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From Selves to Cells: The New Biology of Cells, Illness and Depression

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From Selves to Cells: The New Biology of Cells, Illness and Depression

  1. 1. From Selves to Cells: The New Biology of Cells, Illness and Depression Owen M. Wolkowitz, MD University of California San Francisco (UCSF) School of Medicine Sept. 13, 2014
  2. 2. Outline • An Alternative View of Depression: Is Depression Accompanied by Accelerated Aging? • Ways to Assess Cellular Aging • Causes of Cellular Aging • Naturally Occurring Repair of Cellular Aging • Does Cellular Aging Occur in the Brain? • Can Depression-Associated Cellular Aging be Prevented or Reversed?
  3. 3. Major Depression is an Independent Risk Factor for Excess Mortality • High baseline depressive symptoms are associated with 24% higher mortality over 6 years, after controlling for these covariates:  Sociodemographic factors  Prevalent clinical disease, subclinical disease indicators  Behavioral and biological risk factors • Patients with psychiatric illness have a 14 year lower life expectancy; 77% of this is due to natural causes Schulz et al., 2000 Lawrence et al., 2013
  4. 4. Is depression actually a whole body disease, one manifestation of which is depression? • If depression is purely a “mental illness” or even a “brain disease,” why do depressed individuals have a significantly increased rate of physical diseases usually associated with advanced age*?: • Heart disease and Stroke? • Dementia? • Obesity, Diabetes, Osteoporosis and Metabolic syndrome? • Immune dysfunction? • Premature death (even controlling for suicide)? *Adjusted for age, HTN, diabetes, smoking, perceived health and cognitive function 4
  5. 5. Telomeres and Telomerase • Telomeres are non-coding sequences capping DNA ends that can shorten with somatic cell divisions and serve as a “senescence clock” (a marker of biological age) • Telomerase is a cellular enzyme that forestalls telomere shortening and has additional non-telomeric roles in cell survival. 5
  6. 6. Telomeres are DNA’s Shoelaces
  7. 7. PBMC Telomere Length and Aging Frenck et al, PNAS, 1998 18,000 16,000 14,000 12,000 10,000 8,000 6,000 4,000 2,000 0 0 27 50 72 Age Base pairs (in human leukocytes) • On average, healthy adults lose ~30 -100 base pairs/ year. But this is variable, with some people maintaining or even lengthening telomeres over time. 7
  8. 8. Factors Possibly Associated with Shortened Telomeres
  9. 9. Does Length Really Matter? Short Leukocyte Telomeres… Cawthon et al., 2003 Are Associated with: • Coronary Artery Disease • Diabetes • Vascular Dementia • Immunosenescence Predict Subsequent Mortality 9
  10. 10. Prospective Change in Telomere Length Also Predicts Mortality in Men Change Over 2 ½ Years Men (Epel et al., Aging, 2009)
  11. 11. Is Telomere Length a “Biological Clock”? • Because leukocyte telomere length (LTL) decreases with chronological age and because it is inversely correlated with the incidence of diseases of aging, it is increasingly viewed as a biological clock.
  12. 12. Study Design: • 39 mothers of chronically ill children • 19 mothers of healthy children (control group) • Ages 20- 50 y.o. All analyses controlled for age. • Telomere length and telomerase activity assayed in pooled peripheral blood mononuclear cells (PBMCs) PNAS, 2004 Elissa Epel, PhD Liz Blackburn, PhD Jue Lin, PhD 12
  13. 13. PNAS, 2004 • Telomere Length • Telomerase Activity = High stress = Low Stress High stress women had cell aging comparable to non-stressed women ~13 years older 13
  14. 14. PNAS, 2004 r= -0.45 Longer duration of stress = Shorter telomeres Perceived stress, independent of group, accounted for telomere shortening 14
  15. 15. Your Telomeres are Only as Old as You Think 15 O’Donovan et al., 2012 O’Donovan et al., 2009
  16. 16. Telomere Length in Depression: The NESDA Study • 1,095 current MDD, 802 remitted MDD and 510 controls • TL was shorter in both MDD groups (p< 0.02), corresponding to over 5 years of accelerated aging • TL in remitted MDD did not differ from current MDD, suggesting a long-lasting “imprint” of MDD on Verhoeven J, et al., 2013 telomeres • Greater severity and chronicity of MDD were associated with shorter telomeres (p< 0.01) Duration Severity
  17. 17. Telomere Length & Oxidation and Inflammation in MDD Wolkowitz et al., 2011
  18. 18. Telomere Shortening is Not Specific to Major Depression Other Psychiatric Conditions With Shortened Telomere Length: • Schizophrenia • Bipolar Disorder • PTSD *with early life adversity • Early Life Adversity Hypothesis: Telomere shortening is related to biochemical mediators (e.g., oxidation and inflammation) that traverse psychiatric diagnoses. 18
  19. 19. Early Life Trauma and Telomere Length in Adulthood Kiecolt-Glaser et al., 2011 Tyrka et al., 2009
  20. 20. How Early in Life Can Adverse Events Affect Adult Telomere Length?
  21. 21. P< 0.05, controlling for birth weight, early life adversity and current stress Telomeres in the prenatal stress group were shorter by an average of 178 base pairs, indicating approximately 3.5 years of accelerated biological aging.
  22. 22. Telomerase • Telomerase is a cellular enzyme that forestalls and repairs telomere shortening and has additional important non-telomeric roles in cell survival. 22
  23. 23. Telomerase Activity in Untreated Depression • Changes with Antidepressant Treatment • Prediction of Antidepressant Response • ?Neurotrophic Effects
  24. 24. Lower Telomerase Before Treatment (Sertraline x 8 Wks) and Greater Telomerase Increases After Treatment Predict Better Antidepressant Responses p<0.002 p<0.004 Wolkowitz et al., 2012
  25. 25. Does Telomerase Have Intrinsic Antidepressant and/ or Neurogenesis-Enhancing Effects? Are Telomere Length and Telomerase Measurements in Blood Relevant to the Brain in Depression? 25
  26. 26. Hippocampal Telomerase Modulates Depressive Behavior and Neurogenesis in Mice • Inhibiting HC telomerase inhibits neurogenesis and produces depression-like behavior • Overexpressing HC telomerase increases neurogenesis and has antidepressant-like effects Zhou et al., 2011
  27. 27. Are telomere length and telomerase measurements in blood relevant to the depressed brain?
  28. 28. Leukocyte Telomere Length is Directly Correlated with Hippocampus Volume in Non-Depressed Individuals Left Right Jacobs et al., 2014
  29. 29. • These preliminary findings are consistent with preclinical findings suggesting neurotrophic and antidepressant effects of telomerase (Zhou et al 2011; Jaskelioff et al 2011; Fu et al 2002
  30. 30. Regions of the Brain Implicated in Depression and in Antidepressant Response are Directly Correlated with Peripheral Telomerase Activity Corticolimbic Network (Frontal- Anterior Cingulate- Hippocampus) Implicated in Depression (red arrows) and Positively Correlated with Telomerase Activity in Depression (blue arrows). Adapted from: aan het Rot et al., 2009 Prelim data, Wolkowitz et al., 2014
  31. 31. • So what’s the good news?
  32. 32. Telomeres Can Lengthen! Telomeres lengthen in ~1/4th of adults (MacArthur Aging Study, analysis of high functioning 70 – 79 year olds) over a 2.5 year period Epel et al, Aging, 2009
  33. 33. Telomere Length and/or Telomerase Activity are Associated with Lifestyle* *Associations do not always prove causality Favorable Regulators: • Exercise • Dietary restraint • Multivitamin intake (Vit C, D and E) • Folate • Omega-3 fatty acids • Social support • Stress management • Statins • Estrogen • Fruits and vegetables • Meditation • Sleep • TA-65/ Telomerase Activators (Astragalus membranaceus) • Antidepressants ? Unfavorable Regulators: • Obesity, insulin resistance • Homocysteine • Cigarette smoking • Pessimism Reference: Lin, Epel and Blackburn. Telomeres and lifestyle factors: Roles in cellular aging, 2011
  34. 34. 34 Exercise Right; Sleep Tight Exercise Protects Against Stress Sleep Quality and Telomeres Puterman et al., 2010 Prather et al., 2011
  35. 35. 35 Telomere Length, bp Multisystem Resiliency Moderates the Major Depression/ Telomere Length Association Figure adapted from: Puterman E, et. al, 2013 * “Multisystem Resiliency” defined as healthy emotion regulation, strong social connections and good sleep and exercise patterns
  36. 36. Dean Ornish Lifestyle Study • Telomerase was measured at baseline and after 3 months Mean telomerase activity in 30 men with low-risk Prostate CA Ornish, Lin, Daubenmier et al, The Lancet, 2008
  37. 37. Comprehensive Lifestyle Changes and Telomere Length at 5-Year Follow-up Ornish D et al., Lancet Oncology, 2013
  38. 38. Meditation Retreat Study 3 months of Meditation for 8-10 hr/ day in a retreat setting, vs. Wait-list control Jacobs et al., 2011
  39. 39. Meditation and Telomerase Cliff Saron et al.,
  40. 40. Increased Damaging Factors and Decreased Protective Factors in Depression Wolkowitz et al., 2011
  41. 41. Conclusions • Diseases now considered “mental illnesses” may be re-conceptualized as systemic illnesses, albeit with prominent behavioral manifestations • Understanding cell aging in psychiatric disorders may explain the high medical co-morbidity and should lead to novel treatment targets for depression and the medical comorbidities 42
  42. 42. “Every stress leaves an indelible scar, and the organism pays for its survival after a stressful situation by becoming a little older.” -Hans Selye
  43. 43. The UCSF Depression and Wellness Study (415) 476-7433 or:
  44. 44. Additional Thanks to: Yatrika Ajaya Kirstin Aschbacher Elizabeth Blackburn Heather Burke Stephen Chen John Coetzee Mariana Compagnone Elissa Epel Brittany Fair Christina Hough Jill James Rowen Jin Eve Kupferman Jue Lin Scott Mackin Laura Mahan Sara Mason Synthia Mellon Kelley Miller Allie Morford The Morrow Lab J Craig Nelson Katie Nguyen Aoife O’Donovan Michelle Pardo Brenda W.J.H. Penninx Aric Prather Eli Puterman Victor Reus Dóra Révész Rebecca Rosser Molly St. Denis Yali Su Josine E. Verhoeven Stephanie Yu Funding: The O’Shaughnessy Foundation The Tinberg Family NIMH 1 R01 MH083784