Stress, Adaptation, and

Regulation of HomeostasisChapter 10

P.S. Timiras

Continually Changing Environment

Challenges Steady State

necessary for maintenance of optimal body function

(homeostasis)Homeostasisis maintained by a

complex of neuroendocrine adjustments

Neuroendocrine Adustmentsfocus on the

Hypthalamic-Pituitary-Adrenal (HPA) Axis

Physiological Responses to StressBlood PressureSpeed of ConductionAccelerated Cardiac RhythmRedistribution of Blood from most active to less active organs

CVS

Respiratory Speed & Volume of Pulmonary Respiration

Metabolic Breakdown of GlycogenBlood GlucoseBreakdown of LipidsBlood Lipids

Gastro-Intestinal function

Physiological Responses to Stress (cont.)

HPA axis:CRHACTHCortisolDHEAEpinephrineNorepinephrine

GHRHGnRHGHFSHLH

Hormonal

With age there is:• Breakdown of self-organizing systems

(dynamic instability)• Declining capacity to adapt to the

environment

With consequence• Failure of adaptation• Increased pathology

or• Evolution, progress, creativity,

hormesis

Some Characteristics of Stress

Stress stimulates HPA for maintenance of homeostasis in response to challenges. Examples are:

Physical Stress:HypoglycemiaTraumaExposure to extreme temperaturesInfectionsHeavy exercise

Psychological Stress:Acute anxietyChronic anxietyAnticipation of stressful situationsNovel situations

Specific responses (varying with the types of stimulus)

Non-specific responses (always the same, regardless of the stimulus and mediated through stimulation of neural, endocrine, and immune axes)

Exposure to stress generates:

Stress, Homeostasis, Allostasis, and Allostatic Load

Stress: internal/external challenges threaten physiologic equilibrium

Homeostasis: an "ideal state”in which a

constant internal environmentPromotes optimal function

Allostasis: process by which an organism varies its internal Milieu to match environmental demands

Allostatic load supposedly accumulates throughout lifeand affects multiple bodily systems

Allostatic load: long-term physiological cost stemming from attempts at adaptation (i.e., allostasis).

Some Parameters Used to Operationalize Allostatic Load (AL)*

1, 2. Systolic and diastolic blood pressure(indices of cardiovascular activity)

3. Waist-hip ratio (index of long-term metabolic/lipid deposition)

4, 5. Serum Low Density Lipoprotein (LDL) and total cholesterol levels(indices of atherosclerotic risk)

6. Blood plasma levels of total glycosylated hemoglobin (index of glucose metabolism)

7. 12-hour urinary cortisol excretion(index of 12-hour integrated HPA activity)

8, 9. 12-hour urinary norepinephrine and epinephrine excretion levels

(index of 12 hour integrated sympathetic activity)

10. Serum dehydroepiandrosterone (DHEA) sulfate levels (index of

hypothalamo-pituitary-adrenal (HPA)

inhibitor/antagonist)

11. Serum High Density Lipoprotein (HDL) (index of protection against

atherosclerosis )

Some Parameters Used to Operationalize Allostatic Load, Continued

Beneficial effects of Hormesis may be due

to: DNA repair Immune competence Neurologic acuity Neuromuscular activity Better memory Resistance / adaptation to stress

Janus is the Roman God of gates and doors, of beginnings and endings and, hence, is represented by a double faced head; generally placed on the gates of the city,the menacing face looking towards the outside of the city ready to defend it against any attackers, the benevolent face turned towards the city is a protector and promoter of prosperity and good health.

• High energy consumption

• Active growth & development

• Active 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 othersby

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

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 anaerobicDecreased free radical

accumulation

Greater resistanceto stress

“I cannot, and should not, be cured of my stress but merely taught to enjoy it” Hans Selye,

l950Responses 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 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

•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

CHAPERONES (Heat Shock Proteins)

Prevent production of Inactive proteinProtein 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/GeneticPsychotherapy

•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