Experimental Gerontology 37 (2001) 57±66

www.elsevier.com/locate/expgero

Hormesis and debilitation effects in stress experiments using the
nematode worm Caenorhabditis elegans: the model of balance
between cell damage and HSP levels
Alexander Butov a, Thomas Johnson b, James Cypser b, Igor Sannikov a, Maxim Volkov a,
Mary Sehl c, Anatoli Yashin d,*
a
Ulyanovsk State University, Ulyanovsk, Russia
Institute for Behavioural Genetics, University of Colorado at Boulder, CO, USA
c
Brown University, USA
d
Max Planck Institute for Demographic Research, 114 Doberaner Str., 18057 Rostock, Germany
b

Received 9 April 2001; received in revised form 25 July 2001; accepted 20 August 2001

Abstract
In this article, we discuss mechanisms responsible for the effects of heat treatment on increasing subsequent survival in the
nematode worm Caenorhabditis elegans. We assume that the balance between damage associated with exposure to thermal
stress and the level of heat shock proteins produced plays a key role in forming the age-pattern of mortality and survival in stress
experiments. We propose a stochastic model of stress, which describes the accumulation of damage in the cells of the worm as
the worm ages. The model replicates the age trajectories of experimental survival curves in three experiments in which worms
were heat-treated for 0, 1, 2, 4, 6, or 8 h. We also discuss analytical results and directions of further research. The proposed
method of stochastic modelling of survival data provides a new approach that can be used to model, analyse and extrapolate
experimental results. q 2001 Elsevier Science Inc. All rights reserved.
Keywords: C. elegans; Hormesis; Heat shock proteins; Longevity

1. Introduction
The relationship between thermotolerance and
longevity in Caenorhabditis elegans is well known
(Lithgow et al., 1995; Walker et al., 1998; Michalski
et al., 2000). It has also been demonstrated that heat
shock proteins are induced in response to a variety of
stressors in C. elegans, including heat (Jones and
Candido, 1999), oxidative stress (Yanase et al.,
* Corresponding author. Tel.: 149-381-208-11-06; fax: 149381-208-11-69.
E-mail address: yashin@demogr.mpg.de (A. Yashin).

1999; Link et al., 1999), electromagnetic ®elds
(Junkersdorf et al., 2000), and immunological stress
(Nowell et al., 1999). Heat shock proteins function
during cell stress as molecular chaperones, interacting
with diverse protein substrates to assist in repairing
damaged proteins, by refolding, or in degrading them,
thereby restoring protein homeostasis and promoting
cell survival (Jolly and Morimoto, 2000; Frydman and
Harti, 1994).
Hyperthermia shifts cells into a state of oxidative
stress (Finkel and Holbrook, 2000), and the synthesis
of stress proteins is modulated by antioxidant status
(Peng et al., 2000). The role of oxidative damage and

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PII: S 0531-556 5(01)00161-9

58

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

antioxidant defence in the aging process has been
intensely studied (Harman, 1957; Sohal et al., 1995;
Cutler 1991; Orr and Sohal, 1994; Sohal and Weindruch, 1996). Increased resistance to oxidative stress
has been shown to be associated with increased longevity in C. elegans, perhaps mediated by higher levels
of the antioxidant enzymes superoxide dismutase and
catalase (Larsen, 1993; Van¯eteren, 1993).
In contrast, low doses of stress have been shown to
slow aging and prolong life span for a variety of
species and stresses: hypergravity in Drosophila
melanogaster (Le Bourg and Minois, 1999); radiation
in C. elegans (Johnson and Hartman, 1988); and heat
stress in Drosophila (Khazaeli et al., 1997; Kurapti,
2000), yeast (Shama et al., 1998), and C. elegans
(Michalski et al., 2000), to name a few. The mechanism underlying this increased longevity is thought to
be associated with the protective chaperone function
of heat shock proteins induced during the exposure to
stress. These proteins are thought to provide a longlived protective function, persisting after the exposure
to stress and functioning to repair damage in addition
to those caused by the stressor itself (Kurapti et al.,
2000).
In this paper, we propose a mathematical model
describing a stressor such as heat shock in the nematode worm C. elegans. We assume that each unit of
stress load produces equivalent intracellular damage
in the worm. The same stress also stimulates the
production of heat-shock proteins, which tend to
reduce cellular damage. Imbalance between the
damage production and its removal, results in damage
accumulation shortening the life span of the worm, as
is observed in populations of worms exposed to different durations of heat shock. We assume the presence
of some (random) initial damage in the cell. When the
stress is small, the amount of damage produced by it is
also small. In our model, the production of heat shock
proteins is not strictly proportional to the amount of
damage. After a small stress, heat shock proteins
(HSPs) are over-produced; these HSPs not only
remove damage produced by the stress, but also
remove part of the initial preexisting damage. This
improves function of the entire organism resulting in
increased life span. This scenario corresponds to the
hormesis effect observed in populations of worms
exposed to two or less hours of heat shock (Michalski
et al., 2000; Yashin et al., 2001). Long exposure to

heat produces substantial damage, which cannot be
entirely repaired, even by the higher levels of HSPs
produced during this shock. This amount, however, is
not enough to completely compensate for the damage
produced by the stress, so the functioning of the cells
deteriorates, and life span decreases. This is observed
in the populations exposed to six or more hours of heat
shock. Intermediate duration of heat results in a delay
in restoration of function by HSPs. As a result, the
survival probability is lower earlier in life and higher
later in life when the damage associated with the
stress as well as part of the initial damage are eliminated. This is the scenario in a population exposed to
4 h of heat stress.
Exciting methods involving the use of DNA-chip
microarrays are underway to study kinetics of HSP
mRNA synthesis, which can be used in conjunction
with these models to examine the dynamics of HSP
gene expression and the mechanisms underlying the
increase in longevity seen in organisms exposed to
low levels of thermal stress.

2. Materials and methods
2.1. Experimental data
Worms TJ1060 (spe-9; fer-15) were raised on
NGM plates, prespotted with E. coli, at 25.58C for
3 days at which time they had developed into sterile,
but otherwise phenotypically wild-type adults. Then,
populations were divided into 11 groups and exposed
to heat shocks at 358C for periods of 0, 1, 2, 4, 6, 8, 10,
12, 16, or 24 h (synchronous start, asynchronous
stops). Immediately following the longest heat
shock, the animals were permitted to recover for an
additional 24 h at 208C. They were then transferred to
liquid survival medium and maintained at 208C for the
remainder of the experiment. Beginning with the ®fth
day of life, the number of live and dead worms was
counted daily for all groups. No survivors were
observed after 16 and 24 h of heat shock. Two other
experiments were performed with the same strains of
worms, at two different times, to replicate the results
of experiment 1. In experiment 2, sterilized worms
were divided into nine groups and exposed to heat
shocks at 358C for periods of 0, 0.5, 1, 2, 3, 4, 6, 8
or 10 h. In experiment 3, worms were divided into ten

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

groups and exposed to heat shock at 358C for periods
of 1, 2, 3, 4, 5, 6, 7, or 8 h. Here, we consider only
those results in which worms were shocked for 0, 1, 2,
4, 6 or 8 h.
2.2. Modeling assumptions
We introduce a stochastic model describing the
response to heat shock. We assume that the response
to stress can be described by two characteristic
components: processes A1 and A2 . The A1 component
represents the accumulated damage resulting from a
given thermal shock. Such damage may result
from increased oxidative stress following exposure
to thermal shock (Finkel and Holbrook, 2000). We
assume that the changes in A1 are determined by
t
the rate of damage D1 associated with the level and
t
duration of thermal shock, the activity of repair
mechanisms associated with the production of
HSPs ht and the random component which
magnitude is proportional to the accumulated level
of damage A1 . The effect of HSPs is proportional to
t
the level of damage A1 . This allows us to describe
t
component A1 using the following stochastic differential equation
dA1  D1 dt 2 A1 H 1 ht dt 1 s 1 A1 dWt1 ; A1 . 0:
t
t
t
t
0

1

Here, H 1 and s 1 are parameters of the model, and Wt1
is a standard Wiener process. The A2 component
represents the innate accumulation of oxidative
damage, and other forms of damage resulting from
various processes required for life. We suppose that
the changes in A2 are determined by the rate of
t
damage D2 associated with base damage level (other
than that induced by thermal stress), the activity of
repair mechanisms associated with the production of
HSPs ht and the random component, the magnitude
of which is proportional to the accumulated level of
damage A2 . The effect of HSPs is proportional to the
t
level of damage A2 . This allows us to describe compot
nent A2 using the following stochastic differential
equation
dA2  D2 dt 2 A2 H 2 ht dt 1 s 2 A2 dWt2 ; A2 . 0:
t
t
t
0

2

Here, H 2 and s 2 are parameters of the model, and Wt2
is a standard Wiener process. We assume that the A2
type of damage, although not induced by the heat
shock, can be repaired by the same processes that

59

are induced by the heat stress. Note that the model
can be created and almost properly adjusted without
the A2 component. However, the presence of the
stable phenomenon of `heavy tails' in the survival
curves after 2 or 4 h heating (and respective crossing
of the survival curves) cannot be modelled only by a
single component, A1 . We explain these phenomena
by `side effects' of HSP expression induced by
stress which diminishes the level of A2 . To model
the action of stress, we assume that each cell can be
in one of the two states: stressed wexp ; or unstressed
w1 . The switch of the state of the cell wt from
0
unstressed to stressed state (from w1 to wexp ) occurs
0
immediately following the start of heat exposure.
Process wt is de®ned as

i
V
b w1 ; when t Ó 3; 3 1 Texp
` 0
wt 
3

i;
b exp
X w ; when t [ 3; 3 1 Texp
where parameter Texp is the duration of heating (for
example, heating for 2 h approximately corresponds
to the part of one day, equal to Texp  0.08 < 2 h/
24 h), and it changes in accordance with every period
of heat-treatment in the experiment. Shortly after heat
shock, antioxidant defences are expressed, as long as
the temperature is below some critical value. Accordingly, we suppose that the accumulation of damage
from a thermal shock occurs after some delay (the
amount of time it takes the antioxidant defence system
to become saturated). The intensity of damage D1
t
from thermal shock for the A1 component is de®ned
by


4
dD1  k wt 2 D1 dt;
t
t
with initial value D1  w1 . Coef®cient k in Eq. (4)
0
0
characterizes the average lag time before the organism
begins to react to the thermal shock by producing
reactive oxygen species. It is worthy of note that
this lag time is here also equal to the amount of
time the organism takes to stop producing reactive
oxygen species once the thermal shock is removed.
For the second component (the accumulation of
damage and toxins), the intensity of damages D2 
w2 is held constant (i.e. equal to some base damage
0
level), which results from the assumption that environmental conditions (other than thermal stresses)
leading to the accumulation of toxins are kept

60

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

Fig. 1. Survival curves for C. elegans hermaphrodites calculated from experiment 1 data. H0, control group (no heating); H1, groups for heated
1 h; H2, for 2 h; H3, for 3 h; H4, for 4 h; H6, for 6 h; H8, for 8 h.

constant over time in stress experiments with heat
shocks. We hypothesize that the additional effects of
HSPs (i.e. repair of the A2 damage) are responsible for
the life span extension seen after heat stress.
We draw the assumption about minimum and maximum levels for HSPs in the organism from the
evidence that under usual conditions HSPs genes
of various types (molecular mass) show low levels
of expression that ensure respectively low levels of
concentration (in the model hMIN  0.07) of these
proteins in the total amount of all protein production
(in different species including the nematode
worm C. elegans up to 0.3±2.0% of the total
amount), and during heat stress the output increases
considerably and can achieve 50% (in the model
hMAX  10.0) (Link et al., 1999; Langer and
Neupert, 1994; McKay et al., 1994; Morimoto et al.,
1994). The defence mechanisms initiated by heat
shock are often associated with the production of
additional HSPs, above a baseline level hMIN , and
approach the level hMAX during exposure to thermal
stress.
We make further assumptions about the activity of
HSPs in the absence of thermal shock. After thermal
stress is completed, the residual activity of the
induced HSPs reduces damage produced by innate
metabolism as represented by A2 . The process
ht characterizes the amount of HSPs in a cell and is

described by

À
Á
dht  b1 hMAX 2 ht I wt . D dt

À
Á
1 b2 hMIN 2 ht I wt # D dt;

5

with the initial value h0  hMIN (where I(´) is the
indicator function: Itrue  1; I false  0). Parameter b1 is the time while the production of HSPs
during heat stress reaches the level hMAX . Parameter
b2 is the time while the production of HSPs decreases
to the level hMIN after heating. Parameter b1  10.0 is
taken greater than b2  2.0 in accordance with the
assumption that the production of HSPs during thermal stress requires 5±15 min, while the sequestration
of HSPs in the cytoplasm of cells takes approximately
12 h after termination of the heat in¯uence (Hahn and
Li, 1990; Parsell and Lindquist, 1994). We choose
such values of parameters b1 and b2 because they
are exponentially dependent. Adjustment of other
model parameters is carried out on the empirical and
the modelled survival functions. When duration of
heat shock is small, an increase in ht reduces the
amount of damage described by the components A1
t
and A2 . In our model, we consider the dynamics of the
t
processes A1 and A2 from birth until death. The time
of death of the modelled worm occurs in the case
when either component A1 or A2 exceeds the threshold

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

61

Fig. 2. Calculated survival curves for C. elegans hermaphrodites from simulated data. H0, control group (no heating); H1, groups for heated
1 h; H2, for 2 h; H3, for 3 h; H4, for 4 h; H6, for 6 h; H8, for 8 h.

AMAX Ðthe maximum quantity of the accumulated
damages for each component. So, we simulated the
set of worm life histories and appropriate life spans.
These simulated life spans are then used for construction of the modelled survival functions. As a result,
the life span of worms exposed to such heat shock
increases. This is observed in the groups of worms
heated for less than 2 h. After four or more hours of
heating, the level of HSPs still increases, however, the
level of damage D1 also increases, in accordance with
t

Eq. (4). The dynamics of ht and D1 are such that the
t
amount of HSPs accumulated during the exposure to
heat shock is not enough to reduce component A1 .

3. Results
3.1. Survival curves for experiment 1
In the model, the number of animals in each cohort

Fig. 3. Survival curves for C. elegans hermaphrodites calculated from experiment 2 data. H0±H8 correspond to groups heated for 0±8 h,
respectively.

62

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

Fig. 4. Survival curves for C. elegans hermaphrodites calculated from simulated data for experiment 2. H0±H8 correspond to groups heated for
0±8 h, respectively.

was chosen to correspond to the population size in
each cohort in the actual experiment in which the
duration of thermal stress was varied. Experimental
survival curves of the worms from the ®rst experiment
with various duration of thermal stress are shown in
Fig. 1.
From the experimental data, one can see that when
worms are exposed to heat for 1 or 2 h, life expectancy
is increased (survival curves are shifted to the right of
the control group). After longer exposure to heat, the

death rate at early ages sharply increases (survival
curves are shifted to the left of the control group).
Thus, the effect of hormesis is observed only after 1
or 2 h of thermal stress. However, it should be noted
that after longer duration of heat exposure, there are
still some individuals for which the thermal stress has
caused an increase in life expectancy. These effects
are also re¯ected in the results of the model.
Average survival curves, resulting from applying
our model to the ®rst set of experiments, are shown

Fig. 5. Survival curves for C. elegans hermaphrodites calculated from experiment 3 data. H0±H8 correspond to groups heated for 0±8 h,
respectively.

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

63

Fig. 6. Survival curves for C. elegans hermaphrodites calculated from simulated data for experiment 3. H0±H8 correspond to groups heated for
0±8 h, respectively.

in Fig. 2. In this ®gure, one can see that modelled
survival curves behave as well as the experimental
survival curves corresponding to each duration of
thermal stress. Note the presence of `heavy tails' of
the survival curves, resulting from repair of the A 2
component.
3.2. Survival curves for experiment 2
Experimental survival curves for worms in the
second experiment with 1, 2, 4, 6 and 8 h of thermal
stress and the control group (on which there was no
thermal in¯uence) are shown in Fig. 3. In this experiment, there are some prominent features that were
also observed in the ®rst experiment, namely, the
effect of hormesis and the clear increase of life expectancy (when compared with control) in those groups
receiving short thermal exposures (about 1±4 h).
Modelled survival curves for experiment two are
shown in Fig. 4. As in experiment 1, the modelled
curves for experiment 2 behave in a way similar to
experimental data.
3.3. Survival curves for experiment 3
Experimental survival curves of worms in the third
experiment and modeling curves after various thermal
in¯uences are shown in Figs. 5 and 6. For all experiments both the empirical and the modelled survival

curves show the increase of the average and maximum
life spans for worms heated for 1 and 2 h.
3.4. The effect of hormesis
Using a stochastic model of hormesis, we have been
able to develop a mathematical model that corresponds to the results of experimental observations
from heat-treatments of worms for various periods
of time. The effect of hormesis can be observed
when using only one component, A1 (damage due to
thermal stress). The main part of empirical survival
curves obtained from simulated data when only
component A1 is considered looks similar to that
produced from experimental data: at short heating
until 2 h, the life expectancy is increased; after longer
heating, survival curves are displaced to the left.
However, the effect of increase in survival at
advanced ages (i.e. the `heavy tail' effect) is only
observed when a second component, A2 (associated
with other damages) is added. Thus, by performing
simulation experiments using our model, we can
examine the underlying mechanism of the effects of
hormesis on survival curves. The results of such
modelling can in turn be used to suggest new experiments to uncover fundamental properties of the action
of hormesis in aging. In particular, the model forecasts
that in the case of heating in the oldest ages (for
example with the 10th day of life) the appearance of

64

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

the more `heavy tails' in the survival curves along
with an increase of mortality in the early ages for
the intermediate levels of heating (here, for 4 h).
3.5. Parameters of the model
The choice of numerical values of parameters used
in the stochastic model is based on consideration of
physiological mechanisms appropriate for the nematode worm C. elegans and a result of model adjustment to the data. The following parameters are ®xed
for all experiments:

s 2  0:02; b1  10:0; b2  2:0; wexp  10:5; AMAX
 3:0; hMAX  10:0; hMIN  0:07; k  1:2; D
 0:2; Texp
 0:0 for not heated;Texp  0:4 for heated 1 h;Texp
 0:08 for heated 2 h;Texp
 0:17 for heated 4 h;Texp
 0:25 for heated 6 h;Texp  0:33 for heated 8 h:
For the ®rst experiment the following parameters are
used:
H 1  0:09; H2  0:095; s 1  0:08; w1  0:07; w2
0
0
 0:11; a1  0:8; a2  0:9; b1  0:7; b2  0:2:
For the second experiment:
1

2

1

H  0:135; H  0:125; s 
1

2

dynamic processes of accumulated damage and the
threshold model of mortality. Two sources of damage
are considered. One is associated with the action of
thermal shock per se. Another deals with `natural'
accumulations of damage produced by other factors.
The thermal shock induces the production of heat
shock proteins in the cells. This induction helps
reduce the level of accumulated damage from both
sources by activation repair mechanisms. As a result,
both the effect of longevity hormesis and the effect of
increase in survival for the oldest old become
explained. In this model, we used a simplifying
assumption that cells in different tissues of the
worm organism have the same sensitivity to heat.
This assumption is partly justi®ed by the fact that
experimental worms were sterilized. During the sterilization procedure, cells with mitotic activity possessing the highest sensitivity to stress were destroyed.
However, the effect of different sensitivity of other
tissues to stress on longevity is an interesting question
which could be the subject of future studies.
It is clear that our model cannot describe the development of the nematode worm C. elegans and its
entire biology. It is focused on explanation of longevity hormesis arising in heating experiments. We
show that simple assumptions about the role of heat
shock proteins in the accumulation of damages in the
organism of the nematode worm can be used for
explanation of survival patterns observed in stress
experiments.
Acknowledgements

0:05; w1
0
1



0:073; w2
0
2

 0:067; a  1:3; a  1:6; b  0:6; b  0:25:
For the third experiment:
H 1  0:11; H2  0:12; s 1  0:05; w1  0:07; w2
0
0
 0:085; a1  1:2; a2  1:4; b1  0:64; b2  0:2:

4. Discussion
In this paper, we explain the effect of longevity
hormesis in the nematode worm C. elegans using

The authors wish to thank Professor James W. Vaupel
for the opportunity to use the facilities of the Max Planck
Institute for Demographic Research in Rostock,
Germany, during work on this paper. We also thank
anonymous reviewers for valuable comments.
Appendix
The experimental analysis was carried out using
methods of stochastic simulation modelling. The
À Á
À Á
À Á
1
processesÀ AÁ  A1 t$0 , A2  A2 t$0 , D1  D1 t$0
t
t
t
and h  ht t$0 are time dependent and are de®ned
by the stochastic differential equations.
In the stochastic differentials for the processes A1
t

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

A2
t

A1
0

A2
0

and
the initial values
and
are random variables determining the initial level of the damage, as
shown below:
A1  a1 1 b1 e1 1
0
A2  a2 1 b2 e2 1
0
where e1 ; e2 are independent Gaussian random variables with mean zero and variance one. Variables
a1 ; b1 ; a2 ; b2 are parameters of the model (the notation a1 refers to the positive part of the value a (i.e.
a1  a, if a . 0, and a1  0, if a # 0).
In the stochastic differential equations (1) and (2),
W 1  Wt1 t$0 and W 2  Wt2 t$0 are standard independent Wiener processes and s 1 ; s 2 ; H 1 ; H 2 are
parameters.
Finally, we determine the time of death, t , as
follows:

t  minft1 ; t2 g;
È
É
where ti  min t : Ait $ AMAX ; i  1; 2:
References
Cutler, R.G., 1991. Antioxidants and Aging. American Journal of
Clinical Nutrition 53 (1), S373±S379.
Finkel, T., Holbrook, J., 2000. Oxidants, oxidative stress and the
biology of aging. Nature 408, 239±247.
Frydman, J., Harti, F.U., 1994. Molecular chaperone function of
hsp70 and hsp60 in protein folding. In: Morimoto, R.I.,
Tissieres, A., Georgopoulos, C. (Eds.). The Biology of Heat
Shock Proteins and Molecular Chaperones, Gold Spring Harbor
Laboratory Press, New York, pp. 251±283.
Hahn, G.M., Li, G.C., 1990. Thermotolerance, thermoresistance,
and thermosensitization. In: Morimoto, R.I., Tissieres, A., Georgopoulos, C. (Eds.). Stress Proteins in Biology and Medicine,
Gold Spring Harbor Laboratory Press, New York, pp. 79±100.
Harman, D., 1957. Aging: a theory based on free radical and radiation chemistry. Journal of Gerontology 2, 298±300.
Jolly, C., Morimoto, R.I., 2000. Role of the heat shock response and
molecular chaperones in oncogenesis and cell death. Journal of
the National Cancer Institute 92 (19), 1564±1572.
Jones, D., Candido, E.P., 1999. Feeding is inhibited by sublethal
concentrations of toxicants and by heat stress in the nematode
Caenorhabditis elegans: relationship to the cellular stress
response. Journal of Experimental Zoology 284 (2), 147±157.
Junkersdorf, B., Bauer, H., Gutzeit, H.O., 2000. Electromagnetic
®elds enhance the stress response at elevated temperatures in
the nematode Caenorhabditis elegans. Bioelectromagnetics 21
(2), 100±106.
Khazaeli, A.A., Tatar, M., Pletcher, S.D., Curtsinger, J.W., 1997.
Heat-induced longevity extension in Drosophila. I. Heat treat-

65

ment, mortality, and thermotolerance. Journals of Gerontology
A Biological Sciences and Medical Sciences 52 (1), B48±B52.
Kurapti, R., Passananti, H.B., Rose, M.R., Tower, J., 2000.
Increased hsp22 RNA levels in Drosophila lines genetically
selected for increased longevity. Journal of Gerontology A
Biological Sciences and Medical Sciences 55 (11), B552±
B559.
Langer, T., Neupert, W., 1994. Chaperoning mitochondrial biogenesis. In: Morimoto, R., Tissieres, A., Georgopoulos, C. (Eds.). Heat
Shock Proteins: Structure, Function, and Regulation. Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, pp. 53±83.
Larsen, P.L., 1993. Aging and resistance to oxidative damage in
Caenorhabditis elegans. Proceedings of the National Academy
of Science USA 90 (19), 8905±8909.
Le Bourg, E., Minois, N., 1999. A mild stress, hypergravity exposure, postpones behavioral aging in Drosophila melanogaster.
Experimental Gerontology 34, 157±172.
Link, C.D., Cypser, J.R., Johnson, C.J., Johnson, T.E., 1999. Direct
observation of stress response in Caenorhabditis elegans using a
reporter transgene. Cell Stress Chaperones 4 (4), 235±242.
Lithgow, G.J., White, T.M., Melov, S., Johnson, T.E., 1995.
Thermotolerance and extended life-span conferred by
single-gene mutations and induced by thermal stress.
Proceedings of the National Academy of Sciences of the
USA, 92, 7540±7544.
McKay, D.B., Wilbanks, S.M., Flaherty, K.M., Ha, J.H., O'Brien,
M.C., Shirvanee, L.L., 1994. Stress-70 proteins and their interaction with nucleotides. In: Morimoto, R.I., Tissieres, A., Georgopoulos, C. (Eds.). Biology of Heat Shock Proteins and
Molecular Chaperones. Cold Spring Harbor Laboratory Press,
Cold Spring Harbor, pp. 153±177.
Michalski, A.I., Johnson, T.E., Cysper, J.R., Yashin, A.I., 2000.
Heating stress patterns in Caenorhabditis elegans longevity
and survivorship. Plant Growth Regulation 00, 1±10.
Morimoto, R.I., Tissieres, A., Georgopoulos, C., 1994. Progress and
perspectives on the biology of heat shock proteins and molecular chaperones. In: Morimoto, R.I., Tissieres, A., Georgopoulos,
C. (Eds.). The Biology of Heat Shock Proteins and Molecular
Chaperones, Gold Spring Harbor Laboratory Press, New York,
pp. 1±29.
Nowell, M.A., De Pomerai, D.I., Pritchard, D.I., 1999. Caenorhabditis elegans as a biomonitor for immunological stress in nematodes. Parasite Immunology 21 (10), 495±505.
Orr, W.C., Sohal, R.S., 1994. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128±1130.
Parsell, D.A., Lindquist, S., 1994. Heat shock proteins and stress
tolerance. In: Morimoto, R.I., Tissieres, A., Georgopoulos, C.
(Eds.). The Biology of Heat Shock Proteins and Molecular
Chaperones, Gold Spring Harbor Laboratory Press, New
York, pp. 457±493.
Peng, J., Jones, G.L., Watson, K., 2000. Stress proteins as biomarkers of oxidative stress: effects of antioxidant supplements. Free
Radical Biology and Medicine 28 (11), 1598±1606.
Shama, S., Lai, C.Y., Antoniazzi, J.M., Jiang, J.C., Jazwinski, S.M.,
1998. Heat stress-induced life span extension in yeast. Experimental Cell Research 245 (2), 379±388.

66

A. Butov et al. / Experimental Gerontology 37 (2001) 57±66

Sohal, R.S., Sohal, B.H., Orr, W.C., 1995. Mitochondrial superoxide and hydrogen-peroxide generation protein oxidative
damage, and longevity in different species of ¯ies. Free Radical
Biology and Medicine 19 (4), 499±504.
Sohal, R.S., Weindruch, R., 1996. Oxidative stress, caloric restriction, and aging. Science 273, 59±63.
Van¯eteren, J.R., 1993. Oxidative stress and aging in Caenorhabditis elegans. Biochem. J. 292, 605±608.
Walker, G.A., Walker, D.W., Lithgow, G.J., 1998. A relationship
between thermotolerance and longevity in Caenorhabditis

elegans. Journal of Investigative Dermatology Symposium
Proceedings 3 (1), 6±10.
Yanase, S., Hartman, P.S., Ito, A., Ishii, N., 1999. Oxidative stress
pretreatment increases the X-radiation resistance of the nematode
Caenorhabditis elegans. Mutation Research 426 (1), 31±39.
Yashin, A.I., Cypser, J. W., Johnson, T.E., Michalski, A.I., Boyko,
S.I., Novoseltsev, V.N. Ageing and survival after different doses
of heat shock: the results of analysis of data from stress experiments with the nematode worm Caenorhabditis elegans. 122,
1477±1495. Mechanisms of Aging and Development.

