resilience and reserve in aging · 2019. 12. 17. · resilience and reserve in aging nathan k....
TRANSCRIPT
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Resilience and Reserve in Aging
Nathan K. LeBrasseurRobert & Arlene Kogod Center on Aging
Department of Physical Medicine & RehabilitationDepartment of Physiology & Biomedical Engineering
RCCNAUSTIN2019
Animal Models of Recovery from Surgery
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Can we develop preclinical models to test resilience?NIA initiative in partnership with Austad, Huffman, Ladiges, Richardson, and Salmon
LeBrasseur, J of Gerontology, 2017
Targeting the Biology of AgingParadigms for Translation
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YF MAF OF YM MAM OM0
10
20
30
40
Lean
Mas
s (g
)
***
************
YF MAF OF YM MAM OM0.00
0.02
0.04
0.06
Gri
p S
tren
gth
(N/g
)***
*** *** ***
YF MAF OF YM MAM OM0
10
20
30
40
Fat M
ass
(g)
******
**
YF MAF OF YM MAM OM0
20
40
60
80
Bod
y W
eigh
t (g)
******
*
******
YF MAF OF YM MAM OM0
100
200
300
Rot
aRod
Tim
e (s
)
***
***
YF MAF OF YM MAM OM0
2000
4000
6000
8000
Ope
n Fi
eld
Dis
tanc
e (c
m)
***
YF MAF OF YM MAM OM0
50
100
150
Nes
tlet S
core
(AU
C)
* * *********
Phenotypes of Younger (6 mo), Middle-Aged (12 mo), and Older (20 mo) 4-way Cross Study Participants
Brown, Mazula, Miller, Maleki…unpublished
CB6F1♀x C3D2F1♂
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Anesthesia Challenge
Younger Middle-Age Older0
100
200
300
Tim
e to
Ste
rnal
Rec
umba
nce
(s)
***
***
Younger Middle-Aged Older0
100
200
300
Tim
e to
S
tern
al R
ecum
banc
e (s
)
*
***
Younger Middle-Aged Older0
50
100
150
200
250
Tim
e to
S
tern
al R
ecum
banc
e (s
)
*
Simple. Age-sensitive. Higher variability in older mice.
Brown, Mazula, R. Miller, J. Miller, Maleki…unpublished
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Cisplatin Challenge
YF MAF OF YM MAM OM-40
-30
-20
-10
0
10
Cha
nge
in F
at (g
)
****
YF MAF OF YM MAM OM-4
-2
0
2
4
Cha
nge
in L
ean
(g)
***
***
YF MAF OF YM MAM OM-30
-20
-10
0
10
Cha
nge
in B
ody
Wei
ght (
g)
*
*
YF MAF OF-60
-45
-30
-15
0
Max
Bod
y W
eigh
t Los
s (%
)
**
YM MAM OM-60
-45
-30
-15
0
Max
Bod
y W
eigh
t Los
s (%
)
***
Simple-ish. Age-sensitive. Higher variability in
older mice (weight change, max loss, AUC…).
Brown, Mazula, J. Miller, R. Miller, Maleki…unpublished
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Surgery Challenge
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Surgery Challenge
Brown, Mazula, J. Miller, Roos, Maleki, B. Zhang…unpublished
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Surgery Challenge in Younger, Middle-aged, and Older mice
More complex challenge. Some outcomes age-
sensitive with higher variability in older mice.
Brown, Mazula, J. Miller, Roos, Maleki, B. Zhang…unpublished
YF MAF OF YM MAM OM0
250
500
750
1000
1250
Ste
rnal
Rec
umbe
ncy
(s) **
***
*
YF MAF OF YM MAM OM0
500
1000
1500
Tim
e to
Am
bula
te (s
)
*** ******
15 30 45 60
-20
-15
-10
-5
0
5 Days
Cha
nge
in B
ody
Wei
ght (
%)
YM
MAM
OM
15 30 45 60
-30
-20
-10
0
10
20
Days
Cha
nge
in B
ody
Wei
ght (
%)
YF
MAF
OF
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Murine Models of Physical Resilience
Potential for anesthesia, chemotherapy, and surgical challenges based on:
Age-related changes in select measures of resilience
Higher variability in older mice, indicative of more and less resilient
Translatability
Disease agnostic-ity; integrate multiple physiological systems
Relative simplicity, scalability
Mid-life (12 mo) resilience predictive of later-life (18 & 24 mo) healthspan? Lifespan? In collaboration with Rich Miller.
Encouraging preliminary data
A Texas-sized bucket of data
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Mid-life Resilience as a Determinant of Later-Life Health
-30 -25 -20 -15 -10 -50
50
100
150
200
250
Change in Body Weight (%)
24M
Rot
a-R
od T
ime
(s)
-25 -20 -15 -10 -50
100
200
300
Change in Body Weight (%)
24M
Tre
adm
ill D
ista
nce
(m)
FemalesDay 35
MalesDay 35
-30
-20
-10
0
10
Cha
nge
in B
ody
Wei
ght (
%)
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Murine Models of Physical Resilience
Potential for anesthesia, chemotherapy, and surgical challenges based on:Age-related changes in select measures of resilienceHigher variability in older mice, indicative of more and less resilientTranslatabilityDisease agnostic-ity; integrate multiple physiological systemsRelative simplicity, scalability
Mid-life (12 mo) resilience predictive of later-life (18 & 24 mo) healthspan? Lifespan? In collaboration with Rich Miller.
Encouraging preliminary dataA Texas-sized bucket of data
Can interventions improve later-life resilience? Stay tuned….
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5 10 15 20 25 30
-20
-15
-10
-5
0Time (Days)
Cha
nge
in B
ody
Wei
ght (
%)
5 10 15 20 25 30
-20
-15
-10
-5
0Time (Days)
Cha
nge
in B
ody
Wei
ght (
%)
5 10 15 20 25 30
-20
-15
-10
-5
0Time (Days)
Cha
nge
in B
ody
Wei
ght (
%)
Interventions to Optimize Resilience in Older Mice8 weeks prior to surgical challenge, 8 weeks post
5 10 15 20 25 30
-20
-15
-10
-5
0Time (Days)
Cha
nge
in B
ody
Wei
ght (
%)
ControlAcarboseEstradiolRapamycin
Females Males
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Targeting the Biology of Aging and ResilienceParadigms for Translation
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AcknowledgementsTeam MembersTom WhiteMarissa SchaferXu ZhangZaira AversaVessa PearsallSarah JachimAyumi SakamotoPhillip ZhangBrian KotajarviKurt JohnsonOlivia MalekiJackie Miller (CW)Dan Mazula (VT)Ashley Brown (MCOW)
Kogod Center on AgingJim KirklandTamar TchkoniaJordan MillerEduardo ChiniSundeep Khosla
Glenn LabsJan van DeursenDarren BakerHu Li
CollaboratorsDan TschumperlinHirohito KitaMike TorbensonJoao PassosLaura Niedernhofer (UMN)Paul Robbins (UMN)
SupportNational Institute on Aging (R01 AG55529, R01 AG53832, P01 AG62413, U54 AG44170, R56 AG60907, R21 AG58738)Glenn Foundation for Medical ResearchPritzker FoundationBeverly FoundationLeonard and Mary Lou Hoeft FundRobert & Arlene Kogod [email protected]
@NKLeBRASSEUR