Arthur V. Everitt

The effects of hypophysectomy and continuous food restriction, begun at ages 70 and 400 days, on collagen aging, proteinuria, incidence of pathology and longevity in the male rat.

Hypophysectomy in young male Wistar rats aged 70 days, followed by cortisone acetate replacement therapy throughout life, retarded the rate of aging of tail tendon collagen fibres, inhibited the development of certain diseases of old age (renal disease, cardiac enlargement, hind limb paralysis, and various endocrine and non-endocrine tumors) and significantly prolonged the duration of life. Almost identical anti-aging effects were obtained by lowering the food intake of intact rats to that of hypophysectomized rats, from age 70 days until death. Hypophysectomy in middle age, at 400 days, even with cortisone acetate replacement therapy, produced a sharp increase in the mortality rate; the surviving rats exhibited significantly reduced aging of collagen fibres and of the kidney as measured by protein excretion. Food restriction begun at 400 days also inhibited renal aging, but had no demonstrable effect on collagen aging during the first 100 days. These studies suggest that procedures such as hypophysectomy and food restriction do not switch off an aging mechanism in youth but probably exert a continuing inhibitory influence on certain aging processes throughout life.

The Neuroendocrine System and Aging

The course of aging in most endocrine glands is moderately well documented in man, but is somewhat less understood in the rat. With increasing age in man there is a significant decline in the secretion of hormones by the thyroid, adrenal cortex, testis and ovary; pituitary growth hormone falls but gonadotrophins rise. In man decline in the secretion of testicular and ovarian steroids appears to be due to primary age changes in the gonads, whereas in the rat age changes in the central regulatory mechanisms appear to be responsible for gonadal aging. Such findings have led to the formulation of a number of neuroendocrine theories of aging, which explain peripheral aging on the basis of an aging clock in the brain, primary age changes in neurotransmitter metabolism, age changes in the hypothalamus, pituitary and thyroid, or in the regulatory actions of these glands.

The hypothalamic-pituitary control of ageing and age-related pathology

Abstract The pituitary gland is essential for a normal life span. Certain pituitary hormones like ACTH (by mediation of the adrenocortical hormones) and the posterior pituitary hormones maintain or prolong the life of hypophysectomised or old rats. These hormons are called life-maintaining hormones. Hypophysectomy retards physiological ageing processes in collagen, bone, kidney and ovary. Most of the hormones secreted by the anterior pituitary, the thyroid, the adrenal cortex and the gonads have been shown to accelerate some aspects of physiological ageing or to increase the incidence of age-related pathology in the kidney of cardiovascular system. Hormones which promote ageing changes or age-pathology are called “ageing hormones”. Environmental influences such as stress, food supply and temperature also affect the course of ageing. The effect of these environmental factors is mediated largely through the hypothalamic-pituitary-peripheral endocrines, by altering their output of “ageing hormones”.

Life Extension by Calorie Restriction in Humans

Abstract:  Long‐term reduction in energy intake in the diet (calorie restriction [CR]) extends the life of the laboratory rat by about 25%. However, in humans there are no life‐long studies of CR, but only short‐term trials which indicate that 20% CR acting over periods of 2–6 years is associated with reduced body weight, blood pressure, blood cholesterol, and blood glucose—risk factors for the major killer diseases of cardiovascular disease and diabetes. In addition, recent research has shown that CR for 6 months is able to improve biomarkers for longevity (deep body temperature and plasma insulin) and thus should increase life expectancy. The magnitude of the life‐extension effect of CR in humans can only be estimated. The Okinawans, the longest‐lived people on earth, consume 40% fewer calories than the Americans and live only 4 years longer. Similarly, women in United States consume 25% fewer calories than men and live 5 years longer. From the survival studies of overweight and obese people, it is estimated that long‐term CR to prevent excessive weight gain could add only 3–13 years to life expectancy. Thus the effects of CR on human life extension are probably much smaller than those achieved by medical and public health interventions, which have extended life by about 30 years in developed countries in the 20th century, by greatly reducing deaths from infections, accidents, and cardiovascular disease.

Calorie restriction, aging and longevity

Calorie Restriction in Different Species.- History of Caloric Restriction, Aging and Longevity.- Food Intake, Life Style, Aging and Human Longevity.- Okinawa: A Naturally Calorie Restricted Population.- Aging and the Effect of Calorie Restriction in Rhesus Monkeys.- Dietary Restriction and Aging in Drosophila Melanogaster.- Aging and Dietary Restriction: The Yeast Paradigm.- The Nutritional Geometry of Aging.- Biochemical and Metabolic Mechanisms of Calorie Restriction.- Oxidative Stress, Dietary Restriction and Aging.- Calorie Restriction Mimetics and Aging.- Will Calorie Restriction Stave Off Age-Related Brain Dysfunction, Specifically to Learning and Memory? A Review and Critique of the Rodent Literature.- The Aging Liver and the Effects of Long Term Caloric Restriction.- Food Restriction, Hormones, Genes and Aging.- Hormesis as a Mechanism for the Anti-Aging Effects of Calorie Restriction.- Calorie Restriction in the Clinical Setting.- Calorie Restriction and Obesity.- Caloric Restriction and Cardiovascular Disease.- The Effect of Caloric Restriction on Physiological, Psychological and Behavioral Outcomes in Humans: Results from CALERIE.- Calorie Restriction and Cancer: An Update.- Conclusion: Human Calorie Restriction and Anti-aging Therapy.

Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid

Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrands factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.

Skeletal muscle aging in the hind limb of the old male Wistar rat: inhibitory effect of hypophysectomy and food restriction

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.

The anti-aging action of hypophysectomy in hypothalamic obese rats: Effects on collagen aging, age-associated proteinuria development and renal histopathology

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.

Caloric restriction versus drug therapy to delay the onset of aging diseases and extend life

There are two firmly established methods of prolonging life. Calorie restriction (CR) using nutrient-rich diets to prolong life in lower animals, and life saving medications in humans to delay the development of the major diseases of middle and old age. These two approaches have different mechanisms of action. In rats, CR at 40% below ad libitum intake begun soon after weaning and continued until death, reduces body weight by about 40% and increases lifespan. There have been no lifelong CR studies performed on humans. However, in healthy adult human subjects about 20% CR over a period of 2–15 years, lowers body weight by about 20% and decreases body mass index (BMI) to about 19. This CR treatment in humans reduces blood pressure and blood cholesterol to a similar extent as the specific drugs used to delay the onset of vascular disease and so extend human life. These same drugs may act by mechanisms that overlap with some of the mechanisms of CR in retarding these pathologies and thus may have similar antiaging and life prolonging actions. Such drugs may be regarded as CR mimetics which inhibit the development of certain life shortening diseases, without the need to lower calorie intake. In developed countries, better medical care, drug therapy, vaccinations, and other public health measures have extended human life by about 30 years during the 20th century without recourse to CR, which is so effective in the rat. The percentage gain in human life expectancy during the 20th century is twice that achieved by CR in rat survival. However, rat longevity studies now use specific pathogen-free animals and start CR after weaning or later, thereby excluding deaths from infectious diseases and those associated with birth and early life. There is a need to develop CR mimetics which can delay the development of life-threatening diseases in humans. In the 21st century due to the human epidemic of overeating with a sedentary lifestyle, it may necessary to utilize CR to counter the aging effects of overweight. Since the greatest life-extending effects of CR in the rodent occur when started early in life, long-term antiaging therapy in humans should be initiated soon after maturity, when physiological systems have developed optimally.

Effects of isolation and food restriction begun at 50 days on the development of age-associated renal disease in the male Wistar rat

The development of proteinuria with increasing age was studied in three groups of male Wistar rats: ad libitum fed and isolated, ad libitum fed and group housed 6 to 8 rats per cage, and food restricted (one-third of the isolated ad libitum food intake) and isolated. Studies were begun at age 50 days and continued throughout life. Ad libitum fed rats when isolated ate more food, grew faster, had larger maximum body weights and developed proteinuria at a faster rate than those that were group housed. There was a small increase in the severity of glomerular pathology in old age. However, systolic blood pressure was not affected significantly by isolation, nor was life duration. Food restriction of isolated rats inhibited body growth, prevented the development of proteinuria, reduced the incidence of glomerular and tubular pathology in old age and prolonged life. Electron microscopic examination of the kidneys of old food-restricted rats revealed a much lower incidence of foot process retraction and spreading on the basement membrane of the glomerulus than in ad libitum fed rats. Cardiac enlargement was also prevented by long-term food restriction.