This document outlines a presentation about cellular aging and its relationship to depression. It discusses how depression may be linked to accelerated aging at the cellular level, as evidenced by shorter telomeres and lower telomerase activity in depressed individuals. Certain lifestyle factors like exercise, diet and meditation may help lengthen telomeres and increase telomerase activity, potentially preventing or reversing some effects of depression-associated cellular aging. The presentation explores the implications of this research and how conceptualizing depression as a systemic illness could lead to novel treatment targets.

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. 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. 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. 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. 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. Telomeres are DNA’s Shoelaces

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. Factors Possibly Associated with
Shortened Telomeres

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. Prospective Change in Telomere Length
Also Predicts Mortality in Men
Change Over 2 ½ Years
Men
(Epel et al., Aging, 2009)

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. 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. 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. PNAS, 2004
r= -0.45
Longer duration of stress =
Shorter telomeres
Perceived stress, independent of
group, accounted for telomere
shortening
14

15. Your Telomeres are Only as Old as You
Think
15
O’Donovan et al., 2012 O’Donovan et al., 2009

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. Telomere Length & Oxidation and
Inflammation in MDD
Wolkowitz et al., 2011

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. Early Life Trauma and Telomere
Length in Adulthood
Kiecolt-Glaser et al., 2011 Tyrka et al., 2009

20. How Early in Life Can Adverse Events Affect
Adult Telomere Length?

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. Telomerase
• Telomerase is a cellular enzyme that
forestalls and repairs telomere shortening
and has additional important non-telomeric
roles in cell survival. 22

23. Telomerase Activity in Untreated
Depression
• Changes with
Antidepressant Treatment
• Prediction of
Antidepressant Response
• ?Neurotrophic Effects

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. 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. 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. Are telomere length and telomerase
measurements in blood relevant to
the depressed brain?

28. Leukocyte Telomere Length is Directly Correlated
with Hippocampus Volume in Non-Depressed
Individuals
Left Right
Jacobs et al., 2014

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. 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. • So what’s the
good news?

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. 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
Exercise Right; Sleep Tight
Exercise Protects Against Stress Sleep Quality and Telomeres
Puterman et al., 2010 Prather et al., 2011

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. 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. Comprehensive Lifestyle Changes and Telomere
Length at 5-Year Follow-up
Ornish D et al., Lancet Oncology, 2013

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. Meditation and Telomerase
Cliff Saron et al.,

41. Increased Damaging Factors and Decreased Protective
Factors in Depression
Wolkowitz et al., 2011

42. 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

43. “Every stress leaves an indelible
scar, and the organism pays for its
survival after a stressful situation
by becoming a little older.”
-Hans Selye

44. The UCSF Depression and Wellness Study
(415) 476-7433 or: mood@ucsf.edu

45. 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