Stress, Adaptation, and Longevity
Leonardo da Vinci
Changes with Aging in the Hypothalamo-Pituitary-Adrenal Axis
No significant changes in healthy, non-stressed, elderly
The few changes that occur are rapidly compensated for (e.g. decreased secretion of GCs from the adrenal cortex)
but also less rapid metabolism in the liver & less urine excretion
Therefore the circulating levels remain constant
Also, normal ACTH & cortisol responses to CRH administration
Some alterations of the circadian rhythm
Cortisol, norepinephrine, and epinephrine
STRESS
Figure 10.4 Corticosterone titers in young (3-5 mo) and aged (24-28 mo) rats
0 1 2 3 4
0
20
40
Hours
Cor
ticos
tero
neµg
/100
ml
Stress Recovery
young rats
old rats
*
Old ratsYoung rats
Stress: In biology, any change (stressor) in the environment that may tend to alter an
existing equilibrium and trigger counteracting responses at molecular,
cellular, and systemic levels to preserve/reestablish such an equilibrium
and insure adaptation.Claude Bernard, (1813-1878, Prof. of Physiology at the Collège de France, Paris), suggests that the equilibrium or steady state of the “milieu intérieur” is to remain constant to allow for optimal function and survival.
Types of Stress• Examples of Physical/Chemical Stress
– High/low extreme temperatures– Physical injury
– Hemorrhage– Hypoglycemia, etc.
• Examples of Psychological/Emotional Stress– Fear
– Cognition of danger – Memories
– Sorrow or joy– Hate or love, etc.
Sapolsky, R.M., Why Zebras Don’t Get Ulcers: An Updated Guide to Stress, Stress Related Diseases, and Coping, W.H. Freeman and Co., New York, 1998
From left to right: H. Selye, C. Fortier, P.S. Timiras
H. Selye (1907-1982, Director of the Institute of Experimental Medicine and Surgery, Univesity of Montreal, Que. Canada) focuses on the HPA axis as the main regulator of non-specific stress responses. His major book is: The Physiology and Pathology of Stress: A Treatise Based on the Concept of the General Adaptation Syndrome and the Diseases of Adaptation, Acta Inc., Montreal, 1950.
From left to right: F. Skelton, R. Guillemin (Nobel Prize 1977), Prof. C. LeBlond, P.S. TimirasThe Nobel Prize was awarded for the identification of the hypothalamic hypophysiotropic hormones.
HomeodynamicsA 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)
Funct ions Stimulat ed or Inhibit ed by Physical/ Psychological Stress
Functi ons St imulat ed by St ress:
Cardiovascular• Increased cardiac r at e• Elevat ed blood pr essure• Increased blood c oagulat ion• Redist ribut ion of b lood f rom
peripheral ( skin) and int ernalsyste ms (gast ro-int est inal) toheart, skeleta l m uscles, brain
Respirat ory• Increased respirator y vent ilat ion
Met abolic• Increased glycogen mobilizat ion• Increased glycemia• Increased lipolysis
Hormonal• Increased CRH, ACT H,
Glucoc ort icoids• Increased vasopr essin, NGF• Increased cat echolamines (E & NE)
Functi ons Inhibit ed by St ress:
All funct ions not immediat elynecessary for defense andsurvival are decreased:
• Decreased growth• Decreased appeti t e ( anorexia)• Decreased reproduct ive funct ion
and s ex dr ive• Decreased circulat ion in t issues not
invo lved in st ress r esponse• Decreased response to p ain• Decreased immune funct ion• Decreased th ym us s ize• Decreased th ym ic hormones and
cyto kines
Table 10.7
Table 10.6Pathophysiologic Responses During Stress
During StressEnergy st orage ceases because:↑ sympathetic act ivity
(i.e. increased vigilance/ arousal)↓ parasympathet ic act ivity↓ insulin secret ion
Access t o energy storage is facilitat edand energy storage steps are reversed because of:
↑ glucocorticoid secret ion↑ epinephrine/ norepinephrine secret ion
glucagon secret ion glucagon secretion
Patho physiologic Responses After StressIf physiologic respon ses are insuf f icient and ad apt at ion is inco mplet e,
sym pto ms of poor health are regist ered (e.g. loss of energy whenf reeing energy f rom st orage and retu rning to st orage)
Examples of consequences:Muscle wast ingDiabet es (T ype 2)Ulcers, colit is, diarrh eaInhibit ion of growth ( in childhood)Ost eoporo sis ( in old age)↓ LHRH, ↓ t est ost erone
Table 10.6
Figure 10.10Some
physiologic and pathologic
responses to stress in
selected organs
Risk Factor s ( Allost at ic Load)Endangering Health and Short ening Life Span
Elevat ed Physiologic Ind ices (at r isk)• Syst olic b lood pr essur e: ≥ 14 8 m m Hg• Diasto lic blood pressure: ≥ 83 mm Hg• Waist -hip rat ion : ≥ 0.9 4• Tot al cho lest erol-High Densit y Lipopr ot ein r at io: ≥ 5.9• Tot al glycosylat ed h em oglobin level: ≥ 7.1 %• Urinary co rt isol l evel: ≥ 25. 7 mg/ g cr eat inine• Urinary epinephrine level: ≥ 5 m g/ g creat inine• Urinary no repinephrine level: ≥ 48 mg/g creat inine
Low ered Ph ys iologic Ind ices (at r isk)• HDL cho lest erol level: ≤ 1.4 5 mm ol/ L• DHEA ( Dehyd roepiandro st eron e) le vel: ≤ 2.5 µmol/ L
Table 10.9
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.
Moderate stressof short duration
Allostatic Loadweak or absent
Severe and prolonged stress
Allostatic Loadprogressive & severe
Incidence of Cardio- vascular Diseases
Moderate stressof short duration
Excessive stressof long duration
vigilance
attention
memory storage
number of neurons
neurotransmitter balance
memory storage
stimulate: reduce:
Cognitive Alterations
Figure IV.3 Protection contre Pathologie: fonction cérébrale et mémoire
Allostatic Loadweak or absent
Allostatic Loadprogressive & severe
Moderate & RegularPhysical Exercise
Allostatic Loadweak or absent
Allostatic LoadProgressive & increasing
Excessive & prolongedphysical exercise or lack of regular exercise
Cardiovascular function
Energy mobilization
Immune efficacy
Cognition & vigilance
Mass & strength of muscle & bone
Atherosclerosis
Obesity
Incidence of cardio- vascular diseases
Immunosuppression
Depression, anxiety, memory loss
Bone fragility
Muscle atrophy & weakness
Physical Exercise
Beneficial effects of Hormesis may be due to:
DNA repairImmune competenceNeurologic acuityNeuromuscular activityBetter memoryResistance/ adaptation to stress
C. Elegans2 week lifespanhermaphrodite19,000 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.
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 WORMS (Caenorhabditis elegans):
Genetic ManipulationInactivation of IGF-1
receptor analog
Decreased growthDelayed maturation
Shift of metabolismfrom aerobic to anaerobic
Decreased free radical accumulation
Greater resistanceto stress
Increased longevity 6Xmortality
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
Taken from P.H. Hunter, Protein Folding: Theory Meets Disease,The Scientist, volume 17, number 17, pg. 24-27,2003
CHAPERONES
Intracellular peptides that helpother proteins to fold
Prevent production of Inactive protein
Protein fragmentsProtein aggregates
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 associatedWith 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
Inner Resourcese.g. beliefs,assumptions
Knowledgee.g. years
of education
Social supporte.g. interpersonal
relationsSpiritualitye.g. religious
beliefs
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