Aging in Natural Populations Of Mammals

1. Aging in Natural Populations Of Mammals

2. 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

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

4. 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.

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

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

7. Reproduction Somatic Maintenance INCREASED LIFESPAN Disposable Soma Hypothesis Low extrinsic mortality Somatic Maintenance

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

10. Stress • Stress Response - the set of responses by birds and mammals by the stress axis to potentially harmful environmental challenges • Stressor - anything that upsets the homeostatic balance within an animal • Environmental • Physical • Psychological

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

12. HIPPOCAMPUS STRESS HYPOTHALAMUS CRF PITUITARY ACTH ACTH ADRENALS Cortisol BLOOD Negative Feedback

13. Hypothalamic-pituitary-adrenal Axis Importance of the HPA Axis • Role in somatic maintenance HPA Axis Reproduction Stress Metabolism Immunity • Crucial to organism’s ability to deal with stress

14. GR Hippocampus M R PVN Hypothalamus AVP CRH Anterior Pituitary ACTH Adrenal Cortex Glucocorticoids Mobilization Of Energy Immuno- suppression Suppression Of Growth Suppression Of Digestion Reproductive Suppression

15. 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.]

16. ANABOLIC CATABOLIC LIVER Cortisol has both these effects: GLUCOSE GLUCONEOGENESIS GLYCOGEN ENERGY SUPPLY MUSCLE FATTY GLYCEROL AMINO GLUCOSE ACIDS ACIDS LYMPHOID SKIN CONNECTIVE ADIPOSE

17. Methods to study stress response in Natural Populations • Measurement in feces and urine (noninvasive, need rigor) • Challenge Protocol • Capture • Hormonal Before and After assessment (crude)

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

19. ACTH Bleeds Hormonal Challenge Protocol Units Time 0 30 60 120 BASE Bleed ACTH Injection

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

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

22. Poor Condition Free Cortisol Good Condition Time ACTH

23. 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

24. 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.

25. 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

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

27. Hippocampus

28. The rodent hippocampus

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

30. 1997& 1998 1999 Increase Peak 2000 & 2001 GR mRNA in situ images In snowshoe Hares Decline

31. Age-dependent changes in • brain organization: • collected 23 in 2003 • 39 in 2004 • critical need to age accurately • using sectioning femurs.

32. Time Frame: hormone and brain sectioning and in situhybridization by June-July 2005. 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

33. Future Studies • Individual variation and Quality • use of noninvasive fecal analysis • to make various comparisons • amongst males, females, juvs • 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.