trust, safety, and the social regulation of gene...
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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