reproductive hormones and aging · 5. genetic, ethnic, racial variation on age-related changes of...
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Reproductive Hormones and Aging
James F. Nelson, PhDBarshop Institute for Longevity and Aging StudiesCellular and Integrative PhysiologyUT Health San Antonio
in humans and animal models
the need for more and bigger datasets
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Outline
• Reproductive Hormones: a primer
• How they affect the body (emphasis on aging)
• How they change with age
• Recent hormone-dependent findings relevant to Geroscience
• Knowledge gaps
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Oestriol
Androgens -- 19 carbon
Estrogens --18 carbon
Progestins -- 21 carbon
Key natural*sex steroids:
*countless pharmacologic derivatives
>>
>>
Dihydrotestosterone
OH
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Steroid Receptors
Nature Reviews Drug Discovery 3, 27–41 (2004)
nu
clea
r
Cel
l mem
bra
ne
Estrogens: Era & ERb
Androgens: AR
Progestins: PR, GR1, GR2
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Steroid Receptors
Nature Reviews Drug Discovery 3, 27–41 (2004)
nu
clea
r
Cel
l mem
bra
ne
Knowledge gap:
Post 70’s, absence of characterization of effect of aging on detailed advances in hormone receptor signaling pathways
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Sex Hormones Don’t Just act on Reproductive Targets
( i.e., receptors are everywhere )
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Estradiol and Testosterone Across the Lifespan
Mehmet Tevfik Dorak, in Principles of Gender-Specific Medicine (Third Edition), 2017
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Knowledge gaps: estrone?, estriol?, progesterone?, dihydrotestosterone?
Mehmet Tevfik Dorak, in Principles of Gender-Specific Medicine (Third Edition), 2017
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Sex Hormone Actions Relevant to Aging
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Mehmet Tevfik Dorak, in Principles of Gender-Specific Medicine (Third Edition), 2017
Organizational(e.g. neuronal
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Mehmet Tevfik Dorak, in Principles of Gender-Specific Medicine (Third Edition), 2017
ActivationalOrganizational
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Mehmet Tevfik Dorak, in Principles of Gender-Specific Medicine (Third Edition), 2017
ActivationalOrganizational Dysorganizational
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Examples of the data we need
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Plasma estradiol declines profoundly in women and increases in men (at least in Tromso, Norway)
Bjornerem et al JCEM 2004
n=1952
n=1555
Total Estradiol
Free Estradiol
FSH
DHEAS
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Plasma estradiol declines profoundly in women and increases in men (at least in Tromso, Norway)
Bjornerem et al JCEM 2004
n=1952
n=1555
Total Estradiol
Free Estradiol
FSH
DHEAS
Knowledge gap:
Effects of genetics, race, ethnicity, socioeconomic status?
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Harman, Blackman et al. The Journal of Clinical Endocrinology & Metabolism, Volume 86, Issue 2, 1 February 2001, Pages 724–731,https://doi.org/10.1210/jcem.86.2.7219
The content of this slide may be subject to copyright: please see the slide notes for details.
Plasma Testosterone declines progressively with age in largely
Caucasian, socioeconomically advantaged males
n=890
Harman, Blackman et al. The Journal of Clinical Endocrinology & Metabolism, Volume 86, Issue 2, 1 February 2001, Pages 724–731,https://doi.org/10.1210/jcem.86.2.7219
The content of this slide may be subject to copyright: please see the slide notes for details.
Plasma Testosterone declines progressively with age in largely
Caucasian, socioeconomically advantaged males
n=890
S Mtichell
Harman, MD, PhD
Marc
Blackman, MD
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Profound Individual Variation
Free Testosterone
Total Testosterone
n=890
Harman, Blackman et al. The Journal of Clinical Endocrinology & Metabolism, Volume 86, Issue 2, 1 February 2001, Pages 724–731,https://doi.org/10.1210/jcem.86.2.7219
The content of this slide may be subject to copyright: please see the slide notes for details.
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The Journal of Clinical Endocrinology & Metabolism, Volume 86, Issue 2, 1 February 2001, Pages 724–731, https://doi.org/10.1210/jcem.86.2.7219
The content of this slide may be subject to copyright: please see the slide notes for details.
Profound Individual Variation
Free Testosterone
Total Testosterone
Knowledge Gap:
The basis for and significance
of this variation to healthspan
and lifespan of this variation.
n=890
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Finding a Mouse Model
(to probe the role of sex hormones in aging)
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Criteria
• genetically heterogeneous• models human aging demographics• models reproductive hormonal changes• statistically powered to probe variation and
its implications.
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UM-HET3 – genetically heterogeneous4-way cross
[BALB/cByJ X C57BL/6J] X [C3H/HeJ X DBA/2]
Petrov et al. 2004
Courtesy R. de Cabo
Richard Miller, MD, PhD
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UM-HET3 mice exhibit similar early/midlife male-specific
mortality increase as humans
Humans Mice
0.001
0.100
0 25 50 75 100
Age (Years)
De
ath
Ra
te
FemaleMale
Cheng, Gelfond, Diaz, Strong, Nelson,
Aging Cell (2019)Catherine
Cheng PhD
Jonathan
Gelfond, MD
PhD
( HumanMortality Database )
n = 3690
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Humans Mice
0.001
0.100
0 25 50 75 100
Age (Years)
De
ath
Ra
te
FemaleMale
Cheng, Gelfond, Diaz, Strong, Nelson,
Aging Cell (2019)Catherine
Cheng PhD
Jonathan
Gelfond, MD
PhD
( HumanMortality Database )
n = 3690
What underlies the increased male mortality hazard in
early/mid adulthood?
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Cheng, Nelson, Strong, Gelfond,
(unpublished)
Catherine
Cheng
Jonathan
Gelfond, MD
PhD
Hypothesis: Post-pubertal testicular steroids increase male mortality
testosterone
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Cheng, Nelson, Strong, Gelfond,
(unpublished)
Catherine
Cheng
Jonathan
Gelfond, MD
PhD
Hypothesis: Pre-pubertal castration will increase male survival
0 200 400 600 800 1000 1200 1400
0.0
0.2
0.4
0.6
0.8
1.0
Survival of Pooled Controls
Age
(days)
Female
Male
Castration pre pubertally
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A few, among many, important unanswered questions
1. Mechanisms and tissue targets of androgen-induced excess male mortality.2. Roles of androgens in age-specific mortality and declining healthspan in late life.
3. Roles of androgens/estrogens during the organizational phase on healthspan and longevity 4. Roles of estrogens (estradiol/estrone/estriol) on healthspan and longevity5. Genetic, ethnic, racial variation on age-related changes of reproductive hormones
6. Effects of aging on hormone receptor / signaling cascades and target tissue sensitivity to reproductive hormones.
7. Mechanisms of sex differences in the response to life and healthspan lengthening drugs.
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Acknowledgments
Department of Epidemiology and Biostatistics
Dada Liu, MS
Funding
Glenn Predoctoral Fellowship
NIA Predoctoral Training Fellowship
NIA Interventions Testing Program
NIA Nathan Shock Center
Catherine Cheng
Jonathan Gelfond, MD, PhD
Barshop Aging Animal Models & Longevity Assessment Core
Vivian Diaz
Victoria Villanueva
Aaron Regalado
Cassandra Tolento
Ariana Hall
Alfred Fisher, MD, PhD
Benjamin Eaton, PhD
Randy Strong, PhD