11/6- Endocrine System and Aging Flashcards
Overview of the areas of endocrinology that change with age (list)?
- Glucose homeostasis
- Thyroid hormones
- Growth hormone/IGF-1
- Adrenal hormones
- Androgens (testosterone)
How does plasma glucose change with aging?
- Fasting glucose increases ~1 mg/dL per decade
- 1 and 2 hr post-prandial glucoses increase 8-10 mg/dL per decade
- For those < 50 yo, upper limit of normal after glucose load is 140 for the 2hr level; this increases 10 per decade after 50
- This means that 100 + age = maximum post prandial glucose
Overview of prost-prandial glucose increases with aging?
- Elderly have higher prost-prandial glucose
- Later peak
- Slower recovery (back to fasting)
These pts are NOT diabetic!!
Plasma insulin levels in elderly ____ after glucose challenge
Plasma insulin levels in elderly increase after glucose challenge
Hyperglycemia in elderly is due to what?
Insulin resistance
- Labeled glucose was infused durin a euglycemic clamp into young and old men; the uptake of glucose as expressed in mg/kg/min of lean body weight was reduced more than 25% in the old. This did not increase with increased glucose
- Therefore it is unlikely that changes in the receptor’s affinity for sugar is modified with age; however, a 65 yo man can = a 25 yo in terms of glucose uptake by increasing his serum glucose by roughly 50%
Glycosylated Hb (HbA1c) increases with age. What is normal for elderly person?
Around 7?
What are some of the mechanisms for insulin resistence of aging?
- Increase in visceral body fat with aging (this effect now seems to be mediated by both inflammation and obesity)
- Decreased lean body weight
- Glucose utilization markedly impaired
- Decreased fat cell insulin dependent (GLUT4) glucose transporters; also muscle in rat
- Sedentary lifestyle is associated with peripheral insulin resistance
- Very small impairment in pancreatic insulin release but higher insulin levels
- Non-insulin mediated glucose uptake is decreased < 10% by age
- Decreased suppression of hepatic glucose output
- Decreased alternative agonist (IGF-1) levels
- Preserved counter-regulatory pathways
- Likely post-receptor lesions including those that keep glucose in cell (glucose monophosphate)
[Note: heart doesn’t need insulin to uptake glucose]
___ may mediate some of adiposity’s effects on insulin sensitivity
Inflammation may mediate some of adiposity’s effects on insulin sensitivity!
- May be easier to get rid of the inflammation component of fat since it’s harder to get rid of the fat itself
How did a 6 mo exercise training program change insulin sensitivity in old men?
Describe the interaction between hepatic glucose output and oral glucose intake in the elderly
Hepatic glucose output is less suppressed by oral gluocse intake in the elderly
- Producing more glucose in their fasting state
- Don’t shut off glucose production quickly with food/glucose intake
- Contributes to post-prandial age-related increased in glycemia (100 + age, remember?)
__% of elderly have glucose intolerance test results indicative of diabetes
41% of elderly have glucose intolerance test results indicative of diabetes
Discuss hyperglycemia vs. hypoglycemia complications in terms of elderly population
- Hyperglycemia complications are long-term (vs. hypoglycemia)
- Most of the bad effects of hyperglycemia require years to manifest
- Hypoglycemia requires minutes..
- If person isn’t going to live long enough to experience these bad health outcomes, don’t worry about it as much
- Hypoglycemia is worse in old than young
- The old heart needs glucose (so does the sick heart)
How does illness relate to glucose tolerance in the elderly?
- Elderly people are more likely to have stress-related hyperglycemia
- Systems inducing hyperglycemia are less altered by aging than the hypoglycemic ones
- Norepinephrine increases with age
- Cortisol is unchanged or increased with age in response to illness
- Glucagon is unchanged with age
- Pro-inflammatory cytokines increase with age
- If a older person has hyperglycemia while ill, do not label them diabetic; reevaluate glucose when they are not sick
Epinephrine normally does what to insulin levels? In elderly?
Epinephrine normally antagonizes insulin
- Increased in elderly
- Epinephrine infusion is model of stress such as that seen in illness
- Old have greater insulin resistance due to catecholamine infusion
Key piont: if an older person has hyperglycemia while ill, treat the hyperglycemia but do not label them diabetic; Reevaluate glucose when they are no longer sick (~6 weeks)
Yup
What is AGE?
Advanced glycosylation end product
- Result of non-enzymatic reactions between glucose and amine groups of proteins
- Hemoglobin A1C is the product of such a non-enzymatic glycosylation (Schiff bases -> Amadori products)
- The AGEs dehydrate, precipitate and may contribute to cataract formation in the lens
- Glucose may form other irreversible cross-links between proteins or nucleic acids that compromise function
- Contributes to very stiff collagen
Where do glycosylated proteins accumulate?
With aging, AGEs accumulate in skin and tendon and some other long-lived protein-rich areas
- Not found in other seemingly similar areas
What can be done to decrease serum glucose (and limit AGE)?
Caloric restriction
AGEs will stimulate what?
Atherosclerosis
What is the heart’s favorite fuel?
Fatty acids
- Decreased utilization in elderly; depend more on glucose!
Glucose becomes the fuel of choice for ______ cardiomyocytes
Glucose becomes the fuel of choice for hypertrophied cardiomyocytes
- Glucose is probably preferred in sick young as well as elderly
Glucose burning heart allows what?
Glucose-burning heart allows more work per oxygen
How does glucagon/its effects change with aging?
- Glucagon counters the effects of insulin on blood glucose
- Glucagon levels are unchanged with age in normal humans
- Liver responsiveness to glucagon is unchanged/increased with age
How do Thyroid hormones change with aging?
- Serum T3/4 do not change with aging, but free T3 decreases slightly
- T4 production decreases 25%
- T3 production decreases 33%
- Reduced daily requirement for thyroxine needed for replacement in elderly persons
- No change in response to infusions of TSH
- Perhaps a decreased TSH respopnse to TRH
- Elderly very likely to suppress thyroid function while “ill or malnourished”. This is called euthyroid sick syndrome
What happens in euthyroid sick syndrome?
Conversion from T4 to T3 because don’t want to spend energy on hyperthyroid things???
How does free T3 change in healthy men with age?
Subtle decrease in free T3 in healthy men with age
How does free T4 change with age?
No change in free T4 with age
What do the elderly do with excess T4?
Excess T4 shuttled to RT3 in elderly
_________ TSH is common in centenarians
Slightly elevated TSH is common in centenarians
IMPORTANT POINT ON GH
- Release patterns; most when?
- Changes with aging
- GH is normally secreted in pulsatile spikes; the largest during sleep
- With aging, the spikes all but disappear
- Non-spike GH levels are very low in both young and old and do not change with age
- Integrated 24 hr secretion decreases by up to 80% with adult aging
- Leads to decreases in IGF-1
- Somatostatin levels do not change, but there is increasing sensitivity to its inhibition of GH release in the rat
YOU DON’T KNOW ANYTHING ABOUT GH FROM SINGLE DRAW
Aging results in ____ in GH _____
Aging results in decreases in GH nocturnal peaks
What is IGF-1? How does it change with aging?
- Secreted by what? where? in response to?
- Secretion profile
- Binds what
Insulin-like growth factor 1 mediates most of the effects of GH
- IGF-1 is secreted by the liver into the bloodstream in response to GH
- It does NOT have pulsatile variation
- IGF-1 circulates bound to IGF binding proteins; the effect of age on the IGFBPs is under investigation
- Serum levels decrease 30-50% from age 20 to 80 in both genders
- IGF-1 has paracrine function when secreted within other tissues. This component has been less completely studied
Serum IGF-1 ____ (increases/decreases) with age
Serum IGF-1 decrases with age
Should GH/IGF-1 be replaced?
- Lean body mass increased and fat mass decreased with rhGH treatment; there was a marginal increase in muscle strength
- Significant side effects occurred in both men and women in the GH groups (with/without sex steroids), including:
- Ddema, carpal tunnel sydnrome, and arthralgias
- Diabetes and glucose intolerance developed more in rhGH treated men than in those not receiving GH
Recall, decreased GH may be protective. In what studies was this seen?
Smaller baseball players live longer
What was found in the survival of Snell dwarf mice in challenge-rich vs. challenge-poor environments?
Recall, Snell mice live the longest. They are missing their anterior pituitary and are thus: hypothyroid, GH deficient, prolactin deficient…
In challenge-rich environment:
- Short survival (<25% wild type)
- “Snell mice considered much older than chronological age)
In challenge-poor environment
- Long survival (35% > wild type)
- Effect of caloric restriction was additive to dwarfism
What happens to serum adrenal androgens (DHEA and DHEA-S) in normal men with age?
They decrease
- DHEA is the hormone produced in the largest quantity by the adrenal gland; it is used as a precursor of sex steroidogenesis
- There is no known DHEA receptor outside the CNS
Many older people are taking DHEA-(S) to restore their youth. To what effect?
- Mechanism of action or proof of benefit is not available
- There is a CNS receptor; likely stimulation may make people feel more motivated
- Age-related atrophy of zona reticularis of adrenal glands
What happens to cortisol with aging?
- Decreased ability to maximally produce cortisol in response to max stress, but adequate release for most stresses
- Most 24 hr serum cortisol concentrations are 20-50% higher in both older men and women
- On cellular level decreases in synthetic capacity parallel decreasing replicative potential
- Cortisol release is less completely suppressed by dexamethasone, but also more difficult to normalize once suppressed with long term corticosteroid mgmt
- Tendency for nodules of adrenal hyperplasia in elderly
Describe cortisone levels in elderly following stress
Stay elevated longer after stress
Describe testosterone changes with aging
- Large variability, but overall testosterone decreases with age
- Fall in bioavailable T because of increase in sex hormone binding globulin in older men
- Fall in T may be accentuated by any chronic or acute illness
- Decrease in Leydig cell mass (make T)
- Non-trivial day to day variation in T
- Also decrease in Sertoli cell mass (sperm)
- Oldest documented paternity is age 93
Should we replace testosterone? Pros/cons
Pros:
- Improved quality of life/sense of well being
- Improved libido and sexual function
- Increased bone density and muscle mass
- Possibly improved cholesterol profile
Cons:
- Worsens benign prostatic hypertrophy
- Liver toxicity, hyperviscosity, erythrocytosis
- Worsens sleep apnea or heart failure
- Increased risk of prostate cancer
- Increased risk of heart attack
What is found in elderly in regards to Vitamin D?
- Results?
Mild vitamin D deficiency is common among older people
- Decreased diet intake and absorption
- Decreased sun exposure
- Decreased generation of endogenous VIt D with sun
- Decreased conversion in old kidneys
Contributes to:
- Osteoporosis, falls, and fractures
- Associated with many other outcomes
- Whether replacing Vit D fixes it is unclear (does suppress PTH)
How does angiotensin/its pathway change in the elderly?
- Entire endocrine RAAS pathway is down-regulated by aging
- Angiotensin is critically important when water is not available, but is only a nuisance if it is
- Angiotensin receptor null mice live longer
SUMMARY
- Glucose tolerance impaired
- Fasting glucose increases 1 mg/dL/decade
- Post-prandial glucose increases 10 mg/dL/decade
- Increased serum insulin and HbA1C
- Nocturnal GH peak is lost
- Decreased IGF-1
- Marked decrease in DHEA
Yup
