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

Life extension by calorie restriction in humans.

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.

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.

Differences in muscle fiber growth in slow-twitch muscles of the forelimb and hindlimb of the rat: role of the pituitary and food intake.

This investigation tested the hypothesis that differences in the growth of fore- and hindlimb muscles in the rat are regulated by the pituitary and food intake. Using morphometric techniques, the growth of muscle fibers was compared in two slow-twitch muscles, the flexor carpi ulnaris (FCU) of the forelimb, and the soleus of the hindlimb, in male Wistar rats fed ad libitum, food restricted (FR) or hypophysectomized (hypox) from age 60 days. Growth was defined as an increase in fiber diameter and/or type 1 fiber percentage. The soleus had larger diameter fibers than the FCU in controls and FR, but not hypox rats. The growth in diameter, between 60 and 180 days, of both types 1 and 2 fibers in the soleus and type 2 fibers in the FCU was inhibited by hypox and, to a lesser extent, FR. Neither type 1 fiber diameter nor percentage of type 1 fibers in the FCU increased with age nor was it affected by hypox or FR. The percentage of type 1 fibers was higher in the soleus than the FCU and was further increased in the soleus of hypox rats. Food restriction produced a smaller rise than hypox in type 1 fiber percentage in the soleus. Thus, differences in fore- and hindlimb muscle fiber growth are modulated by pituitary hormones and, to a lesser extent, by food intake.

Dietary approaches that delay age-related diseases.

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 age-related 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.

Food restriction, pituitary hormones and ageing.

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.