Aging in Natural PopulationsOf Mammals

Why and how do mammals get old and die?How is this affected by:a. Reproductionb. Natural Stressors

(competition, predators, etc.)c. Maternal and Cohort Effects

Senescence

the process of decline in physiological functioning that results in increasing mortality rates with increasing age after some point in the lifespan

Theory of SenescenceTheory of Senescence

1. The age at which senescence is first expressed1. The age at which senescence is first expresseddepends on how much mortality occursdepends on how much mortality occursindependent of the effects of senescence.independent of the effects of senescence.

2. Senescence should not be expressed until2. Senescence should not be expressed untilafter the age at first reproduction.after the age at first reproduction.

Reproduction

SomaticMaintenance

Disposable Soma Hypothesis

Total EnergyReserve

Trade-offs

SomaticMaintenance

Reproduction

MaximizingFitness

Reproduction Somatic Maintenance

TotalEnergy Reserve

Reproduction

Disposable Soma Hypothesis

High extrinsic mortality

Reproduction

SomaticMaintenance

DECREASEDLIFESPAN

Reproduction

Reproduction

SomaticMaintenance

Disposable Soma Hypothesis

Low extrinsic mortality

INCREASEDLIFESPAN

Somatic Maintenance

Principal Research Approach:

Target the STRESS AXIS -a crucial system for survival, allows animals to cope with challenges, and deteriorates with age.

Stress Stress Response - the set of Stress Response - the set of responses by birds and mammals by responses by birds and mammals by the stress axis to potentially harmful the stress axis to potentially harmful environmental challengesenvironmental challenges

Stressor - anything that upsets the Stressor - anything that upsets the

homeostatic balance within an animalhomeostatic balance within an animal EnvironmentalEnvironmental Physical Physical PsychologicalPsychological

Response to Stressor is Crucial and Changes with Age,

Condition, Experience, etc.

Crucial components:Crucial components:

1.1. Response to the stressor - Response to the stressor - how rapid is it and how how rapid is it and how intense?intense?

2.2. Negative Feedback - how Negative Feedback - how rapidly is it terminated?rapidly is it terminated?

PITUITARYPITUITARY

ADRENALSADRENALS

HIPPOCAMPUSHIPPOCAMPUS

BLOODBLOOD

HYPOTHALAMUSHYPOTHALAMUS

ACTH

CRFCRFCRFCRF

ACTHACTHACTHACTH

CortisolCortisolCortisolCortisol

STRESSSTRESS

NegativeNegativeFeedbackFeedback

Hypothalamic-pituitary-adrenal Axis

Importance of the HPA Axis

• Role in somatic maintenance

• Crucial to organism’s ability to deal with stress

HPA Axis

Reproduction

Immunity Metabolism

Stress

Hippocampus

Hypothalamus

AnteriorPituitary

GR

MR

AdrenalCortex

MobilizationOf Energy

SuppressionOf Growth

Immuno-suppression

SuppressionOf DigestionReproductive

Suppression

ACTH

Glucocorticoids

AVPCRH

PVN

Stress Response

Good: if short term = Acute Response [Classic Flight or Fight Response]

Bad: if long term = Chronic Response[short term effects are prolonged,with potential permanent consequences - Brain changes,etc.]

CATABOLICCATABOLIC

ANABOLICANABOLIC

LIVER

GLUCONEOGENESIS GLUCOSE

GLYCOGEN

MUSCLE

LYMPHOID

SKIN

ADIPOSE

ENERGYSUPPLY

FATTYACIDS

GLYCEROLGLUCOSE

CONNECTIVE

AMINOACIDS

Cortisol has both these effects:

Methods to study stress response in Natural

Populations Before and After assessment (crude) Before and After assessment (crude)

Measurement in feces and urine Measurement in feces and urine (noninvasive, need rigor)(noninvasive, need rigor)

Challenge ProtocolChallenge Protocol CaptureCapture HormonalHormonal

ACTH Stimulation Test

Inject ACTHInject ACTH Measure glucocorticoid levelsMeasure glucocorticoid levels

Moderate increase is normalModerate increase is normal

Excessive increase or reduced Excessive increase or reduced

response (species response (species dependent) dependent) indicative of chronic indicative of chronic stress. stress.

Hormonal Challenge Hormonal Challenge ProtocolProtocol

00 3030 6060 120120

BASE BleedBASE BleedACTH InjectionACTH Injection

ACTH ACTH BleedsBleeds

UnitsUnits

TimeTime

PITUITARYPITUITARY

ADRENALSADRENALS

HIPPOCAMPUSHIPPOCAMPUS

BLOODBLOOD

HYPOTHALAMUSHYPOTHALAMUS

ACTH

CRFCRFCRFCRF

ACTHACTHACTHACTH

Cortisol / Cortisol / CorticosteroneCorticosterone

Cortisol / Cortisol / CorticosteroneCorticosterone

ACTHACTH

PITUITARYPITUITARY

ADRENALSADRENALS

HIPPOCAMPUSHIPPOCAMPUS

BLOODBLOOD

HYPOTHALAMUSHYPOTHALAMUS

ACTH

CRFCRFCRFCRF

ACTHACTHACTHACTH

Cortisol / Cortisol / CorticosteroneCorticosterone

Cortisol / Cortisol / CorticosteroneCorticosterone

ACTHACTH

Poor ConditionPoor Condition

Good ConditionGood Condition

ACTHACTH

Free Free CortisolCortisol

Time

Hormonal Challenge ProtocolHormonal Challenge ProtocolProgress to date:Progress to date:

- Carried out Challenge on 100 red squirrels50 in 2003 on Lloyd49 in 2004 on Kloo and Sulphur

- Data from 2004 best as exact ages of animals known(oldest 6 yrs old, 1998: about 11 or more)

Blood Component Analysis:- Glucose Done- Blood Hematolgy Done- Free Fatty Acids and Albumin Pending- Hormone Analysis - Cortisol - Pending

Statistical Analysis - Pending

Stress Response is not Static

1. May be modulated over annual cycle to optimize reproduction, survival, or both

2. Modified during development: Programming of the Brain.

3. Modified by experience and AGE.

Changes in the HPA with AGE

Either Age-Dependent Declinesoccur resulting in deathOrNo change can be observed asAxis too critical for any marginof error

Glucocorticoid Receptor Regulation

ACTH

Cortisol

CRH mRNAAVP mRNA

Hippocampus

_

_

_

HypothalamicPVN

AnteriorPituitary

AdrenalCortex

POMC mRNA

POMC

CRH

AVP

GR

MR

Hippocampus

The rodent hippocampus

In Situ Hybridization

MR mRNA probe

GR mRNA probe

CA 1/2

CA 3DG

1997& 1998 1999

2000 & 2001

GR mRNA GR mRNA in situ imagesin situ imagesIn snowshoeIn snowshoeHaresHares

Increase Peak

Decline

Age-dependent changes in brain organization:

- collected 23 in 2003 39 in 2004- critical need to age accurately

using sectioning femurs.

Time Frame: hormone and brain sectioning and in situhybridization by June-July 2005.Papers:Papers on Age-dependent changes in HPA axis:

a. hormonal changesb. Brain changes

Other Papers: Territory Quality - Physiology Correlates. Relationship to reproduction and survival

Future Studies1.Individual variation and Quality

- use of noninvasive fecal analysisto make various comparisonsamongst males, females, juvs

2.Feeding Experiment -- use of blood sampling, stress tests

and/or fecal analysis to comparesquirrels on different treatments

Need to assess first how good blood dataalready obtained predict or are related toBehavior, terrtory quality, etc.