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

1Ronald.Kohanski@nih.gov

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

4

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 …

5

AgingBiology

Molecular

Clinical

StressResponse

Epigenetics

Damage

InflammationImmunity

Metabolism

Proteostasis

Senescence

Building a Conceptual Framework:Hallmarks of Aging

6

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

11

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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