Aging in Natural Populations Of Mammals

Why and how do mammals get old and die? How is this affected by: a. Reproduction b. 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 Senescence 1. The age at which senescence is first expressed depends on how much mortality occurs independent of the effects of senescence. 2. Senescence should not be expressed until after the age at first reproduction.

Reproduction Somatic Maintenance Disposable Soma Hypothesis Total Energy Reserve Trade-offs Somatic Maintenance Reproduction Maximizing Fitness Reproduction Somatic Maintenance Total Energy Reserve

Reproduction Disposable Soma Hypothesis High extrinsic mortality Reproduction Somatic Maintenance DECREASED LIFESPAN Reproduction

Somatic Maintenance Disposable Soma Hypothesis Low extrinsic mortality INCREASED LIFESPAN 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 responses by birds and mammals by the stress axis to potentially harmful environmental challenges Stress Response - the set of responses by birds and mammals by the stress axis to potentially harmful environmental challenges Stressor - anything that upsets the Stressor - anything that upsets the homeostatic balance within an animal homeostatic balance within an animal Environmental Environmental Physical Physical Psychological Psychological

Response to Stressor is Crucial and Changes with Age, Condition, Experience, etc. Crucial components: 1. Response to the stressor - how rapid is it and how intense? 2. Negative Feedback - how rapidly is it terminated?

PITUITARY ADRENALSHIPPOCAMPUSBLOOD HYPOTHALAMUS ACTH CRF ACTH Cortisol STRESSNegativeFeedback

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 Anterior Pituitary GR MR Adrenal Cortex Mobilization Of Energy Suppression Of Growth Immuno- suppression Suppression Of Digestion Reproductive Suppression ACTH Glucocorticoids AVP CRH 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.]

CATABOLIC ANABOLIC LIVER GLUCONEOGENESIS GLUCOSE GLYCOGEN MUSCLE LYMPHOID SKIN ADIPOSE ENERGY SUPPLY FATTY ACIDS GLYCEROL GLUCOSE CONNECTIVE AMINO ACIDS 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 (noninvasive, need rigor) Measurement in feces and urine (noninvasive, need rigor) Challenge Protocol Challenge Protocol  Capture  Hormonal

ACTH Stimulation Test  Inject ACTH  Measure glucocorticoid levels  Moderate increase is normal  Excessive increase or reduced response (species dependent) indicative of chronic stress. response (species dependent) indicative of chronic stress.

Hormonal Challenge Protocol BASE Bleed ACTH Injection ACTH Bleeds ACTH Bleeds Units Time

PITUITARY ADRENALS HIPPOCAMPUS BLOOD HYPOTHALAMUS ACTH CRF ACTH Cortisol / Corticosterone ACTH

PITUITARY ADRENALS HIPPOCAMPUS BLOOD HYPOTHALAMUS ACTH CRF ACTH Cortisol / Corticosterone ACTH

Poor Condition Good Condition ACTH FreeCortisol Time

Hormonal Challenge Protocol Progress to date: -Carried out Challenge on 100 red squirrels 50 in 2003 on Lloyd 49 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 May be modulated over annual cycle to optimize reproduction, survival, or both Modified during development: Programming of the Brain Modified by experience and AGE.

Changes in the HPA with AGE Either Age-Dependent Declines occur resulting in death Or No change can be observed as Axis too critical for any margin of error

Glucocorticoid Receptor Regulation ACTH Cortisol CRH mRNA AVP mRNA Hippocampus _ _ _ Hypothalamic PVN Anterior Pituitary Adrenal Cortex POMC mRNA POMC CRH AVP GR MR

Hippocampus

The rodent hippocampus

In Situ Hybridization MR mRNA probe GR mRNA probe CA 1/2 CA 3 DG

1997& & 2001 GR mRNA in situ images In snowshoe Hares IncreasePeak Decline

Age-dependent changes in brain organization: - collected 23 in in critical need to age accurately using sectioning femurs.

Time Frame: hormone and brain sectioning and in situhybridization by June-July Papers: Papers on Age-dependent changes in HPA axis: a. hormonal changes b. Brain changes Other Papers: Territory Quality - Physiology Correlates. Relationship to reproduction and survival

Future Studies 1.Individual variation and Quality -use of noninvasive fecal analysis to make various comparisons amongst males, females, juvs 2.Feeding Experiment - - use of blood sampling, stress tests and/or fecal analysis to compare squirrels on different treatments Need to assess first how good blood data already obtained predict or are related to Behavior, terrtory quality, etc.