Homeostasis Allostasis Hormesis Vitruvian Man Leonardo Da Vinci
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Homeostasis
Allostasis
Hormesis
Vitruvian Man
Leonardo Da Vinci
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HomeostasisFrom 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 achievedThis “constancy” of the internal environment
allows survival despite continuing changes in the external environment (stress)
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HomeodynamicsA constant environment obtained through a series of
dynamic adjustmentsThis 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)
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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
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Beneficial effects of Hormesis may be due to:
DNA repair Immune competence Neurologic acuity Neuromuscular activity Better memory Resistance/ adaptation to stress
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High energy consumptionActive growth & developmentActive 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
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Suppressing signaling from hormones such as: insulin, growth hormone, insulin-like growth hormone and others
byconstructing mutants with lack of the hormone or the
hormone receptorscan prolong the lifespan
as much as six times the lifespan in C. Elegans, delaying the aging process
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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 lifespanhermaphrodite19,000 genes
959 cells
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IN FLIES (Drosophila melanogaster):
Genetic ManipulationInactivation of IGF-1
receptor analog
Decreased growthDelayed maturation
Shift of metabolismfrom aerobicto anaerobic
Greater resistanceto stress
Increased longevityDecreased mortality
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IN MAMMALS (Rodents):
Genetic ManipulationInactivation of IGF-1, I, GH,PL, & TSH receptor analog
Increased longevity 18-40% Delayed aging & mortality
Decreased growthDelayed maturation
Most functions normal
Shift of metabolismfrom aerobic to anaerobic
Decreased free radical accumulation
Greater resistanceto stress
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“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)
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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 & motivationa greater availability & utilization of metabolic energyfavor DNA repair improve protein folding (chaperone stimulation)prevent/decrease free radical accumulationpromote survival and may delay aging
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Taken from P.H. Hunter, Protein Folding: Theory Meets Disease,The Scientist, volume 17, number 17, pg. 24-27,2003
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CHAPERONES
Prevent production of Inactive protein
Protein fragmentsProtein aggregates
Intracellular peptides that helpother proteins to fold
WITHOUT CHAPERONES
Miss a fold, prompt a disease Amyloidosis Lung, blood, liver diseasesDiabetes, cancer, infections
Severe stress?
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Stress Proteins or Heat Shock Proteins (HSP)
Theyare synthesized in response
To a sudden rise in temperatureOr other types of stress
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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 onIncreased HSPs and their actions as chaperones
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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 youthand continuing into oldage•Avoiding isolation, livingwith family and in community
•Hypnotics & sedatives•Tranquilizers &Anti-anxiety drugs•Hormones •others
•Psychiatric counseling•Meditation•Yoga •Continuing interactionwith family & community
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Coping Skills to Withstand Stress
Knowledgee.g. years
of education
Inner Resourcese.g. beliefs,assumptions
Spiritualitye.g. religious
beliefs
Social supporte.g. interpersonal
relations