Homeostasis Allostasis Hormesis Vitruvian Man Leonardo Da Vinci

Homeostasis From Walter B. Cannon (1871-1945) Wisdom of the Body, 1932 From Greek: homeo “the same” stasis “state” Indicates that for optimal function of the organism, a steady state (or equilibrium) must be achieved This “constancy” of the internal environment allows survival despite continuing changes in the external environment (stress)

Homeodynamics A constant environment obtained through a series of dynamic adjustments This continual need for adjustment is implicated in the term “allostasis” (From Greek allo “different” stasis “state”) Emphasizes the dynamism of adaptive responses to stress This adaptation to stress is often achieved with a price -- a declining ability to adapt and/or an increased pathology and disease *Prof. T. Seeman, Geriatrics, UCLA (UCB alumna)

Hormesis A new term, from the Greek “I excite.” Excitation induced by physical or psychological stress Stimulation of any system by a stimulus of relatively moderate intensity & short duration In contrast to a strong stimulus of long duration that will induce destabilization Recently, several lines of research indicate that hormesis may promote longevity

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

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

constructing mutants with lack of the hormone or the hormone receptors 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

C. Elegans 2 week lifespan hermaphrodite 19,000 genes 959 cells 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.

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

Greater resistance to stress IN MAMMALS (Rodents): Genetic Manipulation Inactivation of IGF-1, I, GH, PL, & TSH receptor analog 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

“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)

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

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

CHAPERONES WITHOUT CHAPERONES 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?

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

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

Interventions to prevent or treat deleterious effects of stress According Grandmother Pharmacologic/Genetic Psychotherapy 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

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