Trust, safety, and

the social regulation of gene expression

Steve W. Cole, Ph.D.

UCLA School of Medicine

Lonely

Integrated

Social isolation

78131

Inflammation

Immunoglobulin G1 production

Type I interferon antiviral response

Cole et al. Genome Biology 2007

Low SES

Social loss / bereavement

Post-traumatic stress

Cancer diagnosis

Discrimination

Loneliness

Social instability

Chronic stress

Low social rank

Caregiving for seriously ill

Anxiety

Early life adversity

Cole et al. PNAS 2011

Powell et al. PNAS 2013

Heidt et al. Nature Medicine 2014

Cole et al. PNAS 2015

McKim et al., Cell Reports 2018

Irwin & Cole, Nature Reviews Immunology 2011

Lonely

Integrated

How not to live

How should we live?

How often do you feel happy?

How often do you feel satisfied?

Life has direction and meaning?

Grow and become a better person?

Hedonic Eudaimonic

Fredrickson et al. PNAS 2013

FOS

FOSB

FOSL1

FOSL2

JUN

JUNB

JUND

NFKB1

NFKB2

REL

RELA

RELB

Eudaimonic

Hedonic

IL1A

IL1B

IL6

IL8

TNF

PTGS1

PTGS2

IGJ

IGLL1

IGLL3

GBP1

IFI16

IFI27

IFI27L1

IFI27L2

IFI30

IFI35

IFI44

IFI44L

IFI6

IFIH1

IFIT1

IFIT1L

IFIT2

IFIT3

IFIT5

IFITM1

IFITM2

IFITM3

IFITM4P

IFITM5

IFNB1

IRF8

IRF2

IRF7

MX1

MX2

OAS1

OAS2

OAS3

OASL

Favorable

Adverse

Fredrickson et al. PNAS 2013

HedonicEudaimonic

Hedonic

Eudaimonic

Fredrickson et al. PLOS One 2015

Cole et al. Psychoneuroendocrinol 2015

Kitiyama et al. Psychoneuroendocrinol 2016

Boyle et al. Psychoneuroendocrinol 2019

Snodgrass et al. Brain Behav Immun 2019

Seeman et al. Psychoneuroendocrinol 2020

Moieni et al. Brain Behav Immun 2020

Kim et al. under review 2020

How to make more eudaimonia?

GenX LAUCLA Gerontology & LAUSD

60-80 yo local resident classroom mentors

for at-risk K-3rd graders in South-Central LA

CT

RA

R

NA

expre

ssio

n(%

ch

an

ge

fro

m b

ase

line

)

-12%

-10%

-8%

-6%

-4%

-2%

0%

2%

4%

6%

Baselin

e

Month

3

Month

9

Seeman et al. Psychoneuroendocrinol 2020

Ventral

Striatum

Dutcher, Bower, Eisenberger, et al. in prep

Eisenberger & Cole, Nature Reviews Neuroscience 2012

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

-2 -1 0 1 2

r = -.71

VS activation

Pro

infl

amm

ato

ryR

NA

(lo

g 2)

Goetz et al. Psychological Bulletin 2010

Porges Int J Psychophysiology 2001

Porges Psychophysiology 1995

Creswell et al. Brain Behav Immun 2012

Antoni et al. Biological Psychiat 2012

Black et al. Psychoneuroendocrinol 2013

Bower et al. Psychoneuroendocrinol 2014

Irwin et al. JNCI Monographs 2014

Bower et al. Cancer 2015

Laudenslager et al. J Behav Med 2016

Antoni et al. Psychoneuroendocrinol 2016

Fredrickson et al. PNAS 2013

Fredrickson et al. PLOS One 2015

Cole et al. Psychoneuroendocrinol 2015

Kitiyama et al. Psychoneuroendocrinol 2016

Boyle et al. Psychoneuroendocrinol 2019

Snodgrass et al. Brain Behav Immun 2019

Seeman et al. Psychoneuroendocrinol 2020

Moieni et al. Brain Behav Immun 2020

Kim et al. under review 2020

Cole Krueger et al. in prep 2020

Collado-Hidalgo et al. Brin Behav Immun 2006

Sloan et al. Cancer Res 2010

Powell et al. PNAS 2013

Eyre et al. Pharmacopsychiatry 2017

Shaashua et al. Clin Cancer Res 2017

Haldar et al., Brain Behav Immun 2018

Hiller et al. Clin Cancer Res 2020

Knight et al. Blood Advances 2020

Take-home points:

• Chronic threat and insecurity activate a defensive genomic program

• That “Conserved Transcriptional Response to Adversity” (CTRA) raises disease risk

• CTRA is mediated by fight-or-flight stress responses

• CTRA can be inhibited by…

1. Pharmacologic interventions targeting CNS threat circuits OR peripheral b2-adrenergic signaling

2. Behavioral interventions to reduce stress, promote coping & enhance efficacy/security

3. Activation of the brain’s reward system, e.g., by eudaimonic engagement

• Prosocial: caregiving / mentoring / generativity

• Goal directed: creative / productive engagement

4. A safe, supportive, secure, and ideally generative social environment

CollaboratorsMike Irwin, Julie Bower, Patti Ganz

John Cacioppo, Louise Hawkley, Bob Rose

Greg Miller, Edith Chen

John Sheridan, Nicole Powell, Daniel McKim

John Capitanio, Erica Sloan

Steve Suomi, James Heckman

Barbara Fredrickson, Karen Grewen

Sonja Lyubomirsky, Katherine Nelson-Coffey, Megan Fritz

Naomi Eisenberger, Janine Dutcher, Mona Moieni

SupportSemel Institute for Neurscience and Human Behavior

NCI CA116778, CA110793, CA109298

NIAID AI33259, AI36554, AI49135, AI52737

NIA AG107265, AG033590, AG034679

JSPS KAKENHI 25285113

MacArthur Foundation

HopeLab Foundation

Norman Cousins Center