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 From To

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 on Increased HSPs and their actions as chaperones

Table 13.3 Major Actions of Thyroid Hormones Calorigenesis Metabolism Brain maturation Behavior Growth & development

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 CharacteristicsGraves’ DiseaseHashimoto’s Thyroiditis Thyroid StatusHyperthyroidHypothyroid TSHGenerally undetectable Normal to elevated T4, T3 (serum)Above normalBelow 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 Lymphocytic InvasionLimitedMarked Female:Male RatioAs high as 10:1

Table 13-7 Common Signs and Symptoms of Hyperthyroidism in the Elderly **Also, apathetic hyperthyroidism (see page 244)** 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?

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 HormoneAlternate source F, D or PP CellsPancreatic GI mucosa Polypepetide B-Cells Pre-proinsulin Proinsulin Insulin (+ connecting C-peptide) A-CellsProglucagon GI mucosa Glucagon(+ glicentin) D-CellsSomatostatin GI mucosa CNS F, D or PP CellsPancreatic GI mucosa Polypepetide

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 & amino Acids arriving in the blood form GI tract

Table 14-7 Characteristics of Diabetes Mellitus glucose uptakeHyperglycemia 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 Vascular changesMicroangiopathies

Table 14-8 Diabetes and Accelerated Aging DIABETESAGING Microangiopathy---CataractsNeuropathy Accelerated AtherosclerosisAtherosclerosis Early decreased fibroblastDecreased fibroblast proliferation proliferationAutoimmune involvementSkin changes