Homeostasis

Allostasis

Hormesis

Vitruvian Man

Leonardo Da Vinci

HomeostasisFrom Walter B. Cannon (1871-1945)

Wisdom of the Body, 1932

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 achieved

This “constancy” of the internal environment allows survival despite continuing changes

in the external environment (stress)

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)

HomeodynamicsHomeodynamicsA 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

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

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

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

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

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

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

“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 & motivationa greater availability & utilization of metabolic energyfavor DNA repair improve protein folding (chaperone stimulation)prevent/decrease free radical accumulationpromote 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

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?

Stress Proteins or Heat Shock Proteins (HSP)

Theyare synthesized in response

To a sudden rise in temperatureOr 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 onIncreased 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 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

Coping Skills to Withstand Stress

Knowledgee.g. years

of education

Inner Resourcese.g. beliefs,assumptions

Spiritualitye.g. religious

beliefs

Social supporte.g. interpersonal

relations