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Neuroendocrinology & Aging: A
Perspective |
E-Newsletter No. 76
By Joseph Meites, Ph.D.*
Charles Edouard Brown-Sequard was probably the first experimental
neuroendocrinologist. Believing that testicular hormone secretion declined with
age, he injected himself with crushed dog and guinea pig testes at 72 years of
age, and announced. to considerable skepticism, that this reinvigorated him.
With no radioimmunoassays to accurately measure hormone levels and no knowledge
of the hypothalamus's commanding role, early investigations were limited.
Hormone-aging studies included measuring changes in endocrine gland size and
weight, examining alterations in their gross and microscopic appearance, hormone
bioassays, and observations of endocrine-related disorders in the elderly.
Several leading investigations concluded that hormones played only a minor role
in aging.
Then in the 1960's and early 1970's, Selmar Aschheim, M.T.Peng, and our own lab
dealt with the relation of the hypothalamus to reproductive decline in rats.
Aschheim and Peng showed that old non-cycling rats failed to exhibit estrous
cycles when transplanted with young ovaries, but young ovariectomized rats
resumed cycling after transplantation of ovaries from old rats. Peng further
demonstrated that young hypophysectomized rats resumed cycling after receiving
the pituitaries of old non-cycling rats. Apparently, neither the ovaries nor the
pituitary caused loss of cycling.
We demonstrated direct hypothalamic involvement in 1969,showing that
electrically stimulating the preoptic area induced ovulation in constant-estrous
rats (as did epinephrine or progesterone injections). This suggested that
sufficient lutenizing hormone-releasing hormone (LHRH) was present in the
hypothalamus to elicit LH, but the necessary stimulus was lacking. The finding
that epinephrine also evoked ovulation suggested catecholamine (CA) might be the
missing stimulus. We found significantly reduced dopamine and norepinephrine in
the hypothalamus of old rats. Drugs that increased hypothalamic CA induced
estrous cycle resumption. Reduced hypothalamic CA also caused growth hormone (GH)
and somatomedin-C secretion to decline in old male and female rats.
L-dopa injections restored pulsatile GH secretion in old male rat to young
levels. A similar decline in GH and somatomedin-C secretion was observed in
elderly men, also possibly related to reduced hypothalamic CA. Four different
laboratories soon reported that drugs which elevated hypothalamic CA
significantly lengthened average lifespan, decreased disease and tumor
incidence, promoted sexual vigor and fertility, and improved memory in rats or
mice.
The pituitary of old rats was also found less responsive to stimulation by
gonadotropin-releasing factor (GnRH), GH-releasing hormone (GHRH), thyrotropin-releasing
hormone (TSH), and corticotropin-releasing factor (ACTH). Similarly, the
pituitary of elderly humans was less responsive to GnRH and GHRH, and evidence
suggests a decline with age in target gland responses to pituitary hormones and
body tissue responses to target gland hormones -- likely of secondary importance
to faults in the hypothalamus.
Because the neuroendocrine and immune systems form a bidirectional network, and
both exhibit a functional lesseing with age, determining how each affects the
decline of the other is important. Reduced immune function appears to partly
result from lower GH and thyroid hormone secretion.
Given to old rats, GH restores thymus gland size and function. Similarly,
thyroxine elevates thymic function in old mice. The immune system's age effects
on neuroendocrine function are presently unknown,but thymic peptides may alter
hypothalamic, pituitary, and target gland hormone secretion.
Because the neuroendocrine and immune systems integrate body functions and
maintain homeostasis, we believe genomic and environmental effects in aging are
mediated through them. Others have emphasized errors in protein synthesis,
increases in "free radicals" with resulting cell damage, cells failing to divide
or function due to loss of a generic program,etc.
No single theory is likely to explain all aspects of aging. The neuroendocrine
approach, although relatively recent, has provided knowledge and insight into
the causes of aging declines, and has suggested interventions that may inhibit
or reverse them and perhaps lengthen life.
* Dr. Meites, who died in 2005 at age 91, was a pioneering neuroendocrinologist
and professor of physiology at Michigan. His full article, "Remembrance:
Neuroendocrinology and Aging: A Perspective," was published in Endocrinology,
1992, 130:3107-3108.