THE DANGER OF STRESS: DISEASE & ACCELERATED BIOLOGICAL AGING

Owen M. Wolkowitz, MD

OBJECTIVES

After participating in this presentation, you should have increased

knowledge and enhanced competence to…

√ Explain to patients the biological effects of stress

√ Explain to pregnant patients how prenatal stress may affect the developing fetus

√ Recommend to patients strategies to lessen the deleterious effects

of stress

The Biological Dangers of Stress

Owen M. Wolkowitz, M.D.Professor of Psychiatry

Director, Psychopharmacology Assessment ClinicUniversity of California, San Francisco (UCSF) School of Medicine

Symposia Medicus, Las Vegas, Sept. 2018

Disclosures

Co-inventor of Patent #US 20130289126 A1 “Cell aging as a unique biomarker of major depression,” assigned to the Regents of the University of California

I have no other Financial Disclosures

No off-label or investigational use

Outline Stress and Depression are Not Just “in Your Head”

How Stress and Depression Get Under the Skin Cell Aging: Telomeres and Health Risk

Mediators of Cell Aging in Stress and Depression Inflammation, Oxidation and Cortisol Telomerase

Early Life Adversity: Lifelong Determinant of Vulnerability

Can Cell Aging be Prevented, Slowed or Reversed? Treatment and Lifestyle Implications

Is depression actually a whole body disease, one manifestation of which is depression?

Depression is the leading cause of disability in North America and is projected to become the second leading cause of disability worldwide by 2020.

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

Physical Disease Burden in Major Depression

Can “Cell Aging” in Stress and Mental Illness Help Explain Medical

Co-Morbidities?

Depression/ Stress

InflammationHPA

Oxidative stress

Hypothesized underlying dysregulated stress & endocrine systems in cell aging

Telomeres/Telomerase

Modified from slide by Brenda Penninx, PhD

Epigenetic Aging

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 rebuilds telomeres and has additional non-telomeric roles in cell survival.

Telomeres are the end caps of our DNA

When telomeres critically shorten, the ends of the DNA are exposed to damage, and the cell

dies

Telomeres May be Our Body’s “Canaries in the Coal Mine” or They May Cause Physical Illness

Quoted phrase by Rita Effros; Image by Marshall Jones

The Relationship of Telomere Length and Telomerase Activity to

Aging, Longevity and Physical and Mental Illness:

A Possible Conduit by Which Stress Impairs Health

PBMC Telomere Length and Aging

Valdes AM, et al., Lancet, 2005

• On average, healthy adults lose ~30-60 base pairs/ year. But this is variable, with some people maintaining or even lengthening telomeres over time.

Cawthon et al., 2003

Short Leukocyte Telomeres…

Are Associated with:

• Coronary Artery Disease

• Diabetes

• Dementia

• Immunosenescence

And Predict Subsequent Mortality

Does Length Really Matter?

Important Note: Excessive telomere length or telomerase activity may also be unhealthy

Women Caregiver 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 EpelElizabeth Blackburn

Jue Lin

PNAS, 2004

• Telomere Length

• Telomerase Activity

High stress women had cell aging comparable to non-stressed women ~13 years older

= High stress

= Low Stress

PNAS, 2004

r= -0.45

Longer duration of stress = Shorter telomeres

Perceived stress, independent of Group, accounted for telomere shortening

Chronic Major DepressionSimon et al., 2006

p< 0.01

Note: Average lifetime duration of depression: 25.7 + 12.1 years

MDD Subjects showed an average of 10 years accelerated telomere aging

Telomeres are shorter in Adults with History of Adverse Childhood Experiences

Tyrka et al, 2010 Kananen et al., 2010

Chen et al., 2015

Q: How Early in Life Can Adverse Events Affect Adult

Telomere Length?

Q: How Early in Life Can Adverse Events Affect Adult

Telomere Length?

Answer: In the Uterus

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.

Maternal Psychosocial Stress During Pregnancy is Associated with Newborn Leukocyte Telomere Length

(cord blood)- Entringer et al., 2013

Scatterplot of association between maternal pregnancy-specific stress and newborn (cord blood) telomere length (r2 = 0.25). Telomere length is adjusted for covariates (newborn gestational age

at birth, weight, sex, and exposure to antepartum obstetric complications).

TelomeraseIn Addition to Preserving and Lengthening Telomeres,

Telomerase May Have Direct Antidepressant and Neurotrophic Effects

Cell Aging by Telomere Loss Can Be Reversed with Telomerase (at least in mice)

•“Jaskelioff et al (2011) demonstrated that multiple aging phenotypes in a mouse model of accelerated telomere loss can be reversed within 4 weeks

of reactivating telomerase. This raises the major question of whether physiological aging, likely caused by a combination of molecular defects,

may also be reversible.”

Commentary by Bernardes de Jesus and Blasco, 2011

Red staining indicates neural

stem cell ability to generate neurons, especially in the hippocanmpus

(Jaskelioff et al., 2011)

In Depression, Telomerase Activity is Positively Correlated with Hippocampal Volume

Wolkowitz et al., 2015

Summary: What Causes Short Telomeres? Oxidative Damage (e.g., smoking)

Inflammation

Cortisol

Stress-Related Adrenaline

Telomerase

Chronic viral infections

Early Life Adversity

It is “possible” (but unproven) that intervening in these pathways could delay cell aging and improve health

So what’s the good news?

Tips for Telomere Health

Favorable Regulators:

Exercise

Dietary restraint

Multivitamin intake (Vit C, D and E)

Folate

Omega-3 fatty acids

Social support

Mindfulness

Stress management

Statins

• Estrogen• Fruits and vegetables• Meditation• Sleep• TA-65/ Telomerase

Activators (Astragalusmembranaceus)

• Antidepressants?; Lithium?

Unfavorable Regulators:• Obesity, insulin resistance• Homocysteine• Cigarette smoking

References: Lin, Epel and Blackburn. Telomeres and lifestyle factors: Roles in cellular aging, 2011;EH Blackburn and E Epel, The Telomere Effect, 2017

(Caveat: Associations do not necessarily suggest causality)

TelomereLength, bp

*

Multisystem Resiliency Moderates theMajor Depression/ Telomere Length

AssociationFigure adapted from: Puterman E, et. al, 2013

“Multisystem Resiliency” defined as healthy emotion regulation, strong social connections and good sleep and exercise patterns

Telomeres May 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. It is not known if this is

“real” or a statistical artifact (“regression to the mean”.)

Epel et al, Aging, 2009

Dean Ornish Lifestyle Study

Mean telomerase activity in 30 men with low-risk Prostate CA

• Telomerase was measured at baseline and after 3 months

• (but no control group)

Ornish, Lin, Daubenmier et al, The Lancet, 2008

Meditation Retreat Study

Jacobs et al., 2011

3 months of Meditation for 8-10 hr/ day in a retreat setting, vs. Wait-list control

Telomerase activity (but no baseline measures)

Provisional Interpretations: Telomere shortening may occur with chronic stress or serious mental illnesses,

although this is variable between people.

Telomere length measurement is probably not yet suitable for clinical use

Telomere shortening is not a specific diagnostic biomarker but may point to the presence of specific physiological abnormalities.

Telomere shortening may result from cumulative exposure to oxidation and/or inflammation, which are often elevated in these conditions

Emerging aging biomarkers, e.g., “epigenetic ageing” may also accelerate with chronic stress (Zannas et al., 2015)

Certain diseases now considered “mental illnesses” may be re-conceptualized as systemic illnesses, albeit with prominent behavioral manifestations

Understanding cell aging in stress and psychiatric disorders may explain the high medical co-morbidity and should lead to new treatment targets

***Lifestyle factors may be important modifiable risk factors***

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

-Hans Selye

Questions?

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