reverse genetic damage and diseases such as cancer.

4. TOPICS StressLonelinessNurturing Childhood Adversity TraumaObesity Health Disparities

5. “Social Genomics” “ Our interpersonal world exerts biologically significant effects “On the molecular composition of the human body.” –Hollander RS. Social genomics: Genomic inventions in society. Science & Eng. 2002,8(4):485-496. Genetic inheritance is not altered. Expression is altered.

6. Stress and Disease Stress and Disease Psychosocial stress may affect basic cellular functions and metabolism, –“Lifestyle diseases”: e.g. cardiac, diabetes And change gene expression –Without changing DNA. –i.e. Epigenetic changes –Embryos and infants may be especially sensitive

7. Stress and Telomeres Stress can accelerate telomere shortening (protective endcaps on chromosomes). (protective endcaps on chromosomes). –Emotional stress releases cortisol. –Cortisol can damage healthy tissue. –Cell repair requires additional cell divisions. –Each cell division shortens telomeres. –So that telomeres provide less protection. Result: DNA ages more rapidly.

8. Further Stress Damage Immune cells patrol the body –First line of defense against infection –Scan for damaged tissue –Mount inflammatory response Chronic stress = Chronic inflammation = Premature telomere shortening = Risk for –Some types of cancer –Cardiovascular disease –Neuro-degeneration/cognitive defects

9. The Psychology of Cells “Developmental Plasticity” –“The environment makes its way into genes and controls what your genome becomes.”. Example: Loneliness (social environment) –Primes the immune system –Activates inflammatory response –Can eventually lead to disease (Azar 2011: see last slide)

10. Loneliness Research White blood cells of lonely subjects: White blood cells of lonely subjects: –1. Over-expressed genes that resulted in inflammation –2. Under-expressed genes involved in antibody production (lymphocytes) Cole SW, Hawkley LC, Arevalo JM, Sung CY, Rose RM, Cacioppo JT. Social regulation of gene expression in human leukocytes. Genome Biol. 2007;8(9):R189.

11. Example: Maternal Nurturing Maternal nurturing of rat pups promoted –DNA methylation at gene which encodes hippocampus glucocorticoid receptors Result: “Favorably altered emotionality” –Plus rate of brain and body aging Continued to affect pups’ stress-response pathway into adulthood. Weaver IC et al. Epigenetic programming by maternal behavior. Neuroscience 7, 847-54 (2004).

12. Childhood Adversity Poverty, loneliness, deprivation, neglect Affect immune function at genetic level Pro-inflammatory genes are more active (“ready for trouble”). Creates health hazard even into adulthood Regardless of adult SES

13. Example: Childhood Adversity Social adversity in childhood –“Tunes immune system to be vigilant for stress” –Primes immune system to use inflammatory response Increases disease risk –“Cortisol runs rampant” –Immunosuppressive –Health consequences (Azar)

14. Chronic Stress or Trauma Chronic Stress or Trauma Since stress is associated with telomere shortening in immune system cells, Traumatized and chronically stressed children are at risk for: –Lifelong faulty immune function Childhood adversity may contribute to –Health disparities as adults

15. SES Health Disparities: Mechanism? Early adversity primes immune system to: Activate inflammatory response. May reprogram immune system Beginning in the womb Increasing risk for disease

16. Example: Gestation Conditions in the womb can affect fetus –Continuing well into adulthood. Example: If a pregnant woman eats poorly –Her child will be at significantly higher risk –For cardiovascular disease as an adult. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet May10,1986;1(8489)1077-1081

17. Mechanism? (continued) Stress, poverty, trauma May prematurely age DNA Accelerate telomere shortening Undermine health lifelong Shorten life span

18. Adult 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

19. Other Implications: OBESITY During times of food scarcity –Physiology becomes more efficient in storing calories to protect against starvation. –Efficient food storage mechanisms will be passed to subsequent generations. If food later becomes more plentiful –Descendants will be at higher risk for obesity –Due to more efficient food storage.

20. Epigenetic Changes Can be inherited by multiple generations –Via epigenetic marks –But is NOT evolution –Does NOT change DNA When the environmental stressor is removed, the epigenetic mark fades –DNA eventually reverts to original programming in a subsequent generation.

21. Epigenetic Therapy Unlike genome, epigenome can be modified Therefore: Can be CORRECTED Therapy: Change cells’ instructions –1. Tell genes which play a role in disease to “Lie dormant”. –2. Reactivate original cell instructions that were silenced by disease.

22. VIA: Epigenetic Marks Learn how to manipulate epigenetic marks –Develop drugs that can Silence bad genes Activate good genes –FDA approved epigenetic drug to treat rare deadly blood malignancies (MDS) (2004) Future targets: Cancers, schizophrenia, autism, diabetes, Alzheimer’s

24. Example: Stress and the Brain Acute stress caused rapid chemical change in rat brains. Hippocampus: Memory –Especially susceptible to stress Fluoxetine (Prozac) reversed some methylation effects of chronic stress. Hunter RG, et al. Regulation of hippocampal H3 histone methylation by acute and chronic stress. Natn Acad Sc. 2009;106 (49): 20912-20917.

25. Treatment Research: Repairing Telomere Damage Women with cervical cancer Treatment: Stress management training –Six sessions of telephone counseling –Reduced emotional stress Promoted telomere repair and growth Drury, Theall, Gleason et al. Telomere length and early severe social deprivation: linking early adversity and cellular aging. Molecular Psychiatry, (2011) 1–9.

26. Prevention Research Women: Post-menopausal, dementia caregivers Vigorous physical exercise –‘‘Increased heart rate and/or sweating.’’ –At least 14 minutes a day Was related to longer telomeres, Puterman E. et al. Power of Exercise: Buffering the Effect of Chronic Stress on Telomere Length. PLoS One, May 2010, 5(5):e10837. e10837.doi:10.1371/journal.pone.00108372010

27. GOAL: Prevention Reduce/prevent inflammation –Inflammation damages epigenome –Aspirin reduces inflammation –Aspirin decreases risk for certain cancers

28. SUMMARY of Part II –Epigenetics explores how the environment can change gene expression. –Inflammation damages the epigenome. –The most important developmental era for the epigenome is during fetal development. –Stress and social adversity trigger inflammatory response, disease. –Contributes to health disparities. –Rapidly growing research field.

29. Key Points Gene expression can be altered by the environment. The alteration can be passed down to subsequent generations. Contributes to health disparities. Suggests new therapies to reverse genetic damage and disease.

30. “The social environment molds and shapes the expression of our genetic heritage until the genetic contribution is sometimes barely evident.” “Social relationships clearly forge our underlying biology.” Shelley E. Taylor, PhD. The tending instinct: How nurturing is essential to who we are and how we live. (2002) “The social environment molds and shapes the expression of our genetic heritage until the genetic contribution is sometimes barely evident.” “Social relationships clearly forge our underlying biology.” Shelley E. Taylor, PhD. The tending instinct: How nurturing is essential to who we are and how we live. (2002)

31. Recommended Reading –Azar B. Psychology of Cells. Monitor on Psychology, May 2011, 42(5):32. –Cloud J. Why DNA isn’t your destiny. Time http://www.time.com/time/magazine/article/0,9 171,1952313,00.html. (Jan.6,2011). –Hampton T. Studies probe role of telomere length. JAMA 2011,305(22):2278-2279. –Stein R.A. Epigenetics – the link between infectious diseases and cancer. JAMA 2011, 305(4):1484-5.