W.D. Denckla, A.V. Everitt, Hypophysectomy, & Aging

Also see:
Removal of the Pituitary: Slows Aging and Hardening of Collagen
“Normal” TSH: Marker for Increased Risk of Fatal Coronary Heart Disease
Inflammatory TSH
Growth Hormone and Edema
Protect the Mitochondria
Metabolism, Brain Size, and Lifespan in Mammals
PUFA Accumulation & Aging
Calorie Restriction, PUFA, and Aging
PUFA, Aging, Cytochrome Oxidase, and Cardiolipin
Denckla’s Death Hormone by Danny Roddy

Quotes by Ray Peat, PhD:
“When W. Donner Denckla demonstrated that the removal of an animal’s pituitary (or, in the case of an octopus, its equivalent optic gland) radically extended the animal’s life span, he proposed the existence of a death hormone in the pituitary gland.”

“The “little mouse,” and the experiments of Denckla and Everitt, show that a simple growth hormone deficiency or lack of pituitary function can double the life span: Intervention in the many other self-stimulating excitatory pathways can produce additional retardation of the aging process, acting at many levels, from from the extracellular matrix to the brain.”

“W.D. Denckla discovered that the pituitary hormones are in some way able to accelerate the process of aging. They block the actions of thyroid hormone, decreasing the ability to consume oxygen and produce energy. The diabetes-like state that sets in at puberty involves the relative inability to metabolize glucose, which is an oxygen-efficient energy source, and a shift to fat oxidation, in which more free radicals are produced, and in which mitochondrial function is depressed. Diabetics, even though it is supposedly an inability of their cells to absorb glucose that defines their disease, habitually waste glucose, producing lactic acid even when they aren’t “stressed” or exerting themselves enough to account for this seemingly anaerobic metabolism. It was noticing phenomena of this sort, occurring in a great variety of animal species, in different phyla, that led Denckla to search for what he called DECO (decreasing consumption of oxygen) or “the death hormone.” (Vladimir DiIman noticed a similar cluster of events, but he consistently interpreted everything in terms of a great genetic program, and he offered no solution beyond a mechanistic treatment of the symptoms.)

Simply increasing the amount of free fatty acids in the blood will act like DECO or “the death hormone,” but growth hormone has more specific metabolic effects than simply increasing our cells’ exposure to fatty acids. The hormone creates a bias toward oxidizing of the most unsaturated fatty acids (Clejan and Schulz), in a process that appears to specifically waste energy. Growth hormone plays an important role in puberty, influencing ovarian function, for example.

Removing animals’ pituitaries, Denckla found that their aging was drastically slowed. He tried to isolate the death hormone from pituitary extracts. He concluded that it wasn’t prolactin, although prolactin had some’of its properties. In the last publication of his that I know of on that subject, he reported that he was unable to isolate the death hormone, but that it was “in the prolactin fraction.” Since rats have at least 14 different peptides in their prolactin family, not counting the multitude of modifications that can occur depending on the exact conditions of secretion, it isn’t surprising that isolating a single factor with exactly the properties of the chronically functioning aging pituitary hasn’t been successful.

Denckla’s experiments are reminiscent of many others that have identified changes in pituitary
function as driving forces in aging and degenerative diseases.

Menopause, for example, is the result of overactivity of the pituitary gonatropins, resulting from the cumulatively toxic effects of estrogen in the hypothalamus.

A.V. Everitt, in his book on the hypothalamus and pituitary in aging, reported on studies in which estrogen caused connective tissues to lose their elasticity, and in which progesterone seemed to be an antiestrogenic longevity factor. Later, he did a series of experiments that were very similar to Denckla’s, in which removal of the pituitary slowed the aging process. Several of his experiments strongly pointed to the prolactin- growth hormone family as the aging factors. Removal of the pituitary caused retardation of aging similar to food restriction. These pituitary hormones, especially prolactin, are very responsive to food intake, and the growth hormone is involved in the connective tissue and kidney changes that occur in diabetes and aging.”

“While Arthur Everitt, Verzar, and others were studying the effects of the rat’s pituitary (and other glands) on collagen, W. D. Denckla investigated the effects of reproductive hormones and pituitary removal in a wide variety of animals, including fish and mollusks. He had noticed that reproduction in various species (e.g., salmon) was quickly followed by rapid aging and death. Removing the pituitary gland (or its equivalent) and providing thyroid hormone, he found that animals lacking the pituitary lived much longer than intact animals, and maintained a high metabolic rate. Making extracts of pituitary glands, he found a fraction (closely related to prolactin and growth hormone) that suppressed tissue oxygen consumption, and accelerated the degenerative changes of aging…A high level of respiratory energy production that characterizes young life is needed for tissue renewal. The accumulation of factors that impair mitochondrial respiration leads to increasing production of stress factors, that are needed for survival when the organism isn’t able to simply produce energetic new tissue as needed. Continually resorting to these substances progressively reshapes the organism, but the investment in short-term survival, without eliminating the problematic factors, tends to exacerbate the basic energy problem. This seems to be the reason that Denckla’s animals, deprived of their pituitary glands, but provided with thyroid hormone, lived so long: they weren’t able to mobilize the multiple defenses that reduce the mitochondria’s respiratory energy production.”

“W.D. Denckla’s version of programmed aging proposed that the pituitary gland was the agent of this programmed aging. He based his idea on the observation that when animals were kept on a semi-starvation diet, starting before puberty, their puberty was delayed and they lived longer than normal, and on later studies showed that when animals’ pituitary glands were removed before puberty, they lived much longer than normal, and all of their tissues and systems aged at a much slower rate. The implication was that if the gland is present and causes aging, its evolutionary purpose is to cause aging, as well as the other process such a reproduction.

The particular function that Denckla focused on as an index of aging was oxygen consumption, which decreases by more than 70% between puberty and old age. He showed that the decrease of oxygen consumption was much less when the pituitary gland was removed, if the animal was given the amount of thyroid hormone that it would normally produce. He found fairly specific pituitary extracts that decreased oxygen consumption, inhibiting the effects of the thyroid hormone, but he never identified a particular pituitary hormone as the antirespiratory aging hormone, or the mechanism responsible for the extract’s effects.”

“On the level of the whole organism, stress causes overactivity of the pituitary, and removal of the pituitary extends life, and retards the hardening of the extracellular connective material (Everitt, et al., 1983).”

“A.V. Everitt’s book on the pituitary and aging mentions some studies that relate to progesterone and aging. Uterine collagen aging, which increases under the influence of estrogen, is lowest in the old rodents that have been bred the most often, and this is probably partly the result of progesterone’s action on collagenase and fibroblasts, as well as its ability to displace estrogen from the tissues. Leo Loeb showed that excess estrogen and aging both produced similar increases in collagen. Alejandro Lipschutz found that chronic estrogen treatment produced fibrosis of practically all tissues, and that cancer later developed in those fibrotic tissues. Then he tested various steroids, and found that progesterone had the strongest antifibromatogenic action, and that pregnenolone was next in effectiveness. (Brief intermittent exposures to estrogen didn’t produce the harmful effects, and now it’s known that progesterone decreases the tissues’ retention of estrogen.) Lipschutz’ 1950 book on steroid hormones and tumors summarizes his work.”

“If your thyroid is working efficiently, your pituitary doesn’t have much to do and you’re not likely to get a pituitary tumor, your adrenals don’t have much to do, and your ovaries don’t get over stimulated. The other glands have an easy job when your thyroid is working right. If your thyroid gets interfered with, you have to rev up your adrenals and your pituitary becomes commander in chief and tells everyone what to do.”

J Clin Invest. 1974 February; 53(2): 572–581.
Role of the pituitary and thyroid glands in the decline of minimal O2 consumption with age.
W D Denckla
Resting O2 consumption rate (BMR) or minimal O2 consumption rate (MOC) declines with age. Data are presented that suggest that a newly described function of the pituitary may be responsible for a considerable part of the total 75% decline in the MOC with age. The new function appears to decrease the responsiveness of peripheral tissues to thyroid hormones. Response curves to injected thyroxine indicated that immature rats were three times more responsive to thyroxine than adult rats. All the major endocrine ablations were performed in this and earlier work, and only pituitary ablation (a) restored in adults part of the responsiveness to thyroxine found in immature rats and (b) arrested the normal age-associated decrease in responsiveness to thyroxine in immature rats. Bovine pituitary extracts were found that decreased the responsiveness of immature rats to thyroxine. Experiments with the new pituitary function suggested a possible endocrine mechanism to explain why partial starvation doubled the lifespan for rats only when started before puberty.

Fed Proc. 1975 Jan;34(1):96.
Pituitary inhibitor of thyroxine.
Denckla WD.
A description is given of a new pituitary function. It is suggested that the new function acts to decrease gradually the responsiveness of the peripheral tissues to thyroid hormones throughout life. It is suggested that the postulated relative hypothyroidism of older animals might contribute to their loss of viability.

Life Sci. 1975 Jan 1;16(1):31-44.
A time to die.
Denckla WD.
A theory of dying is proposed. The evidence and arguments are presented which suggest that the lifespan of mammals is regulated by a biological clock which, in turn acts on the endocrines to produce failure of two specific target tissues, the immune and circulatory systems. Failure of these two systems can account for the similarity among mammals of the final diseases recorded at autopsy. A newly described pituitary factor is used as an example of a possible endocrine mechanism by which the body might control its own demise.

Mech Ageing Dev. 1983 Jul-Aug;22(3-4):233-51.
The anti-aging action of hypophysectomy in hypothalamic obese rats: effects on collagen aging, age-associated proteinuria development and renal histopathology.
Everitt AV, Wyndham JR, Barnard DL.
Hypophysectomy in young male Wistar rats aged 70 days, like food restriction begun at the same age, retarded the life-long rate of collagen aging in tail tendon fibres and inhibited the development of age-associated proteinuria and renal histopathology. Hypothalamic lesions which increased the food intake of hypophysectomized rats from 7 g to 15 g/day and produced obesity did not alter the rate of either collagen aging or proteinuria development, nor reduce life expectancy, but increased the incidence of abnormal glomeruli. In the intact rats elevation of food intake from 7 g to 15 g/day increased the rate of proteinuria development, but did not affect the rate of collagen aging. Hypophysectomy was found to have a greater anti-collagen aging effect than food restriction, when food intakes were the same in both groups. These studies suggest a pituitary-hormonal effect on collagen aging and a food-pituitary-hormone-mediated effect on the development of age-associated proteinuria.

Arch Gerontol Geriatr. 1985 Jul;4(2):101-15.
Skeletal muscle aging in the hind limb of the old male Wistar rat: inhibitory effect of hypophysectomy and food restriction.
Everitt AV, Shorey CD, Ficarra MA.
By age 1 100 days (37 mth) hind leg paralysis was found in 50% of ad libitum fed (control) male Wistar rats, but only 10% of food restricted rats and no hypophysectomized rats of that age had this disease. Gastrocnemius muscle weight declined at a faster rate than whole body weight in old ad libitum fed rats but not in old hypophysectomized or food restricted rats. Light microscopic and ultrastructural changes were studied in the muscles of the hind limbs of 11 control, 5 food-restricted and 5 hypophysectomized rats aged 805 to 1 307 days. Light microscopic changes in muscles involved progressive degeneration demonstrated by the accumulation of adipocytes and degenerative inclusion bodies. The main ultrastructural changes were associated with myofibrillar breakdown. In addition there was thickening of the basal lamina around blood capillaries. However, muscle from hypophysectomized and food restricted rats of the same age range as controls possessed normal morphology with reduced thickening of the capillary basal lamina.

J Gerontol. 1989 Nov;44(6):B139-47.
Aging and anti-aging effects of hormones.
Everitt A, Meites J.
Hormones can promote or inhibit aging depending on the experimental conditions employed. The aging effects of hormones are demonstrated by reducing hormone secretion by hypophysectomy or chronic underfeeding in young or mature rats. These result in depressing whole body metabolism, growth, body temperature and blood glucose levels, heart rate and vital capacity, gene expression, etc., but delaying aging of tissues, suppressing development of pathology and tumors, and, in underfed rats, prolonging life span. The anti-aging effects of hormones are demonstrated by elevating hormone levels in old rats whose hormones have declined as a result of dysfunctions that develop in the neuroendocrine system with age. An increase of hormones in these rats promotes gene expression, elevates protein synthesis, and enhances metabolism, growth, and function of stimulated organs and tissues.

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