Download MCB 135K Discussion

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
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
From
• High energy
consumption
• Active growth &
development
• Active reproductive
function
To
• Reduce energy
consumption
• Arrest of growth,
development,
reproductive function
• High resistance to
stress
Shift in HPA secretory priorities during stress
STRESS
HYPOTHALAMUS
–
CRH
(corticoreleasing
hormone)
–
GHRH
GnRH
GH
Gn
Releasing Hormone
–
–
–
HYPOPHYSIS
somatotropic
hormone
–
ACTH
(adreno corticotropic hormone)
gonadotropic
hormones
ADRENAL CORTEX
Increased production of
gluccocorticoids &
inhibition of gonadal
hormones
GROWTH INHIBITION
INHIBITION OF MALE SEX
ORGANS
FSH, LH
IRREGULARITIES OF
MENSTRUAL CYCLE
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 on
Increased HSPs and their actions as chaperones
Table 13.3
Major Actions of Thyroid Hormones
• Calorigenesis
• Metabolism
• Brain maturation
• Behavior
• Growth & development
Figure 1 3- 3
(-)
CNS

HYPOTHALAMUS
TRH

(-)
PITUITAR Y

CLE ARANCE
TSH

THYROID GLAND



T3
T4
r T3
FREE &
BOUND
TA RGET CELLS

T4

T3
INTRACELLULAR (N UCLEAR) BINDING

METABOLIC RESPONSE
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
circulating T3 levels
but generally within
the normal (lower) range
Simultaneously decreased
secretion and metabolic
clearance of T4 with resulting
essentially normal levels
TSH levels in 10%
of the elderly, associated
peripheral
conversion of T4 to T3
Failure of up-regulation
of
T3 nuclear receptors
in antithyroid antibodies,
present even in the absence of
manifestations of hypothyroidism
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 Generally present
thyroglobulin, T3, T4,
thyroid destroy thyroid
microsomal and
nuclear components
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 of
Hyperthyroidism in the Elderly
Cardiovascular
Congestive heart failure
Atrial fibrillation
Angina (coronary heat disease)
Pulmonary edema
CNS
Tremor
Nervousness
Weakness
Weight loss and anorexia
Exothalmos
(protrusion of eyeball)
THYROID
Goiter?
Thyroid nodules?
**Also, apathetic hyperthyroidism (see page 244)**
Table 13-8 Frequently Missed Common Signs and
Symptoms of Hypothyroidism in Elderly Patients
Cardiovascular
Dyspnea (shortness of breath)
Chest pain
Enlarged heart
Bradycardia (slow heart beat)
MISC.
Anorexia and constipation
Muscular weakness
Mild anemia
Depression
Cold intolerance
Joint 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
B-Cells
A-Cells
D-Cells
orPP
PPCells
Cells
F,F,DDor
Hormone
Alternate source
Pre-proinsulin
Proinsulin
Insulin
(+ connecting
C-peptide)
Proglucagon
GI mucosa
Glucagon(+ glicentin)
Somatostatin
GI mucosa
CNS
Pancreatic
Pancreatic
Polypepetide
Polypepetide
GImucosa
mucosa
GI
Table 14-2
Major actions of insulin
Glucose transport into
muscle & adipose cells
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 & amino
Acids arriving in the blood form
GI tract
Table14 -5 Some fa ct ors responsible for
glucose int olerance* wit h aging
Insulin alterations:
 Unchanged or elevate d plasma levels of insulin.
 Alt erat ion in insulin recept ors and t heir inte rna lizat ion in t arget t issues.
 Decreased num ber of glucose t ran spor t er units in t arget cells.
 Alt erat ions in act iviti es of cellular enzymes involved in po st -recept or cellular
respons es.
 Increased secret ory rati o of pro -insulin (less biologically act ive) t o insulin (mor e
biologically act ive).
Carbohydrate metabolism alterations:
 Decrease of bod y’s muscle mass and increase in adipo sit y.
 Diminished physical act ivity .
 Increased fas ti ng plasma fr ee fa tty acids t hat inhibit cellular glucose oxidati on.
 Increased liver gluconeogenesis.
Table 14-7 Characteristics of Diabetes Mellitus
glucose uptake
Hyperglycemia
glycogenesis
hepatogluconeogenesis
Glycosuria
Polyuria
Polydipsia
Polyphagia
protein catabolism
plasma amino acid
gluconeogenesis
Weight loss, growth inhibition
Negative nitrogen balance
lipolysys
free fatty acids
Ketosis
Acidosis
Microangiopathies
Vascular changes
Table 14-8
Diabetes and Accelerated Aging
DIABETES
Microangiopathy
Cataracts
Neuropathy
Accelerated Atherosclerosis
Early decreased fibroblast
proliferation
Autoimmune involvement
Skin changes
AGING
--Cataracts
Neuropathy
Atherosclerosis
Decreased fibroblast
proliferation
Autoimmune involvement
Skin changes