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