Aging : Heat Shock Proteins, Hormones

by National Institute on Aging

(Page 9 of 15)

Heat Shock Proteins

In the early 1960s, investigators noticed fruit flies did something unusual. When these insects were exposed to a burst of heat, they produced proteins that helped their cells survive the temperature change. Intrigued, researchers looked for these proteins in other animals, and found them in virtually every living thing including plants, bacteria, worms, mice, and yes, humans. Today, the role of these substances, known as heat shock proteins, in the aging process is under scrutiny.

Despite their name, heat shock proteins (HSPs) are produced when cells are exposed to various stresses, not only heat. Their expression can be triggered by exposure to toxic substances such as heavy metals and chemicals and even by behavioral and psychological stress.

What attracts aging researchers to HSPs is the finding that the levels at which they are produced depend on age. Old animals placed under stress - short term, physical restraint, for example - have lower levels of a heat shock protein designated HSP-70 than young animals under similar stress. Moreover, in laboratory cultures of cells, researchers have found a striking decline in HSP-70 production as cells approach senescence.

Exactly what role HSPs play in the aging process is not yet clear. They are known to help cells dismantle and dispose of damaged proteins. They also facilitate the making and transport of new proteins. But what proteins are involved and how they relate to aging is still the subject of speculation and study.

While at the NIA, Nikki Holbrook, Ph.D., and other researchers investigated the action of HSP-70 in specific sites, such as the adrenal cortex (the outer layer of the adrenal gland). In this gland as well as in blood vessels and possibly other sites, the expression of HSP-70 appears closely related to hormones released in response to stress, such as the glucocorticoids and catecholamines. Eventually, answers to the puzzle of HSPs may throw light on some parts of the neuroendocrine system, whose hormones and growth factors might have an important influence on the aging process.

Hormones

Hormones are powerful chemicals that help keep our bodies working normally. Made by specialized groups of cells called glands, hormones stimulate, regulate, and control the function of various tissues and organs. They are involved in virtually every biological process including sexual reproduction, growth, metabolism, and immune function. These glands, including the pituitary, thyroid, adrenal, ovaries, and testes, release various hormones into the body as needed.

As we age, production of certain hormones, such as testosterone and estrogen, tends to decrease. Hormones with less familiar names, like melatonin and dehydroepiandrosterone (DHEA) are also not as abundant in older people as in younger adults. But what influence, if any, these natural hormonal declines have on the aging process is unclear.

Hormone Replacement

In the late 1980s, at Veterans Administration hospitals in Milwaukee and Chicago, 12 men age 60 and older began receiving injections three times a week that dramatically reversed some signs of aging. The injections increased their lean body (and presumably muscle) mass, reduced excess fat, and thickened skin. When the injections stopped, these changes reversed, and the signs of aging returned. What the men were taking was recombinant human growth hormone (hGH), a synthetic version of the hormone that is produced in the pituitary gland and plays a critical part in normal childhood growth and development. At the same time, evidence was accumulating that menopausal hormone therapy with estrogen (alone or in combination with a progestin in women with a uterus) could benefit postmenopausal women by reducing cardiovascular disease, colon cancer, and other diseases of aging. Further studies have indicated that, although estrogen remains an effective way to control hot flashes, long-term use of these hormones may increase risk for several major age-related diseases in some women, especially then treatment is started years after menopause. The finding that levels of testosterone in men decreased with aging raised the question of whether they too might benefit from sex hormone treatment.

As a result of these preliminary observational findings, the NIA launched a series of research initiatives to clarify what influence hormone replacement therapy might have on the aging process. So far, most of these studies have been inconclusive, but have led many investigators to question whether the risks of hormone replacement may outweigh any benefit. Supplements of hGH, for instance, can promote diabetes, joint pain, carpal tunnel syndrome, and pooling of fluid in the skin and other tissues, which may lead to high blood pressure and heart failure. Studies in mice have raised other concerns about the hormone. Investigators have found that mice deficient in growth hormone production live substantially longer than normal mice, while mice overproducing growth hormone live shorter than average lives. This finding suggests that even if hGH replacement therapy is initially beneficial, ultimately it may be harmful and actually might curtail longevity.

Similarly, there is scant evidence that testosterone supplementation has any positive impact in healthy older men. In fact, some studies suggest supplementation might trigger excessive red blood cell production in some men. This side effect can increase a man's risk of stroke.

Estrogen is perhaps the most well studied of all hormones. Yet results from the Women's Health Initiative (WHI), the first major placebo-controlled, randomized clinical trial of estrogen therapy with or without progestin to prevent some chronic diseases of aging, surprised the medical community. There were more cases of stroke, blood clots, heart disease, and breast cancer in postmenopausal women using estrogen and progestin in the study, and more cases of possible dementia in women over age 65, than in those using the placebo. But, there were also fewer bone fractures and cases of colon cancer. In postmenopausal women using estrogen alone, there were more cases of stroke and fewer bone fractures than in those women on placebo. Other studies indicate that menopausal hormone therapy is effective in controlling moderate-to-severe menopausal symptoms, so research is ongoing to evaluate benefits and risks in menopausal and younger postmenopausal women.

As research continues, the pros and cons of hormone replacement may become more precisely defined. These hormonal supplements appear to increase risk and provide few clear-cut benefits for healthy individuals and do not seem to slow the aging process.

About the Author

www.nia.nih.gov
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form NIA to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people.