It is tempting to believe that restoration of hormone levels to those that exist in young persons should universally be a desirable goal.
In principle, the approach is simple, but hormone replacement therapy is a long-term proposition, possibly continuing for the rest of a patient’s life.
The circulating levels of growth hormone, testosterone, estrogen, dehydroepiandrosterone (DHEA), and other hormones decrease with age.
Supplementations with melatonin or DHEA, or injection of growth hormone, have all been promoted in highly visible books.
However, the question of whether melatonin levels also decrease with age is controversial.
While some hormone replacement strategies have been shown in clinical trials to modify some of the physiological attributes associated with aging, negative side effects occur frequently with those interventions shown to have some benefit, such as growth hormone.
Negative side effects occur less frequently with interventions for which evidence of benefit is either absent or equivocal, such as DHEA.
Although the epidemiological data are overwhelmingly positive regarding some health benefits of estrogen replacement therapy, a recent study has raised a concern about ovarian cancer after long-term use.
In another example, Anisomov reported that melatonin supplementation increases the mean life expectancy of mice by about 5%.
However, they also found that spontaneous tumor incidence increased in the melatonin-treated mice.
Thus, more research is needed to determine the proper application of hormones within a clinical environment.
Estrogen Replacement Therapy (ERT)
ERT is a special case of hormone replacement therapy and deserves particular attention here because of its long clinical history and apparent record of success in increasing both the length and quality of life in postmenopausal women.
Estrogen is particularly recommended for preventing osteoporosis, but it may also reduce the risk of dementia and cardiovascular disease.
The incidence of cardiovascular disease in women is negligible before menopause and increases dramatically thereafter.
Some epidemiological data have suggested that ERT reduces the occurrence of coronary artery disease, and possibly cerebrovascular disease, by 25% to 50% in treated women compared with non-users.
These findings are supported by evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls.
It has been estimated that favorable changes in plasma lipids may account for approximately 25% of the cardioprotective effect of estrogens, and that other effects are therefore likely to be important.
The influence of estrogens on carbohydrate metabolism, atheroma formation and cardiovascular hemodynamics may also play an integral role in the overall beneficial effect of the hormones.
Animal and human studies have shown that the administration of estrogens leads to a restoration of endothelial function, an increase in cardiac output, an increase in arterial flow velocity, a decrease in vascular resistance, and a decrease in systolic and diastolic blood pressure.
However, the conclusion that estrogen protects postmenopausal women against cardiovascular disease is now being questioned, based mainly on experiments examining secondary prevention in women with pre-existing heart disease.
These studies have caused the American Heart Association to withdraw its support for ERT as a preventive measure against coronary vascular disease.
Media reports have led to some insecurity and concern about the use of sex steroids after menopause.
The incidence of breast cancer increases continuously with aging, and although ERT does not induce breast cancer, it may promote the growth of existing tumors.
It has been estimated that if 1000 women start ERT at the age of 50 and continue for five years, two more cases of breast cancer will be diagnosed within the next 20 years.
This small increase of morbidity is not accompanied by an increased mortality due to breast cancer, but a small increase in ovarian cancer has been recently reported.
Nevertheless, the data available today show a clear decrease of total mortality up to the age of 75 years in women using ERT.
The gain in quality of life and the reduction in all-cause mortality that is associated with ERT have prompted many practitioners to proclaim ERT to be the first true anti-aging therapy.
However, no results have yet been reported of randomized studies comparing effects of ERT with placebos, beginning at the menopausal transition, in women with no known pre-existing coronary heart disease or dementia.
Until such data become available, the risks versus benefits of ERT are likely to remain controversial.
Therefore, the risks and benefits of long-term ERT need to be evaluated individually for each subject.
The Growth Hormone Paradox
A serious concern in the search for interventions that increase life expectancy is that interventions having short-term benefits could have adverse effects with long-term treatment.
An excellent example of this is growth hormone (GH).
It has been well documented that circulating levels of growth hormone drop with increasing age.
It has also been shown that GH replacement in adults with pituitary disease and GH deficiency has beneficial effects on body composition, reducing fat and increasing lean body mass, muscle strength, and bone mass.
Daniel Rudman investigated whether growth hormone injections into older men would restore muscle mass typical of younger men.
They injected growth hormone three times a week into 12 men over a period of six months, and looked for changes in body composition and IGF-I levels.
They found that IGF-I levels did rise and that lean body mass increased, while fat mass decreased, suggesting that growth hormone injections did reverse the changes in body composition that were due to age and deconditioning.
This report encouraged the use of growth hormone as an anti-aging intervention.
However, more recent data obtained with mice suggest the opposite conclusion.
Lifelong overproduction of growth hormone shortens longevity in mice, while under-production or an inability to respond to growth hormone lengthens it.
Transgenic mice over-expressing growth hormone exhibit severe kidney lesions and increased incidence of neoplasms, while overproduction of growth hormone in adult humans leads to a condition known as acromegaly, which is characterized by excessive growth of certain organs and tissues (especially bone), but also premature heart and lung failure.
Thus, efforts to restore circulating growth hormone to youthful levels in older individuals may be misguided.
Furthermore, the evidence from both nematodes and fruit flies suggests that decreased activity of the growth hormone/insulin-signaling pathway is associated with increased life expectancy, rather than the reverse.
Further research is needed before growth hormone supplementation in humans can be considered either safe or useful for long-term intervention.
There is an important caveat with regard to injection of growth hormone, in that it does not replicate the normal pulsatile pattern of growth hormone production seen in humans.
A very low baseline level characterizes this pattern, with intermittent low amplitude peaks during waking hours and much larger peaks during periods of deep sleep.
An alternative approach of using growth hormone releasing hormone (GHRH) has been tried, but with limited success.
Somewhat better success has been obtained using a variety of GHRH and growth hormone releasing peptide mimetics, such as small peptides and aromatic ring compounds.
In his conclusion, Jason Wolfe states: "… it is premature to conclude that GH reverses aging, just as it is premature to conclude that it does not."