Hormones and Aging
    Growth hormone
    Melatonin and DHEA
    Testosterone
    Estrogen
Genes and Aging
    Yeast
    Drosophila
    Mouse
    C. elegans
    Humans
References


Return to Notes
 

HORMONES AND AGING
 

Return to Top of Page

Recently there has been great deal of interest in hormonal actions on aging.Five hormones that have attracted particular attention in relation to aging are testosterone, growth hormone (GH), melatonin, estrogen, and dihydroepiandrosterone (DHEA).Both DHEA and melatonin are available as over-the-counter drugs with relatively low cost while GH can be obtained only by prescription at inhibitive cost (over $10,000/year).Many articles and recently books have touted these agents as miracle aging hormones and in some cases with little scientific evidence to substantiate these claims.The following is a brief review of the effects of these hormones in the aging process.

GROWTH HORMONE

Return to Top of Page
The following are some of the more important functions of GH:

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

Return to Top of Page
Regardless of all the interest and hype on the effects of melatonin and DHEA as a therapeutic hormonal agent on the aged, experimental data are incomplete and all claims about these two compounds are certainly suggestive but, nevertheless, scientifically unproven.

TESTOSTERONE

Return to Top of Page
Testosterone (steroid) levels decrease slowly during middle age resulting in the following:

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

Return to Top of Page
Estrogen’s actions on the cardiovascular system and bone density is already well established.Recently, estrogen has been implicated as an important mediator of 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.

Return to Top of Page

GENES AND AGING

Return to Top of Page
It is becoming more apparent that maximum life span has a significant genetic component.Recent identification of genes across many species has implicated a multigenic factors in determining longevity.There appears to be an incredible evolutionary conservatism in the aging process.Genes implicated with aging in single animals such as Caenorhabditieselegans, or better known as C. elegans, when inserted in human cells express the same functions in humans (and vice-versa).With genetic manipulations, the current emphasis is not to extend life span by a year or two or maybe a decade but rather in doubling, tripling or even extending lifespan longer.

The following is a short list of recent genes implicated with aging in a variety of species of animals, including humans:


 

1. YEAST

Return to Top of Page
a. LAG-1 (Longevity Associated Gene) increases the number of
cellular division in the yeast.An equivalent gene in 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.


 

2. DROSOPHILA

Return to Top of Page
a. SOD gene.Increases life span.

 

3. MOUSE

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.


 

4. C. ELEGANS

Return to Top of Page
a. Age-1 gene.When mutated induces aging.This gene probably
functions for the elimination of (O·2) by products of energy metabolism.

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.


 

5. HUMANS

Return to Top of Page
a. Werner’s gene on the short arm of chromosome8 codes for the enzyme helicase which is responsible for the proper functioning of DNA.Helicase straightens out the- helical structure of DNA, which is the crucial first step for DNA function, such as replication, transcription, repair, etc.Mutation of this gene leads to accelerated aging (progeria).

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.

Return to Top of Page

REFERENCES

Return to Top of Page
1.Adams, J. and Cory, S. 1998, The Bcl-2 Protein Family:Arbiters of Cell Survival.Science,281: 1322-1326.

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.

Return to Top of Page