1. Homeostasis
Allostasis
Hormesis
Vitruvian Man
Leonardo Da Vinci

2. 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)

3. 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)

6. 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

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

8. 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

9. 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

10. 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.

11. 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

12. 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

13. “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)

14. 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

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

16. 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?

17. 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

18. 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

19. 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

20. 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