GROWTH HORMONE
a. Increases protein synthesis (synergistic to insulin).
b. Increases muscle mass (muscle fibers are primarily made up of
proteins, i.e. actin and myosin).
c. Increases bone strength, indirectly.
d. Mediates longitudinal growth of bones by stimulating secretion of
Insulin-like Growth Factor I (IGF-I).
e. Increases amino acid transport into cells.
f. Increases carbohydrate and fat metabolism (antagonistic to insulin).
g. May contribute to immune function.
GH demonstrates a pulsatile secretion with the highest output occurring
at night, during early hours of sleep.As
we age the frequency of GH secretion stays the same but the magnitude decreases
significantly.The following graph
shows the decline inGH with aging:
The
levels of GH in blood declines by more than 50% from a peak during puberty,
reaching elderly levels by age 35-40.This
decline in GH may contribute to the observed aging deterioration of tissues
leading to reduction in muscle mass (lean body mass), decrease kidney function,
increase lipid deposition, and weakening of the heart.
If indeed GH does attribute to deterioration of tissues with aging the administration ofGH may either retard or even reverse these aging changes.The question becomes “is GH replacement therapy a viable option to improve tissue deterioration?”
Several studies have been conducted to see the efficacy of GH administration on aging tissues.In a study conducted by Marcus et al. (1990)GH administration to elderly for a period of 6 months resulted in positive metabolic effects with increase in lean body mass, decrease in adipocity, and increase in bone density.However, when this study was extended for a year, significant side effects were noted (such as carpal tunnel syndrome, diabetes mellitus, and gynecomastia).In another study, elderly volunteers were injected subcutaneously with 30mg/kg GH for 6 months.After six months there was 8.8% increase in lean body mass; 1.6% increase in lumbar vertebral bone density, and 14.4 % decrease in fatty tissue mass.Risk factors were as described above, including hypertension and possible risk of cancer.
Because of these side effects researchers are testing other compounds such as GHRH (growth hormone releasing hormone) and IGF-I.These compounds have been shown to minimize the side effects.Recently, orally active aromatic compounds developed synthetically have been shown to mimic GHRH.
Interestingly, exercise mimics many of the benefits of GH.In fact, no effect of GH on muscle mass of the elderly is observed when exercise is included with GH therapy.This should not be surprising since young people secrete GH while exercising. Exercise possibly should be substituted in place of GH therapy whenever possible.
MELATONIN AND DHEA
TESTOSTERONE
a. Decrease in muscle mass
b. Increase in body fat
c. Decrease in bone density
d. Various changes in sexual functions
With short-term therapy the following is observed:
a. Increase in libido
b. Increase in muscle strength
c. Decrease in abdominal fat
d. Increase in hemoglobin and hematocrit
Short-term therapy does not appear to worsen symptoms of prostatic hypertrophy
or stimulate development of prostate cancer.
Side effects of short-term therapy include:
1. Benign prostatic hyperplasia
2. Sleep apnea
3. Lipid abnormalities
4. Erythrocytosis
5. Hypercoagulability
Effects of long-term therapy is currently in progress.
ESTROGEN AND THE NERVOUS SYSTEM
The following are some of the recent reported benefits of estrogen on the nervous system.
a. Improves memory and cognition in some types of dementia.
b. Exerts major influence on the development and function of the
brain.
c. Regulates activities of the genes in the hypothalamus (i.e.
opioid peptide genes that regulate mood and behavior).
d. Regulates the expression of the following genes:
1. progesterone receptor
2. C-fos
3. Somatostatin
4. GnRH
5. Oxytocin receptor
e. Aromatization of testosterone to estrogen regulates expression of
genes important for the dimorphic functioning of male and female nervous system.
f. Plays role in neuronal survival effecting growth, differentiation,
and plasticity of neurons (i.e. effects memory and learning).
g. Builds and maintains synapses.
h. Antioxidant.
The following is a short list of recent genes implicated with aging in a variety of species of animals, including humans:
P21 gene, disrupts cellular division and death.
b. RAS-1 and RAS-2 genes:RAS-1 shortens while RAS-2 lengthens
lifespan.
c. PHBI gene increases lifespan.
d. Clock genes (also found in C. elegans, mouse, and humans)
when mutated induces cells to divide more slowly, probably
controlling the pace of metabolism.The function in humans
is not known.
Klotho gene.When mutated causes premature death due to a variety of disorders commonly found in elderly humans such as artheriosclerosis,
osteoporosis, emphysema, etc.
(Klotho is named after the Greek goddess who spins the thread of life).
This gene is also
found in
humans.
b. Clock genes: clk-1, clk-2, and clk-3.When all these genes are activated animals live 3 to 4 times longer.
c. Daf genes: Regulates the path of maturing larvae to adulthood in times of food shortage or overcrowding.It induces sidetracking of normal development into dormant state known as dauer stage, thus prolonging life.Daf-genes can also prolong life of adult
C. elegans upon activation.
Daf-2 gene regulates glucose metabolism.It downregulates
utilization of glucose in times of stress (i.e. food supply) and
hence helps the animal survive.
The same mechanism maybe be occurring in human cells since daf-2 gene is found in the same family of proteins as the receptor that binds insulin in humans.
In C. elegans, if food is in short supply,daf-2 gene initiates a series of events putting animal in hibernation.Similar decreases in metabolism has been observed with calorically restricted rats and in metabolic control of insulin receptor.
b. Other types of accelerated aging in humans such as Hutchinson-Gilford Syndrome and Cockayne Syndrome have
been implicated to yet unidentified mutation of genes.
As indicated earlier aging mechanism has been conserved in evolution. The following is a brief description of homologues*genes in C. elegans and mammals (human).
|
C. elegans
|
Mammals
|
Role in Cell Death
(Apoptosis)
|
Function
|
|
|
|
|
|
|
CED-9
|
Bcl-2
|
prevents
|
opposes Bax
|
|
----
|
Bax
|
promotes
|
opposes Bcl-2
|
|
----
|
Bcl-x (Long)
|
prevents
|
opposes Bcl-x (Short)
|
|
----
|
Bcl-x (Short)
|
promotes
|
opposes Bcl-x (Long)
|
|
CED-3
|
ICE
|
promotes
|
protease
|
|
CED-4
|
Apaf-1
|
promotes
|
?
|
|
|
|
|
|
|
*Human
homologue of CED-9 gene, Bcl-2, when transferred into
C.
elegans
lacking CED-9 blocks the action of CED-3 and CED-4.
|
|||
2.Ashkenazi, A. & Dixit, V.M. 1998.Death Receptors:Signaling and
Modulation.Science,281: 1305-1309.
3.Bagatell, C.J. and Bremna, W. 1998.Androgens in Aging Men:Do Men
Benefit from Testosterone Replacement?J. ofAnti-AgingMed., 1 (No. 4): 359-365.
4.Evan,
G.and Littlewood, T. 1998.A
Matter of Life and Cell Death.
Science,281:
1317-1322.
5.Kimura,
D., et al., 1997.Daf-2, an Insulin
Receptor-Like Gene that
Regulates Longevity
and Diapause in C. elegans.Science,277:
942-946.
6.Marcus,
A., et al., 1990.Effects of Short-term
Administration of Recombinant Growth Hormone to Elderly People.J.
Clin.
Endoc.
Metab., 70: 519-527.
7.Thakeur,
M. 1999.Estrogen and Brain Aging.
J.
ofAnti-Aging Med., 2 (No. 2): 127-133.
8.Wolfe,
J. 1998. Growth Hormone:A Physiological
Fountain of Youth.
J.
of
Anti-Aging Med.,
1 (No. 1): 9-25.
