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The Human Life Span Is Not That Limited: The Effect of Multiple Longevity
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Article  in  The Journals of Gerontology Series A Biological Sciences and Medical Sciences · August 2004
DOI: 10.1093/gerona/59.7.B697 · Source: PubMed

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Journal of Gerontology: BIOLOGICAL SCIENCES Copyright 2004 by The Gerontological Society of America
2004, Vol. 59A, No. 7, 697–704

The Future of Aging Interventions

The Human Life Span Is Not That Limited:

The Effect of Multiple Longevity Phenotypes
Robert Arking,1 Vassily Novoseltsev,2 and Janna Novoseltseva2

1
Department of Biological Sciences, Wayne State University, Detroit, Michigan.
2
Institute of Control Sciences, Russian Academy of Sciences, Moscow.

There is an ongoing debate as to whether or not human longevity is approaching its limits. The
debate and its outcome are important since they might affect public policy. We review the
evidence presented by both schools. We add our empirical observation that there exist multiple
longevity phenotypes, each of which arises from the alteration of fundamental aging processes.
The current debate only considers two of the three known mammalian longevity phenotypes. The
overlooked phenotype is the delayed onset of senescence phenotype, which can be induced by
various interventions, including pharmaceuticals. The existence of multiple phenotypes means
that an overview of potential life expectancy outcomes for a species should be based on the
analysis of all longevity phenotypes likely to occur in that species.

expectancies if they are to plan well for the future. These

A N ongoing debate within the biogerontological
community focuses on the question as to whether or
not human longevity is approaching its limits. Theoretical
needs apply to other developed countries as well.

bases for estimating longevity limits exist but are indirect.
As a result, much of the ensuing discussion necessarily
focuses on the robustness of the approach or the in-
terpretation of the data used in the extrapolation. One
school of thought, summarized in Olshansky and Carnes (1),
and exemplified by the writings of Carnes and colleagues (2)
and Olshansky and colleagues (3,4), suggests that human
longevity is most likely approaching a statistical maximum.
Their analysis suggests that there is in fact a lower limit to
death rates, and thus an upper limit to life expectancy. A
different school, illustrated by the views of Oeppen and
Vaupel (5), contends that the entire history of estimating
human longevity limits has been a dismal failure since
almost every estimate has been falsified by events, and it is
likely that the same will happen to the few remaining
estimates.
The debate and its outcome are important since they
might affect public policy. The United States’ Social
Security program requires that the responsible officials
make forecasts of the number of future beneficiaries so as to
determine the future solvency of the program. As described
by Carnes and colleagues (2), this forecasting method has
often involved linear extrapolation of past trends in
mortality and/or life expectancy. Given the extraordinary
continued success in reducing premature mortality during
the past century, it was only to be expected that past data
would underestimate future changes, thereby raising real
concerns about the validity of future estimates. The Social
Security program as well as other public and private
programs need biologically realistic estimates of life
SUMMARY OF THE ARGUMENTS
The Oeppen–Vaupel argument rests on the fact that world
record life expectancy at birth in the developed nations has
been increasing steadily since 1840 at an overall rate of 2.5
years per decade. It must be noted that such trends have not
been observed for any single country during this time
period. Nonetheless, some countries (e.g., Japan) have had
higher yearly increases in longevity over shorter periods of
time as compared to the mean world rate. This has been due
to a multitude of continuing small improvements in various
aspects of our environment. If this trend should continue,
then a life expectancy of 100 years would be reached in
about six decades. Given the adage that the past is the best
predictor of the future, it is argued that policy makers should
‘‘. . . base their calculations on the empirical record of
mortality improvements over corresponding spans of the
past’’ (5, p. 1031; note that this is the same protocol often
used by the Social Security System). But there are different
measures of mortality improvement. Since the Carnes–
Olshansky-postulated limit to human life expectancy covers
a range of 82–97 years (more realistically perhaps 82 for
men and 88 for women) (2), and since the life expectancy
of many cohorts alive today is approaching the lower
boundaries of this life span limit, then we should expect to
see signs of a deceleration in the rate of increase of life
expectancy at birth and at age 65. This has been observed
(3). However, one might also expect to see signs of an
acceleration in the late life qx values. This is not observed,
at least in the sense that maximum longevity continues
to increase (6). Rather, what is observed is a continuing

697
698 ARKING ET AL.
deceleration of the late life qx values (6–8). Thus each
argument uses somewhat different predictions, each of
which is supported by some data. Given these contradictions
between their predictions and observation, Oeppen and
Vaupel (5) conclude that human longevity is not approach-
ing a detectable limit, should one even exist.
Carnes and Olshansky do not accept the above analysis
because it is based on the prior one-time victories over
various aspects of premature mortality. In those cases,
relatively small investments yielded large increases in life
expectancy. But these easy victories in which the life
expectancies of younger individuals have been increased
have been won already, and there is no reason to think that
comparable life expectancy increases can be obtained by
various interventions with older individuals. The difficulty
of continuing to increase the life spans of elderly persons
will ensure that the increases in life expectancy will slow
and eventually come to an end. In addition, the analysis of
50 years worth of morbidity and mortality records for
animals raised under controlled conditions at the Argonne
National Laboratories led Carnes and colleagues (9) to
conclude that the intrinsic mortality signatures of mice,
beagles, and humans were indistinguishable. This finding
led Carnes and Olshansky to the concept of a ‘‘biological
warranty period’’—that is, biological senescent processes
set a statistical limit on the length of time that humans can
survive before the increased age-related pathology load
causes their functional ability to drop below some critical
threshold. The essential aspect of the Carnes–Olshansky
analysis is that the continued extension of postreproductive
life span in humans is fundamentally contradicted by the
evolutionary theory of aging, which posits that somatic
maintenance processes should decline as reproduction draws
to a close (10,11). Much work has shown that this
theoretical relationship does occur and that it does determine
the particulars of a species’ aging processes. Thus, the
Carnes–Olshansky argument is that attributes of reproduc-
tion of humans and other species are relatively fixed
biological attributes, and if senescence is an inadvertent
byproduct of attributes of reproduction, then age-dependent
declines in physiological attributes of humans and other
species are expected. They point out that such declines can
be modified by biomedical interventions precisely because
they are not programmed. To test the relationship between
reproduction and senescence, they calculated what they term
the ‘‘effective end to reproduction’’ (EER), which occurs at
the age when 75% of the reproduction that will be ac-
complished by females has been accomplished. They used
mouse data to calculate the regression equation describing
the relationship between the EER and the ‘‘median age
at death’’ (MAD) of female mice. Assuming that humans
and mice follow the same kinetics in this case, they then
calculated that women with an EER of 32–38 years would
have a MAD of 82–97 years (Note, however, that this
procedure does not take into consideration the debate as to
whether the age at human menarche decreases and that of
human menopause increases as economic development pro-
ceeds (12–16). If it does occur, then this would indicate
that both EER and MAD may be significantly influenced
by more than one variable). Human data on the loss of tes-
tosterone in men (17) is generalized to suggest that approxi-
mately 80% of functional capacity in all systems is lost by
the age of 80 years, and further extended to suggest that
most postreproductive females are suffering from various
age-related pathologies [although a different approach
estimates an approximately 30% loss of function by age
80 (18), there is general consensus that there is a significant
loss of function by age 80 years]. They calculate that it
would take an 85% decline in all-cause mortality rates from
the 1985 level to yield a life expectancy of 50 years at age
50 (4). Such a decline is beyond our present capabilities, and
so they conclude that, ‘‘Barring major advance in the
development and use of life extending technologies or the
alteration of human aging at the molecular level, the period
of rapid increases in life expectancy in developed nations
has come to an end’’ (4, p. 637).
ANIMAL STUDIES
One fact that has emerged from the past several decades
of aging research is that aging is not simple. The work that
my colleagues and I have done on Drosophila longevity
bears this out in a manner pertinent to the current debate.
We reported that aging in our Ra strain of wild-type flies
is rather complex, being characterized by at least three
different extended longevity phenotypes, each of which was
induced by specific stimuli and had different demographic
mortality and survival profiles (19). As shown in Figure 1A,
the first longevity phenotype (Type 1) is a delayed onset of
senescence, which leads to a significant increase in both
mean and maximum life span of the experimental strain.
The second longevity phenotype (Type 2), shown in Figure
1B, is an increased early survival, which leads to
a significant increase in mean but sometimes not in
maximum life span. The third longevity phenotype (Type
3), shown in Figure 1C, is an increased later survival, which
leads to a change in the maximum (LT90) but not in the
median life spans.
Analysis of the mortality data supports these statements.
The Type 1 phenotype yields a Gompertz curve that is sig-
nificantly different from that of the control strain (Figure 2A).
Analysis of the data suggests that the Type 1 phenotype
involves a 33% reduction in the mortality rate doubling
time (MRDT) of the long-lived strain relative to the normal-
lived strain. The MRDT is a commonly used indicator of
comparative aging rates (20). However, neither the Type 2
long-lived populations (Figure 2B) nor the Type 3 long-
lived populations (Figure 2C) show any alteration in aging
rates relative to their controls.
Moreover, it should be pointed out that the same
phenotype may be induced by multiple different stimuli.
For example, the Type 1 delayed onset of senescence
phenotype may be induced in flies by (a) caloric restriction
(CR) (21), (b) temperature shifts (22), (c) the down-
regulation of the insulin-like signaling pathway (23,24),
(d) up-regulation of the antioxidant defense system (ADS)
plus altered mitochondrial properties (25), and (e) additive
effects of mechanisms (c) and (d) combined (Hwangbo and
colleagues, in preparation). These presumptive mechanisms
in flies probably exert varied specific effects, but all seem to
lead to high levels of somatic maintenance and thus to
 THE HUMAN LIFE SPAN IS NOT THAT LIMITED 699

Figure 1. A, Survival curves of the normal-lived Ra strain and of two long-

lived strains (La and 2La) sequentially derived from it by a direct selection for
delayed female fecundity. The data points represent the observed survival data,
and are based on the age-specific values obtained from two or three replicate
Figure 2. Age-specific logarithmic mortality curves and their Gompertz
cohorts consisting of at least 250 mixed sex individuals each. The Ra, La, and
approximations. See Arking and colleagues (19) for experimental details. A,
2La curves are significantly different (log-rank test ¼ 530.16, df ¼ 2, p , .0001).
Age-specific logarithmic mortality curves of the normal-lived Ra strain and of
See Arking and colleagues (19,50) for experimental details. The continuous
two long-lived strains (La and 2La). The data points and their Gompertz
lines are the Weibull approximations of the empirical data. See Arking and
approximations are presented (RaG, LaG, and 2LaG). The curves Ra and La (as
colleagues (19) for statistical details. B, Survival curves of the normal-lived Ra
well as Ra and 2La) are significantly different (p ¼ 0) whereas La and 2La strains
strain and the PQR strain selected from it by direct selection for paraquat
have no significant difference. B, Age-specific logarithmic mortality curves of
resistance. The data points represent the observed survival data, and are based on
the normal-lived Ra strain and the PQR strain. The data points and their
the age-specific values obtained from mixed sex cohorts of 250–450 animals
Gompertz approximations are shown (RaG and PQRG). Statistical analysis
each. The two curves are significantly different (log-rank test ¼ 24.76, df ¼ 1, p
confirms that the curves Ra and PQR differ significantly (p , .0036), the
, .00005). The continuous lines are the Weibull approximations of the
intercepts are significantly different whereas the slopes Ra and PQR have no
empirical data. See Vettraino and colleagues (51) and Arking and colleagues
significant difference. C, Age-specific logarithmic mortality curves of the
(19) for experimental details. C, Survival curves of the normal-lived Ra control
normal-lived Ra control strain and the longer-lived heat-treated strain (RaHx).
strain and the longer-lived Ra heat-treated strain. The animals were subjected to
The experimental points and the Gompertz approximations (RaG and RaHxG)
a non-lethal heat shock (378C for 90 minutes) early in life at days 5–7 after
are shown. Statistical analysis does not reveal a significant difference between
eclosion. They were then maintained under controlled optimal conditions and
the curves Ra and RaHx (p , .35). The intercepts do not differ significantly.
their survival monitored. The two curves are significantly different (log rank test
¼ 17.84, df ¼ 1, p , .00005). See Keuther and Arking (52) and Arking and
colleagues (2002) for experimental details. The continuous lines are the Weibull
approximations of the empirical data. These three longevity phenotypes are empirical observa-
tions. They do not, however, arise from random events with
a significant delay in the onset of observable loss of function limited significance. They in fact represent the operation of
(i.e., senescence). This empirical evidence demonstrates that the organism’s homeostatic mechanisms, and can be
not only do multiple longevity phenotypes exist but that mathematically modeled as the outcome of variations in
each of them may be induced by a variety of stimuli, some antioxidant defense, environmental conditions, or energy
of which may interact in an additive manner. allocations to reproduction (Figure 3 and Appendix). These
700 ARKING ET AL.

Figure 3. Simulation of different types of aging in Drosophila. A, Type I: effect of increased antioxidant defense b. The simplest way to reproduce Type I aging is to
change the corresponding genetic mean value b. We simulate three populations in which the oxidative vulnerability decreases (b ¼ 1.2 3 10
4; 1.0 3 10
4; 0.8 3 10
4).
The other parameters are unchanged; S0 ¼ const, rS ¼ 0.001; W ¼ const, rS ¼ 0.001. Similar patterns can be created by simultaneous changes in b, S0, and W (not
shown). C, Type II: rectangularization of a survival pattern by a decrease in external mortality. External mortality in a population is described by a Makeham
coefficient, m ¼ const. When m decreases (m ¼ 0.01; 0.005; 0.0001), the survival pattern moves right to the pattern with m ¼ 0; mortality becomes closer to that caused
by the natural senescence only. The final pattern is that for a randomized rate of aging, Rr ¼ R0  nR, where nR is Gaussian variable with mean ¼ 1.0 and r2R ¼ 0.02. B,
Type III: manipulations with reproduction. High mortality in an initial population is caused by the extreme reproductive effort (the energy proportion devoted to
reproduction is shown). Fecundity pattern for an R-strain with the plateau Wr ¼ 42.6 eggs/day is presented by the thick curve (55). Thin line shows the original
fecundity scores (53). D, Type III: manipulations with reproduction. Decreased investment to reproduction (Wr ¼ 50, 45, and 40 eggs/day) results in a reshaping of the
survival pattern by moving it to the right.

factors are generally agreed to be fundamental to the biology
of aging. It therefore follows that the appearance of multiple
longevity phenotypes may be anticipated in any species
subject to these fundamental factors. This finding suggests
that an overview of potential life expectancy outcomes for
a species should be based on the analysis of all longevity
phenotypes likely to occur in that species.
As expected, this diversity of longevity phenotypes is not
restricted to insects. All three are known in mice. The Type
1 delayed onset of senescence phenotype is known to occur
in calorically restricted mice (26), in dwarf mice (27), in
mice lacking the insulin receptor in their adipose tissue (28),
and in mice expressing a down-regulation of the insulin-like
growth factor-1 (IGF-1) receptor (29). The Type 2 increased
early survival phenotype is noted in exercising mice (30).
The Type 3 increased late survival phenotype is observed
when comparing the survival of inbred mice with that of
their F1 hybrids [for example, BALB/cJ or DBA/2J mice to
that of their F1 BDA hybrid (31)].
However, only two of these three longevity phenotypes
are known to occur in humans. The reduced early mortality
and increased mean life span but unchanged maximum life
span observed in the Type 2 phenotype is characteristic of
exercising humans versus their sedentary controls (30),
while the increased late survival characteristic of the Type 3
phenotype is characteristic of human centenarians (32–34).
Both of these phenotypes have been taken into account in
the Carnes–Olshansky analysis, but the potential contribu-
tion of the Type 1 delayed senescence phenotype has been
overlooked. It may be argued that it was overlooked due to
the absence of its occurrence in humans. But the whole point
of using the fly and mouse as model systems is to identify
evolutionarily conserved mechanisms and processes not
clearly observable in humans (35–39).
The occurrence of these three longevity phenotypes in
mice strongly implies their parallel existence in humans.
There is every reason to believe that the Type 1 phenotype
can be expressed in primates. For example, it certainly
appears as if the caloric restriction-induced Type 1 pheno-
type is expressed in macaque monkeys (40) and humans (41)
subjected to caloric restriction. This is almost certainly a
conserved longevity mechanism and a conserved longevity
phenotype. In addition, there are suggestions of shifts in
certain human mortality curves consistent with such a pheno-
type (42,43).
DISCUSSION
The Oeppen–Vaupel argument depends on the continued
increase of world record life expectancy at a rate compar-
able to that of the past (i.e., 2.5 years per decade). No
mechanistic basis for this prediction is offered, and this
absence is a weak aspect of their argument. Given the fact
that the easy victories have already been won, as Carnes and
Olshansky point out, then this implies that such a large
increase will occur only if new techniques allow the slowing
down of senescence in postreproductive adults (3) or the
 THE HUMAN LIFE SPAN IS NOT THAT LIMITED
delayed onset of senescence in presenescent adults. The
genetic results described herein justify the optimism of both
Olshansky and colleagues (4) and of Oeppen and Vaupel (5)
that such new interventions might someday be developed.
They also show that the interventions serve to significantly
extend the ‘‘biological warranty period’’ by delaying the
onset of senescence and its associated increase in age-
specific mortality rates (Figure 2A). In addition, we will
point out below how the new data of Mair and colleagues
(22) suggest that some future interventions might be ef-
fective in postsenescent adults as well.
The Carnes–Olshansky analysis and its reliance on the
evolutionary theory of aging sets real limits on the increased
life expectancy that might be obtained from interventions on
senescing (i.e., postreproductive) humans. Their overlook-
ing the implications of the Type 1 phenotype means they
assume that all possible longevity interventions that might
affect their predictions are restricted to the postreproductive
portion of the life span. They explicitly state that ‘‘There are
no life-style changes, surgical procedures, vitamins, anti-
oxidants, hormones, or techniques of genetic engineering
available today with the capacity to repeat the gains in life
expectancy that were achieved during the 20th century. If
there is to be another quantum leap in life expectancy at
birth (20 to 30 years or more), these large gains will have to
come from adding decades of life to the lives of people who
reach the ages of 70 and older’’ (3, p. 1492). But the Type 1
interventions in animal models act prior to the age of EER
so as to delay the onset of senescence. As explained in the
next paragraph, this intervention effectively ‘‘loads’’ the
extra longevity not in the postreproductive senescent phase
but rather into the reproductive presenescent phase. This
results in the significant temporal extension of the low levels
of age-specific mortality characteristic of such organisms.
It is instructive to use the existing mouse data to
extrapolate the possible effects of such an intervention on
human longevity. For the sake of argument, let us consider
a cohort life span to be composed of a ‘‘health span,’’ during
which the animals are healthy and the mortality rate is low,
constant, and age-independent; and a ‘‘senescent span,’’
during which the animals are senescing, losing function, and
the mortality rate is increasing in an age-dependent manner.
Let us define the health span as that period of time
beginning with reproductive maturity and lasting until that
time when the logqx values begin to increase. For the
purposes of the present discussion, we shall arbitrarily
define that age to be when 10% of the population will have
died (LT10). Consequently, the senescent span will cover the
period of time from the LT10 until the last animal in the
cohort dies. (By these criteria, the control fly population in
Figure 1A would have a health span of approximately 30
days, while the long-lived population would have a health
span of ;55 days.) Female mice genetically engineered to
have a 50% reduction in the levels of their IGF-1 receptor
(IGF-1R) genes have a Type 1 extended longevity due to
a delayed onset of senescence (see Figure 2 of ref. 29). The
health span of the control female mice covers the period
from approximately 3 to 12 months while that of the ex-
perimental female mice covers the period from approxi-
mately 3 to 21 months. Death occurs at 27 and 32 months,
701
respectively. Thus, the senescent span of the female control
mice is approximately 15 months while that of the female
experimental mice is approximately 11 months. Not only is
there a 33% increase in the mean life spans (756 6 46 vs
568 6 49 days) and an approximately 18.5% increase in the
maximum life span, but the health span of the treated female
animals increased from 9 months to 18 months while the
senescent span decreased from 15 months to 11 months. As
suggested by Figure 2A, the doubling of the health span
likely came about because the age-specific mortality rates of
the treated mice did not rise at the same time as did
the control, but rather stayed near the low extrinsic level
characteristic of their controlled environment. Other genetic
interventions that also interfere with the insulin- or gluco-
regulatory mechanisms of the body bring about a similar
phenotype (28). If we assume, as did Carnes and colleagues
(2), that mice and humans will react rather similarly,
then this means that such an intervention would increase the
human female health span from approximately 35 years
(ages 20 to 55 years) to approximately 70 years (ages 20 to
90 years) while decreasing the human senescent span from
approximately 45 years (ages 55 to 100 years) to approxi-
mately 33 years (ages 100 to 133 years). The point of this
numerical exercise is not so much the actual numbers as it
is to emphasize that the next ‘‘. . . quantum leap in life ex-
pectancy at birth . . .’’ will come from intervening in
younger adults rather than in older senescent adults.
Note that the effects of these new types of interventions
are consistent with the views of both Olshansky and col-
leagues (3) and Vaupel and colleagues (44), both of whom
predict that new interventions will be necessary if life ex-
pectancy at birth is to continue to increase.
It may well be argued that genetic alterations of a few
mice do not constitute an effective human anti-aging
intervention because of (a) the great difficulties associated
with genetic engineering of humans and (b) the long time
likely to elapse until an effective nongenetical intervention
is approved for general use. The point of using genetically
altered mice is not to develop genetic engineering
techniques suitable for human use but rather to identify
the genetic pathways regulating longevity so that one can
devise suitable pharmaceutical interventions that will induce
the expression of the same longevity phenotype. It was this
mindset that led to the recent identification and character-
ization of the insulin-like signaling pathway (ISP) as a major
evolutionary conserved longevity-regulating mechanisms
operative in all laboratory models, including humans.
Pharmaceutical interventions capable of inducing the
expression of a Type 1 longevity phenotype are a reality.
The Food and Drug Administration (FDA)-approved drug,
4-phenylbutyrate, induces a delayed onset of senescence in
Drosophila by inhibiting certain histone deacetylases and
thereby activating various antioxidant and other genes (45).
Caloric restriction will bring about a Type 1 longevity
phenotype in mice (26) and humans (41), and a similar
phenotype can be induced in rats by high doses of the FDA-
approved glucoregulatory drug metformin (46). Related
FDA-approved glucoregulatory drugs are believed to exert
similar effects on laboratory animals. Other laboratories
are searching for different caloric restriction mimetic
702 ARKING ET AL.
drugs (40). Nonetheless, the phenylbutyrate and metformin
cases constitute a proof of concept. It is these types
of pharmaceutical interventions applied to presenescent
humans that will bring about the next quantum leap in life
expectancy at birth. The fact that these drugs are already
FDA approved will likely speed up their eventual translation
from laboratory to clinic.
There are two major implications of these genetic
researches for the current discussion of human demography.
The first implication is that humans are likely composed
of subpopulations with various longevity phenotypes, all
of which should be taken into consideration when estimating
the likely longevity limits of our species. Another implication
is that the normally rare Type 1 phenotype may be induced in
younger animals by means of targeted pharmaceutical
modulation of the insulin/glucoregulatory mechanisms. This
induced phenotypic plasticity will likely result in a delayed
onset of senescence and a significantly extended longevity
for some increasingly larger subset of the population.
There is a third implication regarding other future
interventions inherent in some recently published data
dealing with caloric restriction in Drosophila (22). Shifting
flies from an ad libitum diet to a caloric restriction diet, or
vice versa, affected the age-specific mortality rates such that
the animals after the shift rapidly expressed the mortality
rate characteristic of animals raised all their lives on the new
diet. In other words, even older animals rapidly lowered
their intrinsic mortality rate to a level characteristic of
younger animals. This observation is consistent with the
recent findings that the caloric restriction effect appears to
take place at the cellular level (47), and that caloric
restriction is known to exert significant effects at the
molecular level within several months after initiation in
older rodents (48). Should caloric restriction mimetic drugs
be found to bring about a similar decrease in age-specific
mortality rates when administered to older mice, then it
might be possible in the future to significantly increase the
life span of postreproductive humans as well. Administering
the drug at this stage would result in an extension of the
senescent span. Thus, this option is just an extension of our
present efforts to increase the longevity of elderly postre-
productive humans. What is interesting is the possibility
that a caloric restriction mimetic drug may bring about either
a delayed onset of senescence or just a slowed senescence,
depending on the age of the recipient.
It is true that these particular anti-aging interventions are
still being studied in animals. It is true that the necessary
clinically approved human biomarkers are not yet in place.
It is true that theoretical possibilities are difficult to model. It
is true that one could marshal other practical objections.
Whether the clinical use of such interventions takes place in
one decade or in three decades is a matter of conjecture at
this time—but that it will take place is highly probable. And
it is this information that public policy decision makers need
to know.
Other probable but presently theoretical events affecting
longevity have been modeled. The increasing obesity of the
United States population is an indication that many people
are following nonhealthy lifestyles. The probable negative
effect of this trend on longevity has been modeled (49). It is
unlikely that present or future Type 1 pharmaceutical anti-
aging interventions will work effectively in an unhealthy
background. One can envision a future in which the
population stratifies into two components. One component
being a subset of people practicing a healthy lifestyle
conducive to a pharmaceutically induced extended longev-
ity, while the other comprises a perhaps larger group of
people practicing an unhealthy lifestyle refractive to such
interventions and perhaps conducive to a shorter than
normal longevity. The potential stratification of our society
into very long-lived and rather short-lived subpopulations
would have ramifications beyond the financial stability of
the U.S. Social Security program. It would be useful to have
these apparently contrary trends analyzed in detail by the
demographic community.
Given these probable developments, it would be useful if
the likely effects of such interventions could be factored into
the demographic predictions, if only to alert the policy
makers that the demographic future is likely to keep chang-
ing in unexpected ways. It would be perfectly acceptable
to include this information in the more speculative part of the
forecast of our future demography until the necessary clinical
data are in place. Policy makers need time to adjust to the
coming realities, as the past decades of political debate has
shown. Their need for time to digest the data will likely be
even more prevalent when that future appears to be more
complex than that which they may have assumed. The genie
is out of the pill bottle, which is an appropriate metaphor to
keep in mind as we enter into the century of biology.
ACKNOWLEDGMENT
Address correspondence to Dr. Robert Arking, Department of Biological
Sciences, Biological Sciences Building, 5705 Gullen Mall, Wayne State
University, Detroit, MI 48202. E-mail: rarking@biology.biosci.wayne.edu
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Received and Accepted December 10, 2003
Decision Editor: James R. Smith, PhD
APPENDIX
Survival Patterns Attainable in Simulated Drosophila
Populations
To simulate the three types of aging presented above, we
will model aging in an individual (A), and in a population
(B) via homeostatic model of oxidative stress and aging
(54,55). Then we will change the parameters of individual
and population aging to yield the types of aging that
corresponds to the general types from above.
A. Aging: injuring of individual homeostatic mechanism
by oxidative stress.—Oxidative stress is accumulated in the
organism with age. The rate of accumulation at age x is
RðxÞ ¼ bWðxÞ;
where W(x) is the age-related pattern of oxygen con-
sumption rate, and b is an oxidative vulnerability. We
704 ARKING ET AL.
assume b ¼ const. As for the patterns of oxygen
consumption, W(x) ¼ const in males, and W(x) changes in
females in agree with individual fecundity pattern.
The main feature of the homeostatic modeling of aging
is that the accumulation of oxidative stress injures the
homeostatic capacity S(x) of physiological systems in
the organism. The damage accumulation results in the
age-related ‘‘exponential’’ decrease of S from the initial
value, S0:
SðxÞ ¼ S0  exp ½2:
An energy resource of the organism is assumed to be
equal the oxygen level in the cells, Q(x). It is supported by
the oxygen delivery system with homeostatic capacity S(x).
At age x the current ‘‘steady state’’ exists
QðxÞ ¼ P2;
where P is atmospheric oxygen pressure. The oxygen
resource decreases with age alongside with the decreasing
S(x). At some age xD, zero level is achieved: Q(xD) ¼ 0, and
senescence-caused death occurs (55).
In the above theory there are only three parameters: b, S0,
and W0. In males, they are assumed to be constants. These
parameters dictate the life history patterns S(x) and Q(x)
ending with the individual’s death.
The parameters values for a typical Drosophila males are
as follow: W0 ¼ 80–150 (ll2/day), S0 ¼ 1.5 4 2.5 (ll2/day/
mmHg), b ¼ 0.8 4 2.0 (310
4). b is measured in (1/ll2).
For females, a pattern W(x) is governed by the egg
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production. These parameters (for P ¼ 150 mm. Hg) yield
Q0 about 100 (mm. Hg) and LS about 30 4 100 (days).
B. Mimicking a population: addition of phenotypic
variability.—Usually populations, not individuals are stud-
ied. A homogeneous population can be simulated as a set of
genetically identical flies with phenotypic variations (N ¼
500). Phenotypic variability of the population is generated
by the Gaussian scattering of the parameters S0 and W0:
Sn0 ¼ S0 nS ; Wn ¼ W0 nW :
Here nS and nW are Gaussian random variables with the
mean values equal to unity and the variances r. The typical
are values rS ¼ 0 4 0.05 and rW ¼ 0 4 0.02.
Thus the parameters characterizing the population are the
genotypic mean values b, S0, and W0, and phenotypic vari-
ances rS and rW. Due to phenotypic variability the life
spans of individuals differ, and the model produces a
‘‘natural’’ survival pattern Surv0(x). In this pattern only
senescence-related mortality is presented. The external
influences can be simulated by a Makeham coefficient m(x):
Survm ðxÞ ¼ Surv0 ðxÞ exp½2mx:
The model allows generating a number of varying
survival patterns, which may be related to the patterns
observed experimentally in different species. In particular,
Figure 3 demonstrates the examples of type I–type III
patterns discussed above.