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