kohanski nia geroscience - aging in challenging environments · 2020. 5. 28. · building a...
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Geroscience for Aging in Challenging Environments
Ronald A. Kohanski, Ph.D.Division of Aging Biology
National Institute on AgingTrans-NIH Geroscience Interest Group
• Exposures and Latent Disease Risk• Identifying Hallmarks and Key Characteristics
Building a Conceptual Framework:Hallmarks of Aging
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AgingBiology
StressResponse
Epigenetics
Damage
InflammationImmunity
Metabolism
Proteostasis
Senescence
Molecular
What is contained in each hallmark of aging?
Transposons
Metabolism
Fibrosis
Stem Cells Inflammation
Proteostasis
SenescenceMicrobiome
EpigenomeTelomeres
Anil et al. (2011) Systems biology of the autophagy-lysosomal pathway, Autophagy, 7:5, 477-489, DOI: 10.4161/auto.7.5.14811 3Adapted from Niforou et al. (2014).. Redox Biology. 2. 10.1016/j.redox.2014.01.017.
Building a Conceptual Framework:Hallmarks of Aging and Organ Systems
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Lung
Heart
Kidney
Liver
ArteriesVeins
Bone
Skin
Muscle
Brain
Marrow
Pancreas Intestines
StressResponse
Epigenetics
Damage
InflammationImmunity
Metabolism
Proteostasis
Senescence
Building a Conceptual Framework:Aging as a risk factor …
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AgingBiology
Molecular
Clinical
StressResponse
Epigenetics
Damage
InflammationImmunity
Metabolism
Proteostasis
Senescence
Building a Conceptual Framework:Hallmarks of Aging
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AgingBiology
Burdens ofChronic Disease
Cancer
CVD
Immunity
OsteoporosisSarcopenia
FrailtyHearing
Vision
Diabetes
Dementia
CKD
Arthritis
MoreDisease
&Less
Function
COPD/IPF
Neurodegeneration
Mobility
Molecular
Clinical
StressResponse
Epigenetics
Damage
InflammationImmunity
Metabolism
Proteostasis
Senescence
Multiple Chronic Conditinos
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• Age-Distribution of MCC • Humans
• Hypertension• Ischemic Heart Disease• Hyperlipidemia• Diabetes• Arthritis• Chronic Kidney Disease• COPD• Osteoporosis• …
0102030405060708090
0 - 1 2 - 3 ≥ 4
% o
f Age
Gro
up
# of Chronic Diseases
18 - 44y 45 - 64y≥ 65y
Multiple Chronic Conditions
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• Human
1. Cancer2. Cardiac Hypertrophy3. Kidney Failure4. Hypertension5. Lung
Function/Disease6. Bones7. Joints8. Muscles9. Skin
• Lab animal
A. CancerB. Cardiac HypertrophyC. Kidney FailureD. SplenomegalyE. PneumoniaF. BonesG. JointsH. MusclesI. Skin
Scoring Functions in Adults
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Cognition Response time, memory
Response time, memory
Appearance Appearance/Complexion
blue or pale all over BMI, skin tone, hair
Change in weight, skin tone, hair
Pulse Pulse rate 0 to >100 +/- exertion +/- exertion
Grimace Reflex irritability
… when stimulated
Response to stimulation in periphery and centrally
Response…
Activity Activity Motion and resistance
Motion and Resistance
Motion and Resistance
Respiration Respiratory Effort
Irregular to regular
Lung function parameters
Lung Function Parameters
Newborn ML-Adult LL-Adult
Geroscience : Aging in a Challenging Environment
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MOBILITY
COMMUNICATION
HYGENE
NUTRTION
COMMERCE
ENVIRONMENT
FRAILTY
RESILIENCE
DIABETES
CANCER
STROKEARTHRITIS
SARCOPENIA
CVD
DEMENTIA
Transposons
Metabolism
Fibrosis
Stem Cells Inflammation
Proteostasis
SenescenceMicrobiome
EpigenomeTelomeres
MEDICATIONS
BEHAVIORS
ENVIRONMENT
Building a Conceptual Framework:Environment as a Risk Factor
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Environmental Risk superimposed onage-related risk for breast cancer?
Den
sity
(den
sity
x 1
00=%
)
Age at diagnosis
Adapted from Matsuno etal, Can Epidem Biomarkers & Prev 2007
Japan (Osaka)
1993-199712
USA SEER (Caucasian in HI)
Japanese American (in HI)
Stem Cells
Epigenome
The aging biology ofage-related risk for breast cancer
Adapted from Matsuno etal, Can Epidem Biomarkers & Prev 200713
Stem Cells
Epigenome
Individual susceptibility across the life span
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Individual susceptibility across the life span:Outcomes for aging
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For environmental exposures: sample collection mapped to the hallmarks of aging
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Transposons
Metabolism
Fibrosis
Stem Cells Inflammation
Proteostasis
SenescenceMicrobiome
Epigenome
Telomeres
MRIUltrasound
Implied from
lineages
Samples:FecalNasal
Blood CellMethylomes
PlasmaProteome
Blood Cells &Plasma
Blood & Breath
Leukocytes
Bucal &
NasalSwabs
FatBiopsies
Samples in a doctor’s visit
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buccal nasal fecal
cells microbiomes
blood
urine
cellsplasma
lymphoid
breath
metabolome
proteome
proteostasis
metabolism
myeloid
hormones
Medications
epigenome
telomeres
fatbiopsy
senescence
MRIUltrasound
fibrosis
cells
Stem cells
hair
Stem Cells
Transposons
Metabolism& Metabolome
Fibrosis
Inflammation
Proteostasis& Proteomes
SenescenceMicrobiome
Epigenome
Telomeres
Combining Functional and Molecular Metrics in Adults
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CognitionResponse time, memory
Response time, memory
Appearance
blue or pale all over
BMI, skin tone, hair
Change in weight, skin tone, hair
Pulse 0 to >100 +/-exertion +/- exertion
Grimace… when stimulated
Response to stimulation in periphery and centrally
Response…
ActivityMotion and resistance
Motion and Resistance
Motion and Resistance
Respiration Irregular to regular
Lung function parameters
Lung Function Parameters
Newborn Adult LL-Adult
buccal nasal fecal
cells microbiomes
blood
urine
cellsplasma
lymphoid
breath
metabolome
proteome
proteostasis
metabolism
myeloid
hormones
Medications
epigenome
telomeres
fatbiopsy
senescence
MRIUltrasound
fibrosis
cells
Stem cells
hair
Rates of Aging in Humans
19Ahadi et al. Nat Med . 2020 Jan;26(1):83-90
Conclusions for Aging
• Molecular hallmarks can be used to understand interactions between the environment and aging
• Example from breast cancer
• Clinically useful information about the trajectories of human aging can be obtained in 2-3years of doctor’s visits
• Trajectories are individual
• Studies in laboratory animals establish principles and validate useful tools
• Biology of aging and geroscience can be done in humans
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Conclusions forAging in Challenging Environments
• Explore how a variety of environmental factors influence the aging process and disease outcomes in aging populations
• Environmental effects that are chronic, acute, and combined
• PAR-19-249 Aging Processes • (NIEHS, NIA, OBSSR)
• PAR-19-250 Aging Populations • (NIEHS, NIA, NINR, NIMHD, OBSSR)
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