AGING AND CALORIC RESTRICTION: A BRIEF INTRODUCTION
Aging and death are prominent sources of concern for individuals of North America (Neimeyer 2004). It is not surprising that longevity and immortality have pervaded almost every culture at some point in time. The ancient Egyptians believed that preserving the body of the deceased would lead to preservation of the physical form in an after-life. More recently, the arts of western culture have addressed the cost of immortality in a fantastical fashion, for example, in Bram Stoker’s Dracula and JRR Tolkien’s Lord of the Rings. The signs of normal aging, especially through the later decades of one’s life are clearly visible in many ways. Obvious physical changes include whitening of hair, loss of tone of facial muscle and skin (wrinkles), decreased muscle tone and mass, and loss of mobility/increased rigidity to name but a few examples. The reasons why these changes occur are not well understood.
The effects of dietary restriction on longevity were first described in a spider by W. Jones as early as 1884 (Jones, 1884). Dr. Jones reported that a spider deprived of food was able to live over 200 days with no visible physical changes. Since Dr. Jones` initial observation, more thorough research has revealed that dietary restriction is able to extend the lifespan of spiders fed relatively lower amounts of flies than spiders fed relatively more flies (Austad 1989). At the time, these were interesting results, but these studies elicited a need to investigate whether longevity mediated by dietary restriction was a phenomenon shared by more advanced organisms. Subsequent research aimed at mammals revealed that rats and mice also live longer on calorie-restricted diets (Fernandes 1976; McCay 1989). The next step was to evaluate whether primates could experience life-preserving effects due to caloric restriction. Indeed, there is some preliminary evidence to suggest that this is the case as well (Lane, 2001). The contributions of caloric restriction to human longevity have not been evaluated for a couple of reasons. First, one must consider that in a human based trial, a proper control group would be very difficult to establish. Controls are necessary for comparison with a treatment group, and are ideally identical to constituents of the treatment group minus the treatment or manipulation. Even if one were to eliminate the contribution of environment to differences between two humans by exposing them to the identical environment since birth, there still remains the contribution of genes since each of us is genetically unique. To circumvent this, one could use identical twins in the study, however, concerns about ethics would arise. Restricting one of the twins` diet to verify whether caloric restriction mediates increases in lifespan while allowing the other to eat to satiation, and having prior knowledge that other mammals will live longer under calorie restricted diets would raise ethical alarms in the parents, the twins, and the scientific community at large.
Increasing an organism’s lifespan requires that the body’s systems that maintain the organism’s viability need to function longer. That is, an organism’s life span is inextricably linked to the cells and tissue that make it breathe and live. Thus, one would expect to find that these organ systems are better preserved at the same age in organisms whose longevity has been extended by caloric restriction. One of the most visible signs of normal aging in the elderly is muscle wasting. Sarcopenia (“loss of flesh”, from Greek) is the loss of muscle strength, mass and muscle quality due to normal aging (Doherty, 2003). Though the mechanisms underlying sarcopenia have not been defined, studies suggest that sarcopenia may be attenuated by caloric restriction. In fact, several recent studies have examined the effects of caloric restriction on aging muscle (McKiernan 2004; Hepple 2005; Phillips 2005). These studies have shown that the amount of muscle fibers and the ability of muscle to utilize oxygen are significantly more preserved in rats that have been calorie-restricted in young adulthood or continuously throughout life. In addition, calorie-restricted rats also appear to experience significantly less muscle cell death. These findings are promising, and suggest that caloric restriction may promote attenuation of aging-related processes, such as sarcopenia.
In addition to longevity, perhaps by protection from natural aging processes, caloric restriction has also been used in animals to evaluate its effect on age-related diseases. Age is a risk factor for several diseases including many types of cancer, osteoporosis, atherosclerosis and neurological diseases leading to dementia, including Alzheimer’s disease and Parkinson’s disease. Though age is a very general term to be used as a risk factor, some of the underlying processes that occur during aging explain the use of “age“ as a risk factor. For example, age is a risk factor for the development of atherosclerosis, the hardening of blood vessels (Insull, 2009). Hardening of blood vessels forces the heart to pump harder to deliver blood through the hardened walls of these blood vessels which normally exhibit much more elasticity. Since the heart has to pump harder, there is an elevated risk of developing heart failure in this condition. Atherosclerosis can also affect the volume of blood reaching the brain if it occurs in blood vessels in the brain. Since blood delivers oxygen to tissues, this can potentially result in lower levels of oxygen delivery (hypoxia) to the brain. Hypoxia has also been reported to increase the development of AD (Sun, 2006).
Age is a risk factor for various types of cancers, including but not limited to colorectal, lung, breast and prostate cancers (Hayat, 2007). The incidence of these cancers is projected to reach over 900,000 cases by the year 2010 (Hayat 2007). Survival rates of some of these cancers can be very low. People with lung cancer have an observed 5-year survival rate of 11% and those with colorectal cancer have a 5-year survival rate of 46% (Hayat 2007). Research has shown that caloric restriction can reduce the occurrence of tumours induced by radiation or chemicals in mice (Yoshida 1997; Pearson 2008) of those that are transplanted into rats (Rous 1914) and of those that occur spontaneously (Tannenbaum 1949) in mice.
The most common age-related neurological disorders leading to dementia are Alzheimer’s and Parkinson’s disease (AD and PD, respectively) (Nussbaum, 2003). AD pathology is primarily comprised of protein aggregates (plaques) in the extracellular space in the brain, ie the space between neurons. It has been shown that these plaque deposits are toxic to neurons and neuronal loss is a major consequence of AD (Yankner 1990). Studies have shown that caloric restriction can retard the development of plaques and memory deficits associated with AD in mice genetically engineered to develop AD (Wang 2005; Qin 2006; Qin 2008). Although the underlying mechanisms are not understood, these results have been substantiated by different laboratories. Research has shown that caloric restriction can significantly reduce PD symptoms in Rhesus monkeys chemically induced to present with symptoms of PD (Maswood 2004).
One should exercise caution when interpreting results from studies claiming caloric restriction is a means to combat age-related diseases. Notably, the papers referred to here which are concerned with AD and PD, do not account for the possibility that these diseases would still manifest themselves through the later years of the calorie restricted animals. Take, for example, the mice genetically engineered to suffer AD. Normally, mice will never develop AD pathology. However, mice can be genetically modified to express human genes (transgenic mice) which encode proteins that will produce AD pathology ie plaques. In the calorie restriction studies, researchers have to sacrifice both non-calorie restricted mice and calorie-restricted mice at the same time to negate effects of age on AD pathogenesis. By doing this, they are supposedly controlling the experiment in a way that only the effect of caloric restriction on plaque formation is being assessed at the time the animals are sacrificed and the brains examined for features of AD. Suppose, however, that the calorie-restricted transgenic mice also live longer. It is impossible to know for sure, since the authors had to sacrifice both groups of mice at the same time. Thus, caloric restriction in these paradigms does not address whether AD will still occur later in life. It is likely that the calorie-restricted mice will still develop AD pathology because they are genetically designed for this to occur. The results of these studies imply that AD may be delayed, but they do not support the hypothesis that calorie-restriction has a direct or curative effect with respect to AD. There are forms of AD that can occur much earlier in one’s life (age 40) than normal (over the age of 65) (Mullan, 1992). These are genetic forms of AD in which there are mutations in genes that are inherited from parent to child. AD transgenic mice used in the aforementioned studies carry mutations in the same genes (ie the Swedish family mutation) (Sturchler-Pierrat 1997). Since caloric restriction delays the pathogenesis of AD in transgenic mice carrying gene mutations for the early onset form of AD, caloric restriction may delay the development of early onset AD.
Caloric restriction has been touted as an effective, safe and noninvasive way to produce anti-aging effects as detailed above. In addition, it has no associated cost and is really a preventative measure available for anyone to undertake. Comparing this with expensive pharmaceuticals or surgical procedures at the time of necessary treatment, caloric restriction may represent a remarkable opportunity for preventative treatment. However, research into caloric restriction makes an assumption that is somewhat troubling. It is assumed that one’s diet is already rich enough in caloric intake so that it may be reduced by 30 to 40%. This would not be a problem for most people in Canada, the U.S. and other developed countries. Beyond these countries, however, there are many countries in which a significant portion of the population does not have the luxury of being able to reduce their caloric intake due to either preexisting conditions of or subsequent development of malnutrition and starvation. Unfortunately, caloric restriction is essentially only available for those that are fortunate to be living in societies that are conducive for an individual to experience old age, age-related diseases and for those that can effectively restrict their caloric intake without compromising proper nutrition.
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