The hypothalamus controls the vegetative functions of the body which are necessary to sustain life. The classical methods of studying hypothalamic regulatory functions are electric stimulation of specific hypothalamic areas and electrolytic lesions in these regions. Calorie restriction has been found to depress most pituitary functions as shown by decrements in serum levels of growth hormone, prolactin, follicle stimulating hormone, luteinizing hormone, and thyroid stimulating hormone. If aging is a regulated process related to growth and development then the site of control is likely to be in the hypothalamic-pituitary complex and associated suprahy-pothalamic areas. B. M. Mitruka et al. have specified certain criteria for the choice of animals in gerontological research. Removal of the pituitary by the intra-aural technique of R. Koyama can be achieved easily in the rat, but is more difficult in the hamster because the pituitary is smaller, flatter, and possesses lateral projections.

Australasian Journal on AgeingVolume 30, Issue 4 p. 173-174 The changing face of ageing research and practice in Australia over the last 50 years Arthur V Everitt, Arthur V Everitt Centre for Education and Research on Ageing, ANZAC Medical Research Institute, Concord Hospital, The University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorDavid G Le Couteur, David G Le Couteur Centre for Education and Research on Ageing, ANZAC Medical Research Institute, Concord Hospital, The University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorHal Kendig, Hal Kendig Centre for Education and Research on Ageing, ANZAC Medical Research Institute, Concord Hospital, The University of Sydney; and Ageing, Work and Health Research Unit, Faculty of Health Sciences, The University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author Arthur V Everitt, Arthur V Everitt Centre for Education and Research on Ageing, ANZAC Medical Research Institute, Concord Hospital, The University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorDavid G Le Couteur, David G Le Couteur Centre for Education and Research on Ageing, ANZAC Medical Research Institute, Concord Hospital, The University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorHal Kendig, Hal Kendig Centre for Education and Research on Ageing, ANZAC Medical Research Institute, Concord Hospital, The University of Sydney; and Ageing, Work and Health Research Unit, Faculty of Health Sciences, The University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this author First published: 16 December 2011 https://doi.org/10.1111/j.1741-6612.2011.00575.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume30, Issue4December 2011Pages 173-174 RelatedInformation

The liver undergoes changes in structure and function in old age. There are age-related changes in liver mass, blood flow and hepatocyte and sinusoidal cell morphology. These changes are associated with significant impairment of many hepatic metabolic and detoxification activities. This has implications for systemic aging and age-related disease. For example the age-related impairment of the hepatic metabolism of lipoproteins predisposes to cardiovascular disease. The effects of caloric restriction in the liver are beneficial in terms of ameliorating many of deleterious phenotypic effects of ageing, but from the mechanistic point of view, caloric restriction does not just simply reverse or delay age-related cellular changes. Instead caloric restriction appears to act via discrete cellular mechanisms such as sirtuin pathways that impact cellular bioenergetics, apoptosis and other cellular functions. The liver has as a pivotal coordinating role when dietary intake is reduced, therefore many of the effects of caloric restriction are mediated by the liver.

Many human beings are now overeating and becoming overweight. Long-term studies in the laboratory rat show that 40% food or calorie restriction (CR) without malnutrition retards primary aging, delays the onset of age-related diseases and extends life by 20–50%. No life-long CR-survival studies exist in humans. However, Okinawans on 40% CR for half their adult life live 4 years longer than Americans. Overeating leading to obesity in middle age reduces life expectancy by up to 13 years. Overweight increases mortality from cardiovascular disease, diabetes and cancer. There is no doubt that reducing food intake by 20% over 6 years in healthy middle-aged subjects reduces the risk factors for cardiovascular disease and diabetes. Several studies have shown that low levels of cardiovascular and diabetic risk factors in middle age increase life expectancy by 5–10 years. An alternative to CR is a healthy lifestyle of consuming a prudent diet (high in fruit, vegetables, whole grains and fish), maintaining a normal body weight, performing daily physical exercise and not smoking which leads to a 55% reduction in all-cause mortality over 24 years. During the twentieth century life expectancy at birth in developed countries increased by 28 years due mainly to medical advances in reducing infant, maternal and later-life mortality, plus better nutrition. Thus life extension was not secondary to reduced food intake, which actually increased leading to overweight and obesity in about 50% of adults by early twenty first century. On present evidence it is likely that long-term CR with a healthy lifestyle to prevent overweight and obesity would add only about 5–10 years to human survival. Food restriction is not recommended in old age.

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 Willebrand's factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.

: 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.

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.

Reducing food intake in lower animals such as the rat decreases body weight, retards many aging processes, delays the onset of most diseases of old age, and prolongs life.A number of clinical trials of food restriction in healthy adult human subjects running over 2-15 years show significant reductions in body weight, blood cholesterol, blood glucose, and blood pressure, which are risk factors for the development of cardiovascular disease and diabetes.Lifestyle interventions that lower energy balance by reducing body weight such as physical exercise can also delay the development of diabetes and cardiovascular disease.In general, clinical trials are suggesting that diets high in calories or fat along with overweight are associated with increased risk for cardiovascular disease, type 2 diabetes, some cancers, and dementia.There is a growing literature indicating that specific dietary constituents are able to influence the development of age-related diseases, including certain fats (trans fatty acids, saturated, and polyunsaturated fats) and cholesterol for cardiovascular disease, glycemic index and fiber for diabetes, fruits and vegetables for cardiovascular disease, and calcium and vitamin D for osteoporosis and bone fracture.In addition, there are dietary compounds from different functional foods, herbs, and neutraceuticals such as ginseng, nuts, grains, and polyphenols that may affect the development of age-related diseases.Long-term prospective clinical trials will be needed to confirm these diet-disease relationships.On the basis of current research, the best diet to delay age-related disease onset is one low in calories and saturated fat and high in wholegrain cereals, legumes, fruits and vegetables, and which maintains a lean body weight.Such a diet should become a key component of healthy aging, delaying agerelated diseases and perhaps intervening in the aging process itself.Furthermore, there are studies suggesting that nutrition in childhood and even in the fetus may influence the later development of aging diseases and lifespan.

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.

Reducing the intake of food in rodents inhibits body growth, retards most physiological ageing processes, delays the onset of pathology and prolongs life. Food restriction (FR) reduces pituitary hormone secretion and in consequence has been called 'functional hypophysectomy'. Direct life-long comparisons in the rat showed that hypophysectomy (HYP) (a complete absence of pituitary hormones) has a greater anti-ageing action than FR (a partial lack of pituitary hormones) on collagen, kidney and muscle. This suggests that pituitary hormones accelerate ageing. Recent American research on genetic variants of the mouse indicates that pituitary growth hormone (GH) may accelerate ageing and shorten life. Both the Snell and Ames dwarf mice have a deficiency of pituitary GH and live 50% longer than normal mice. The Snell dwarf mouse has retarded ageing of both collagen and immune functions. The Ames dwarf mouse has high antioxidant enzyme activities in liver and kidney. A transgenic human GH mouse is short lived, has a low activity of antioxidant enzymes in liver and kidney and an early development of disease in these organs. It is postulated that FR by reducing the secretion of pituitary hormones, such as GH, diminishes the oxidative damage of certain tissues, thereby delaying the development of age-related diseases in these tissues and by this means extends life.

Long-term food restriction is known to inhibit development and aging in the rat. These actions may be mediated by the pineal hormone, melatonin, whose secretion is increased by food restriction. This mechanism was investigated by studying the effects of pinealectomy in ad libitum fed and food restricted rats of both sexes living under normal conditions of temperature (23 degrees C) and lighting (12 h light:12 h dark cycle) over a period of 400 days. Pinealectomies were performed at the age of 5 days. Pinealectomy did not affect the amount of food eaten per day. Vaginal opening occurred at age 35 days in ad libitum fed female rats and was delayed to 49 days (P < 0.001) in rats whose food intake was restricted by 35%, but only to 41 days (P < 0.001) if food restricted (FR) rats were pinealectomized (Px). The inhibitory effect of food restriction on body growth and tail tendon collagen fibre aging was the same in both intact and pinealectomized rats. At the conclusion of the study in middle age at 400 days, plasma melatonin levels 4 h into the dark cycle were higher in food restricted than in ad libitum fed rats (P = 0.015). This study provides evidence for a role of the pineal in mediating the inhibitory action of food restriction on vaginal opening, but not on body growth or collagen aging in tail tendon up to middle age.

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.

Two groups of aged rats, a dietary restricted group fed approximately 10 g per day from 6 weeks of age and a group fed ad lib throughout their life span, were compared with a young adult group on an 8-arm radial maze and a flavor memory task. The young adult displayed efficient performance on the radial-arm maze within the 15 day test period. In contrast, both aged groups exhibited significantly poorer performance in the maze in comparison with the young adult group neither aged group differed from chance at the end of the 15 days. The flavor memory task required the animals to consume a novel flavor. Their loss of neophobia, as indexed by their subsequent consumption, was then taken as an indication of the extent to which they remembered the novel flavor and its effects. The young adult group lost their neophobia more rapidly than either of the aged groups, which did not appear to differ from each other. Taken together, this pattern of results indicates that dietary restriction does not protect animals from the memory loss observed in aged animals.

Journal Article Minireview: Aging and Anti-Aging Effects of Hormones Get access Arthur Everitt, Arthur Everitt 1University of SydneyAustralia Search for other works by this author on: Oxford Academic PubMed Google Scholar Joseph Meites Joseph Meites 2Department of Physiology, Michigan State University Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Gerontology, Volume 44, Issue 6, November 1989, Pages B139–B147, https://doi.org/10.1093/geronj/44.6.B139 Published: 01 November 1989 Article history Received: 16 January 1989 Accepted: 18 May 1989 Published: 01 November 1989

ラットの老化の速度は, 90日齢を過ぎたところで食餌摂取量を制限したり, 下垂体を切除したりすることによって遅らせることができる。これら2つの処置は, ラットの尾の腱のコラーゲン繊維の老化を遅らせ, 腎糸球体毛細血管の基底膜の肥厚を阻止する。また加齢に伴って発症する疾患, たとえば腎疾患, 後肢の麻痺, 腫瘍の発症を阻止する。下垂体切除は食餌摂取量を低下させるが, その抗老化作用は, この処置をうけたラットと摂食量を同じにした場合に, 無処置のラットにみられる食餌制限の効果よりも大きい。最長寿命は, 無処置の雄ウイスター系ラットでは1,201日であったが, 下垂体切除ラットでは1,335日に, 食餌制限ラットでは1,525日に延長した。多くの下垂体ホルモン, 甲状腺ホルモン, 副腎皮質ホルモン, 精巣ホルモンは幾つかの組織の老化の速度に影響することが示されている。コラーゲンの老化の速度は, 主に食餌のエネルギー含量によって決定されるが, 加齢に伴う腎疾患の発症はエネルギーとたん白質両者の摂取量によって影響される。まだ仮説の域を出ないが, 脳の中枢, たとえば視床下部が, 食餌摂取と下垂体ホルモンの分泌の変化を通して, 老化の速度と加齢に伴う疾病の発症をコントロールしていることが考えられる。