FUNCTIONS STIMULATED BY

Definitions of Stress

The term "stress’ was originally taken from the field of engineering, where it means:

"A force (measured in lbs/in²) exerted against a body & the deformation/ changes caused in that body by such a force"

In biology, the term is used to mean:

"Any change (stressor) in the environment that may tend to alter an existing equilibrium

(optimal steady state) and trigger counteracting responses at molecular, cellular, and systemic levels to preserve/reestablish such an equilibrium and insure adaptation"

Stress and stressor are often used interchangeably.

However, stress includes: stressor+ adaptive responses.

Stressor refers to the environmental change/challenge but not to the body’s responses it induces.

types of stress

Examples of Physical/Chemical Stress

High or low extreme temperatures
Physical injury
Hemorrhage
Hypoglycemia, etc.

Examples of Psychological/Emotional Stress

Fear
Cognition of danger
("why zebra do not get ulcers")
Memories
Sorrow or joy
Hate or love, etc.

stress in historical perspective

Claude Bernard (1813-1878), Physiologist

Contributed to our understanding of glucose metabolism/diabetes, the sympathetic nervous system, etc.

Formulated the hypothesis that:

"Constancy of the internal environment

is indispensable for life"

"Cells (and molecules) can exert their normal function only under steady-state conditions" i.e.:

a metabolic environment that is optimal for the individual’s function and survival

Walter Cannon (1871-1945), Physiologist

Coined the word "homeostasis" or steady-state or state of stable equilibrium.

In "The Wisdom of the Body," (1932) he formulated his theory that the internal regulation of body activity in response to external stimuli is regulated by the

hypothalamic-sympathetic-medullary (HSM) system,

as in the Fright, Flight or Fight Syndrome

Hans Selye (1907-1982), Endocrinologist

Like Cannon, Selye focused on the adrenal gland, but particularly on the adrenal cortex as part of a functional axis (HPA), consisting of:

The Hypothalamus

The Pituitary (Anterior)

The Adrenal Cortex

as central to the regulation of homeostasis

Upon exposure to stress, adaptive adjustments for maintenance of homeostasis would occur in sequence:

1. A short alarm reaction

2. A long period of adaptation

(as in hormesis)

3. A period of exhaustion followed by morbidity-- the so-called diseases of adaptation-- and death

Robert Sapolsky Biologist at Stanford University

Demonstrated in various animals after stress:

Increased secretion of glucocorticoids, hormones from the adrenal cortex
Increased level of circulating glucocorticoids damages neurons in the hippocampus

increased hippocampal neuronal loss fails to inhibit CRH (corticotropin releasing hormone) secretion from the hypothalamus
Increased CRH level stimulate the pituitary to release more ACTH (adrenocorticotropic hormone)
increased ACTH stimulates release of glucocorticoids from the adrenal cortex leading to neurodegenerative/ cardiovascular diseases of old age

Teresa Seeman Geriatrician at UCLA

Coined the word "allostasis" from the Greek "allos" meaning "different, divergent," to indicate that homeostasis is obtained via continuing dynamic changes/adjustments in a number of different reactions

Repeated exposures to stress and repeated allostatic responses will represent an allostatic load, i.e., a risk factor contributing to the morbidity of old age

Functions Stimulated by

Physical and Psychological Stress

Cardiovascular:

Increased cardiac rate
Elevated blood pressure
Redistribution of blood from peripheral
(skin) and internal (gastrointestinal)
systems to heart, skeletal muscles, brain

Respiratory:

Increased pulmonary ventilation

Metabolic:

Increased glycogen mobilization
Elevated glycemia
Increased lipolysis

Hormonal (Higher Synthesis & Release of):

CRH, ACTH, glucocorticoids
Vasopressin, NGF
Catecholamines (E and NE)

Nervous:

Increased brain excitability
Behavioral changes
Eventual loss of neurons?

Functions Inhibited by

Physical and Psychological Stress

All functions not necessary for defense and survival are decreased:

Slow down growth

Decreased appetite (anorexia)

Decreased reproductive function & sex drive

Decreased circulation in tissues not involved in stress resonse

Decreased response to pain (analgesia)

Decreased immune function

PHYSIOLOGICAL CHANGES

IN FIGHT/FLIGHT STRESS RESPONSE

Increased blood pressure

Increased heart rate

Increased force of heart contraction

Shift of blood flow (distribution away from the skin and splachnic regions and more to heart, skeletal muscle and brain)

Contraction of spleen capsule (increased hematocrit)

Increased depth and rate of respiration

Mobilization of liver glycogen to glucose

Mobilization of free fatty acids from adipose tissue

Mydriasis (widening of pupil)

Accommodation for far vision

Widening of palpebral fissure (eyelids open wide)

Pilo-erection (erection of hair)

Inhibition of gastrointestinal motility and secretion, contraction of sphincters

Sweating (cold sweats as skin blood vessels are constricted)

STRESS DEFENSE MECHANISMS

Necessary for the maintenance of homeostasis:

Specific mechanisms: varying with the stimulus

Non-specific mechanisms: always the same and mediated through the stimulation of the neuroendocrine-immune axis

STRESS

May stimulate (over-activate) and simultaneously

inhibit or block a number of important functions

Long-term/severe functional stimulation/inhibition may lead to impaired homeostasis and diseases of adaptation

Mild stress may lead to up-regulation of mechanisms for maintenance of homeostasis (hormesis)

Hormesis

From the Greek "hormo- I excite"

Initially based on the thesis that small and large doses of ionizing radiation produce opposite results:

High doses are harmful (e.g. shorter life span)

Small doses are beneficial (e.g. reduced cancer, longer life span)

Thus, hormesis is the stimulation of any system by small amounts of an agent or small intensity of a stimulus

Recently the concept of hormesis has been extended to aging research and therapy. Adaptation to stress is based on the up regulation of maintenance and repair pathways.

Stress of moderate intensity may serve as a "check-up" for the preparedness of the organism to adapt and survive. Up regulation examples include:

Increased DNA repair?
Increased immune competence and therefore decreased mortality from cancer and infections and increased life span
increased neurologic acuity
increased neuromuscular activity
Better memory, early maturation, others

Examples of Hormetic Actions:

Beneficial (PROS) and Detrimental (CONS) Consequences

1. Flies that over express heat shock proteins

Pros:

increased longevity

decreased mortality

Cons:

Decreased growth

Longer period of development

2. In worms, mutants are more resistant to stress than wild forms

Cons:

Decreased metabolic rate

Decreased fertility

Longer period of development

when food is reduced,

wild types survive better

3. Mammals, including primates,

Pros:

under caloric restrictions show

increased longevity

better ability to withstand stress

Cons:

Decreased growth

Decreased fertility

Low body temperature

Can accumulation of free radicals be viewed as a stress?
Does hormesis bring the same benefits in humans who are continually exposed to stress of daily life?

4. In humans:

Differences in stress responses depending on individuals, organs, age

Quantification of stress responses (mild to severe)
Adjusting levels of mild stress to age-related changes in stress sensitivity

Determining the biological significance of relatively small hormetic effects that may or may not have large beneficial effects during the entire life span