Stress, Adaptation, and Regulation of Homeostasis

1. Stress, Adaptation, and Regulation of Homeostasis Chapter 10 P.S. Timiras

2. Continually Changing Environment Challenges Steady State necessary for maintenance of optimal body function (homeostasis) Homeostasis is maintained by a complex of neuroendocrine adjustments Neuroendocrine Adustments focus on the Hypthalamic-Pituitary-Adrenal (HPA) Axis

3. Physiological Responses to Stress CVS Blood Pressure Speed of Conduction Accelerated Cardiac Rhythm Redistribution of Blood from most active to less active organs Respiratory Speed & Volume of Pulmonary Respiration Metabolic Breakdown of Glycogen Blood Glucose Breakdown of Lipids Blood Lipids Gastro-Intestinal function

4. Physiological Responses to Stress (cont.) Hormonal HPA axis: CRH ACTH Cortisol DHEA Epinephrine Norepinephrine GHRH GnRH GH FSH LH

5. With age there is: • Breakdown of self-organizing systems (dynamic instability) • Declining capacity to adapt to the environment With consequence • Failure of adaptation • Increased pathology or • Evolution, progress, creativity, hormesis

6. Some Characteristics of Stress • Stress stimulates HPA for maintenance of homeostasis in response to challenges. Examples are: • Physical Stress: • Hypoglycemia • Trauma • Exposure to extreme temperatures • Infections • Heavy exercise • Psychological Stress: • Acute anxiety • Chronic anxiety • Anticipation of stressful situations • Novel situations

7. Exposure to stress generates: Specific responses (varying with the types of stimulus) Non-specific responses (always the same, regardless of the stimulus and mediated through stimulation of neural, endocrine, and immune axes)

8. Stress, Homeostasis, Allostasis, and Allostatic Load Stress: internal/external challenges threaten physiologic equilibrium Homeostasis: an "ideal state”in which a constant internal environment Promotes optimal function Allostasis: process by which an organism varies its internal Milieu to match environmental demands Allostatic load: long-term physiological cost stemming from attempts at adaptation (i.e., allostasis). Allostatic load supposedly accumulates throughout life and affects multiple bodily systems

9. Some Parameters Used to Operationalize Allostatic Load (AL)* • 1, 2. Systolic and diastolic blood pressure • (indices of cardiovascular activity) • 3. Waist-hip ratio (index of long-term • metabolic/lipid deposition) • 4, 5. Serum Low Density Lipoprotein (LDL) • and total cholesterol levels • (indices of atherosclerotic risk) • 6. Blood plasma levels of total glycosylated • hemoglobin (index of glucose metabolism) • 7. 12-hour urinary cortisol excretion • (index of 12-hour integrated HPA activity) • 8, 9. 12-hour urinary norepinephrine and • epinephrine excretion levels • (index of 12 hour integrated • sympathetic activity)

10. Some Parameters Used to Operationalize Allostatic Load, Continued • 10. Serum dehydroepiandrosterone (DHEA) • sulfate levels (index of • hypothalamo-pituitary-adrenal (HPA) • inhibitor/antagonist) • 11. Serum High Density Lipoprotein (HDL) • (index of protection against atherosclerosis )

11. Beneficial effects of Hormesis may be due to: DNA repair Immune competence Neurologic acuity Neuromuscular activity Better memory Resistance / adaptation to stress

12. Janus is the Roman God of gates and doors, of beginnings and endings and, hence, is represented by a double faced head; generally placed on the gates of the city,the menacing face looking towards the outside of the city ready to defend it against any attackers, the benevolent face turned towards the city is a protector and promoter of prosperity and good health.

13. Several lines of investigations have shown that manipulation of the genome will result in changes of the phenome. These changes involve alteration of the endocrine signaling with a shift To From • High energy consumption • Active growth & development • Active reproductive function • Reduce energy • consumption • Arrest of growth, • development, • reproductive function • High resistance to stress

14. Suppressing signaling from hormones such as: insulin, growth hormone, insulin-like growth hormone and others by constructing mutants with lack of the hormone or the hormone receptors can prolong the lifespan as much as six times the lifespan in C. Elegans,delaying the aging process

15. Increased longevity 18-40% Delayed aging & mortality Shift of metabolism from aerobic to anaerobic Decreased free radical accumulation Greater resistance to stress Decreased growth Delayed maturation Most functions normal IN MAMMALS (Rodents): Genetic Manipulation Inactivation of IGF-1, I, GH, PL, & TSH receptor analog

16. “I cannot, and should not, be cured of my stress but merely taught to enjoy it” Hans Selye, l950 Responses to stress are indispensable to our survival as they allow us to maintain the internal equilibrium necessary for optimal function Responses to stress are multifactorial (depend on interactions of several systems)

17. If the response to stress is moderate & of short duration, it may stimulate hormesis: • the functions of alertness, vigilance & motivation • a greater availability & utilization of metabolic energy • favor DNA repair • improve protein folding (chaperone stimulation) • prevent/decrease free radical accumulation • promote survival and may delay aging

18. If response to stress is severe & prolonged it may represent • a major risk for the “diseases of adaptation” • (e.g. cardiovascular, cognitive, emotional, metabolic diseases) • & shorten the lifespan

21. CHAPERONES (Heat Shock Proteins) Intracellular peptides that help other proteins to fold Prevent production of Inactive protein Protein fragments Protein aggregates WITHOUT CHAPERONES Miss a fold, prompt a disease Amyloidosis Lung, blood, liver diseases Diabetes, cancer, infections Severe stress?

22. Stress Proteins or Heat Shock Proteins (HSP) They are synthesized in response To a sudden rise in temperature Or other types of stress

23. ON FLIES, WORMS, RODENTS: LONGEVITY is associated With stimulation (up-regulation) Of genes involved in response to stress including those of HSP HSPs act as chaperones and promote greater tolerance/resistance to stress (thermic and others) Hence, increased longevity and hormesis may depend on Increased HSPs and their actions as chaperones

24. Interventions to prevent or treat deleterious effects of stress According Grandmother Pharmacologic/Genetic Psychotherapy • Hypnotics & sedatives • Tranquilizers & • Anti-anxiety drugs • Hormones • others • Psychiatric counseling • Meditation • Yoga • Continuing interaction • with family & community • Good nutrition • Regular exercise • Good habits • Regular medical visits • Good education in youth • and continuing into old • age • Avoiding isolation, living • with family and in • community