Lifespan
Project Launched
by Richard Weindruch and Stephen R. Spindler
Page 1 of 4
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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