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MCB 135K Discussion. April 20, 2005. Topics. Adaptation to Stress Hypothalamo-Pituitary-Thyroid Axis Carbohydrate Metabolism, Diabetes, and Aging. Beneficial effects of Hormesis may be due to:. DNA repair Immune competence Neurologic acuity Neuromuscular activity - PowerPoint PPT Presentation
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MCB 135K Discussion
April 20, 2005
Topics
• Adaptation to Stress
• Hypothalamo-Pituitary-Thyroid Axis
• Carbohydrate Metabolism, Diabetes, and Aging
Beneficial effects of Hormesis may be due to:
DNA repair
Immune competence
Neurologic acuity
Neuromuscular activity
Better memory
Resistance/ adaptation to stress
• 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
FromTo
STRESS
HYPOTHALAMUS
HYPOPHYSIS
ADRENAL CORTEX
Increased production of gluccocorticoids &inhibition of gonadal hormones
GHRH GH
GnRH Gn
somatotropichormone
gonadotropic hormones
GROWTH INHIBITION
INHIBITION OF MALE SEX
ORGANS
IRREGULARITIES OF
MENSTRUAL CYCLE
FSH, LH
Releasing Hormone
CRH(cortico-releasinghormone)
ACTH(adreno cortico-tropic hormone)
– –
–
–
–
–
Shift in HPA secretory priorities during stress
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
“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)
• 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
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
Table 13.3Major Actions of Thyroid Hormones
• Calorigenesis
• Metabolism
• Brain maturation
• Behavior
• Growth & development
Figure 13-3
CNS
HYPOTHALAMUS
TRH
PITUITARY
TSH
THYROID GLAND
T3 T4 rT3
TARGET CELLS
T4 T3
INTRACELLULAR (NUCLEAR) BINDING
METABOLIC RESPONSE
CLEARANCE
FREE &BOUND
(-)
(-)
3, 5, 3’, 5’ Tetraiodothyronine (thyroxine, T4)
3, 5, 3’ Triiodothyroine (T3)
Table 13-2: Some MORPHOLOGIC Changes in the Thyroid Gland with Aging
FOLLICLES:- Are distended
- Change in color- Epithelium flattened w/
reduced secretion
Fewer mitoses
Increased connective tissue;
Fibrosis
Atherosclerotic changes
Table 13-2 (con’t.): Some SECRETORY Changes in the Thyroid Gland with Aging
Simultaneously decreased secretion and metabolic
clearance of T4 with resulting essentially normal levels
Failure of up-regulation of
T3 nuclear receptors
peripheral conversion of T4 to T3
TSH levels in 10% of the elderly, associated
in antithyroid antibodies, present even in the absence of
manifestations of hypothyroidism
circulating T3 levels but generally within
the normal (lower) range
Table 13-1: Some Critical Aspects of Thyroid Hormone Regulation
1. Major source of circulating T3 from peripheral deiodination of T4 (NOT from thyroid gland secretion)
2. The negative feedback at the pituitary anterior lobe is mainly through T4 (taken from circulation & converted into T3)
3. The peripheral deiodination of T4 depends on the physiological state of the organism. It allows an autonomy of response of the tissues to the hormones.
4. Deiodination can convert T4 (a less biologically active hormone) to T3 (a more active hormone). This conversion depends on the activity of the various deiodinating enzymes.
Table 13-6 Autoimmune Diseases of the Thyroid Gland
Characteristics Graves’ Disease Hashimoto’s Thyroiditis
Thyroid Status Hyperthyroid Hypothyroid
TSH Generally undetectable
Normal to elevated
T4, T3 (serum) Above normal Below normal
Antibodies(ABs) Stimulatory ABs compete with TSH at receptor sites
Loss of TSH control over thyroid function
Some ABs block TSH actions
Autoantibodies against thyroglobulin, T3, T4, thyroid destroy thyroid microsomal and nuclear components
Generally present Generally present
Lymphocytic Invasion Limited Marked
Female:Male Ratio As high as 10:1 As high as 10:1
Table 13-7 Common Signs and Symptoms ofHyperthyroidism in the Elderly
**Also, apathetic hyperthyroidism (see page 244)**
CardiovascularCongestive heart failure
Atrial fibrillationAngina (coronary heat disease)
Pulmonary edema
CNSTremor
NervousnessWeakness
Weight loss and anorexiaExothalmos
(protrusion of eyeball)
THYROIDGoiter?
Thyroid nodules?
Table 13-8 Frequently Missed Common Signs and Symptoms of Hypothyroidism in Elderly
Patients Cardiovascular
Dyspnea (shortness of breath)Chest pain
Enlarged heartBradycardia (slow heart beat)
MISC.Anorexia and constipation
Muscular weaknessMild anemiaDepression
Cold intoleranceJoint pain
With Age:
• Incidence of Diabetes Mellitus Type 2 (late onset diabetes, non-insulin dependent diabetes) increases considerably
• Diabetes Mellitus Type 2 is the most common form of diabetes
• Onset occurs years before symptoms are appreciated– therefore, it is important to screen high risk
individuals
Morphologic Changes
• A certain degree of atrophy
• An increased incidence of tumors
• Presence of amyloid material & lipofuscin granules (signs of abnormal cellular metabolism)
Table 14-1 Major pancreatic hormones
Pancreas Hormone Alternate source
F, D or PP Cells Pancreatic GI mucosaPolypepetide
B-Cells Pre-proinsulinProinsulinInsulin(+ connectingC-peptide)
A-Cells Proglucagon GI mucosaGlucagon(+ glicentin)
D-Cells Somatostatin GI mucosa CNS
F, D or PP Cells Pancreatic GI mucosaPolypepetide
Glucose transport into
muscle & adipose cells
Table 14-2 Major actions of insulin
blood glucose
intracellular metabolic use of glucose
glycogen synthesis in liver and muscle cells
gluconeogenesis (in liver)
intracellular transport of amino acids & lipids & protein and triglyceride synthesis
overall body growth (general effect)
When blood glucose is high (hyperglycemia), glucose balance is maintained by:
Insulin secretion Glucose cellular uptake (in muscle)
Endogenous production of glucose
Utilization of glucose (muscle & adipose cells)
Storage of glucose (in liver as glycogen), fat & aminoAcids arriving in the blood form GI tract
Table14-5 Some factors responsible forglucose intolerance* with aging
Insulin alterations: Unchanged or elevated plasma levels of insulin. Alteration in insulin receptors and their internalization in target tissues. Decreased number of glucose transporter units in target cells. Alterations in activities of cellular enzymes involved in post-receptor cellular
responses. Increased secretory ratio of pro-insulin (less biologically active) to insulin (more
biologically active).
Carbohydrate metabolism alterations: Decrease of body’s muscle mass and increase in adiposity. Diminished physical activity. Increased fasting plasma free fatty acids that inhibit cellular glucose oxidation.
Increased liver gluconeogenesis.
Table 14-7 Characteristics of Diabetes Mellitus
glucose uptake Hyperglycemia glycogenesis hepatogluconeogenesis
GlycosuriaPolyuriaPolydipsiaPolyphagia
protein catabolism plasma amino acid gluconeogenesisWeight loss, growth inhibitionNegative nitrogen balance
lipolysys free fatty acidsKetosisAcidosis
Vascular changes Microangiopathies
Table 14-8 Diabetes and Accelerated Aging
DIABETES AGINGMicroangiopathy ---Cataracts CataractsNeuropathy NeuropathyAccelerated Atherosclerosis AtherosclerosisEarly decreased fibroblast Decreased fibroblast proliferation proliferationAutoimmune involvement Autoimmune involvementSkin changes Skin changes