Lifespan Project Launched
by Richard Weindruch and Stephen R. Spindler
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The Goal: To Find Practical Methods of
Retarding The Aging Process
For the first time, the co-directors of The Life Extension Foundation's groundbreaking Lifespan Project discuss the newly launched, multi-year program's approaches to exploring the impact of nutrients, drugs and hormones on extending lifespan. The results may well blaze new pathways, not only in understanding how to increase longevity, but also in lending solid credibility to the emerging science of 'biogerentology.'
As Roy Walford nicely discusses in his book "Maximum Life Span," the extension of lifespan has been one of our species' oldest preoccupations and greatest dreams. Dr. Walford makes the point that, since the beginning of time, life extensionists and immortalists have been forced to deal with negative attitudes about their goals. This negativity has been expressed in various forms, including myths, literature and religious beliefs (as Walford puts it, ". . . most religions love death").
The good news is that the study of the biology of aging, sometimes called biogerontology, has now emerged as a serious and active area of scientific inquiry. It had remained a "fringe science" until relatively recent times, but this changed with the establishment of the National Institute on Aging, as part of the National Institutes of Health, in 1974. NIA's founding was a milestone event for American aging research.
Another milestone occurred on March 3, with the arrival at the animal facilities at the University of California at Riverside and the University of Wisconsin at Madison, of 300 four-week-old male mice of a particularly long-lived strain (this number ultimately will reach 1,600 mice). Their arrival launched The Lifespan Project, funded by the Life Extension Foundation to determine how nutrients, hormones and drugs now being used by life extensionists influence longevity in adult mice. We will also be testing these substances to determine their influence on certain biologic measures of the rate of aging.
The mice will be young adults at the onset of testing in August. Among the agents to be tested are alpha lipoic acid, acetyl-L-carnitine, aminoguanidine, coenzyme Q10, lycopene, melatonin, NADH, procysteine and pregnenolone. These compounds were selected on the basis of several theories of aging, discussed below.
A Funding Difficulty
Biogerontology now attracts investigators from diverse backgrounds. This is due, in part, to increased availability of funds to conduct aging research, although the funding picture is still not good enough, with only about 10 percent to 20 percent of grants submitted to the NIA actually being funded. It is extremely difficult to obtain NIA funding for research like The Lifespan Project because peer reviewers typically judge such work to be too descriptive and non-focused. Such studies are often labeled as "fishing expeditions."
A fundamental tool in aging research is the survival curve. This graphs the percentage of a population alive as a function of age. Survival curves for humans in the United States as well as laboratory mice illustrate the nature of caloric restriction, which extends maximum lifespan, and its possible ramifications.
Consider two types of survival statistics: average lifespan, meaning the average age of death for the population, and maximum lifespan, often calculated as the average age of death for the population's longest-lived 10 percent. Looking at the survival curves for persons in the U.S. in 1900, 1940, 1980 and 1988, one sees that average lifespan has increased from about 47 years in 1900 to 75 years in 1988. Yet, despite this 60-percent rise in average lifespan, maximum lifespan has increased far less (based on some analyses, it has not increased at all).
Maximum Lifespan Stagnant
The major point is, despite this century's landmark medical and public-health advances which have produced a huge increase in average lifespan, the maximum lifespan for humans-about 120 years-has yet to be extended. Nor has the species-specific maximum lifespan been convincingly extended in other mammals (with rats and mice being the usual subjects), except for caloric restriction without deficiency in the intake of essential nutrients. The increase in maximum lifespan caused by caloric restriction, and the fact that restricted rodents stay biologically "younger longer," suggest to most gerontologists that at least some basic aging processes are being decelerated by caloric restriction.
Different approaches have been used to investigate the biology of aging. Among questions asked, for example, are, why does one type of mouse, called Peromyscus, live about twice as long as another type, Mus? The same questions are posed within a species; for example, what are the biochemical and behavioral traits shared by people who live beyond 100?
Perhaps the most commonly used approach is the comparison of differently aged animals. Most such studies have compared young (but sexually mature), middle-aged, and old mice or rats for some parameter deemed important by the investigator. Another approach is to study models showing certain features of accelerated aging and to determine the genetic and biochemical reasons for this acceleration.
However, the approach that is most germane to The Lifespan Project seeks to determine if a treatment can slow the rate of aging, as evaluated by lifespan, the age of onset and incidences of the diseases of aging, and whether indicators of "biological age" are influenced by the treatment.
A number of strategies have been employed in attempts to retard the aging process in different species. Research of this type is conducted either to develop an intervention that might be applicable to humans or to make clearer the root causes of aging.
Among the strategies, lowering of core body temperature has been found to retard aging and extend lifespan in cold blooded animals. But only caloric restriction has been shown to extend species-characteristic maximum lifespan in nearly all species tested, including invertebrates, fish, and warm-blooded vertebrates such as mammals.
Caloric Restriction Features
The effect of caloric restriction on primate longevity, including the longevity of humans, has never been adequately tested. There are trials being conducted in rhesus monkeys subjected to a 30-percent reduction in caloric intake, a study which should provide relevant survivorship data in about 20 years. There are observations in humans (Kagawa, 1978; Albanes, 1990; Anderson et al., 1996) and data from physiologic alterations during caloric restriction in normal weight humans (Velthuis-te Wierik et al., 1995; Walford et al., 1992), which support the idea that humans will respond to reduced caloric intake in a manner similar to other animals.
In "The Retardation of Aging and Disease by Dietary Restriction" (Weindruch and Walford, 1988), we identified the salient features of caloric restriction. For the purposes of this article, five aspects of caloric restriction are important: Calories are most critical. The lifespan-extending effects of caloric restriction depend on calorie restriction per se. The most common level of caloric restriction investigated is about 40-percent less than average unrestricted food intake. Forty percent caloric restriction produces mice and rats of very different size and body composition than their control-fed counterparts. Even mild caloric restriction (10 to 20 percent) produces some life-extension and disease-prevention effects. The strong inverse relationship between energy intake and longevity has led co-author Richard Weindruch to favor mechanisms for caloric restriction with strong links to energy metabolism. As discussed below, a major theory in this regard is the free radical theory of aging.
Restricting fat, protein, or carbohydrates without caloric reduction does not increase the maximum lifespan of rodents. Nor does overall vitamin supplementation, the antioxidants tested to date, variations in the type of diet, dietary fat, carbohydrates or protein. Again, we refer here to maximum species-specific lifespan, not merely strain-specific lifespan. In contrast, the lifespan of short-lived strains of mice and rats can be increased by dietary manipulations other than caloric restriction, probably by influencing disease susceptibility or progression, not basic aging. However, even in these strains, caloric restriction gives by far the most impressive results.
Many Species Affected
Caloric restriction is effective in diverse species. Most caloric restriction studies have been in rats or mice. However, caloric restriction also extends lifespan in single celled protozoans, rotifers, water fleas, fruit flies, spiders and fish.Restricted animals stay biologically "younger longer." Caloric restriction in mice and rats extends biologic youth and postpones or prevents most major diseases (cancers, kidney disease, cataracts, etc.). Accordingly, the caloric-restricted rodent provides a model to study aging with minimal distortion from diseases. About 90 percent of the 300 or so age-sensitive outcomes studied stay "younger longer" in caloric restricted animals. For example, decreases in certain immune responses begin in normal mice at one year of age, but begin at two years of age in restricted mice.Caloric restriction markedly retards disease progression in short-lived mice and rats. Many mouse and rat strains are available for gerontologic studies. These can be subdivided into short-lived strains (mean lifespans less than about 15 months) and long-lived strains (mean lifespans greater than approximately 25 months). We believe that long-lived strains provide superior models and have selected one for use in The Lifespan Project.
Short-lived strains have a distinct disease profile, which results in the death of the animals prematurely, at an age considered young for the species. However, short-lived strains provide excellent models for humans who are genetically prone to certain diseases. Caloric restriction greatly retards cancers (including breast, colon, prostate, lymphoma, etc.), renal diseases, diabetes, hypertension, hyperlipidemia, lupus, and autoimmune hemolytic anemia, to name a few. These data are so convincing that disease-prone families may prove to be the source of volunteers for the first controlled clinical trials of caloric restriction.
Caloric restriction started in middle age also retards aging. This type of caloric restriction is most germane to potential human application. We found that caloric restriction that is started in middle aged mice extended maximum lifespan by 10 to 20 percent and blocked cancer development (Weindruch and Walford, 1982). This study involving two strains of mice allowed free access to food until 12 months of age, and then gradually restricted food by about 30 percent. We will soon publish results showing caloric-restricted rats studied at 17 months of age (late middle age) and again at 30 to 32 months of age show fewer signs of aging in skeletal muscles, as compared with age-matched normally fed controls (Aspnes et al., in press).
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