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

3. 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

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

5. High energy consumption Active growth & development Active reproductive function 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 Reduce energy consumption Arrest of growth, development, reproductive function High resistance to stress From To

6. Shift in HPA secretory priorities during stress

7. 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

8. Among invertebrates, the most used models have been the fly (Drosophila melanogaster) and the nematode (C. elegans) Suppression of the receptor for insulin/IGF hormone will produce a mutant nematode that will live 6x longer than corresponding controls and be more resistant to all stress, but they will not grow, undergo development, or reproduce. C. Elegans 2 week lifespan hermaphrodite 19,000 genes 959 cells

9. IN FLIES (Drosophila melanogaster): Genetic Manipulation Inactivation of IGF-1 receptor analog Decreased growth Delayed maturation Shift of metabolism from aerobic to anaerobic Greater resistance to stress Increased longevity Decreased mortality

10. IN WORMS (Caenorhabditis elegans): Genetic Manipulation Inactivation of IGF-1 receptor analog Decreased growth Delayed maturation Shift of metabolism from aerobic to anaerobic Decreased free radical accumulation Greater resistance to stress Increased longevity 6X mortality

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

12. “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)

13. 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 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

14. Taken from P.H. Hunter, Protein Folding: Theory Meets Disease, The Scientist, volume 17, number 17, pg. 24-27,2003

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

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

17. 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

18. Interventions to prevent or treat deleterious effects of stress According Grandmother Pharmacologic/GeneticPsychotherapy 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 Hypnotics & sedatives Tranquilizers & Anti-anxiety drugs Hormones others Psychiatric counseling Meditation Yoga Continuing interaction with family & community

19. Coping Skills to Withstand Stress Knowledge e.g. years of education Inner Resources e.g. beliefs, assumptions Spirituality e.g. religious beliefs Social support e.g. interpersonal relations