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.