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Cell Cycle 10:24, 4230-4236; December 15, 2011; 2011 Landes Bioscience Rapamycin increases lifespan and inhibits
spontaneous tumorigenesis
in inbred female mice
Vladimir N. Anisimov,1,* Mark A. Zabezhinski,1 Irina G. Popovich,1 Tatiana S. Piskunova,1 Anna V. Semenchenko,1 Margarita L. Tyndyk,1 Maria N. Yurova,1 Svetlana V. Rosenfeld1 and Mikhail V. Blagosklonny2,* 1Department of Carcinogenesis and Oncogerontology; N.N.Petrov Research Institute of Oncology; St. Petersburg, Russia; 2Department of Molecular and Cellular Biology and Department of Cell Stress Biology; Roswell Park Cancer Institute; Buffalo, NY USA Key words: rapamycin, mTOR, aging, longevity, gerosuppressants
The nutrient-sensing TOR (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an
inhibitor of TOR, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that
lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 y.
Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of 2 mo. Rapamycin
inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed
spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Thus
we demonstrated for the first time in normal inbred mice that lifespan can be extended by rapamycin. This opens an
avenue to dev
elop o p2012 Lande
timal doses and schedules of rapamyci s Bio
n as an anti-agin s
undesirable effects precluding both its lifelong use and life exten-sion. Therefore, it is important to investigate lifelong use of Until very recently, the prospect of pharmacological decele di
pamycin in ut
define e.
d strains of mice to develop regiments (doses of mammalian aging appeared remote.1 In 2009, it was dem- and schedules) that extend lifespan. Previously, we have demon- onstrated that rapamycin, known as an immunosuppressant, strated that lifelong administration of rapamycin in an intermit-extended lifespan in mice when it was fed to them late in life.2 tent fashion (every other 2 weeks) extends lifespan in short-lived Yet this result was not unanticipated.3 The target of rapamycin cancer-prone mice.35 However, one may argue that this life exten-(TOR) pathway is involved in senescence of yeast4-7 and mamma- sion is due to cancer prevention in short-lived mice. Here, we lian cells in culture.8-16 Rapamycin decelerates yeast chronologi- present a 2-year-long study in inbred 129/Sv mice that received cal senescence5 and suppresses the conversion of cell cycle arrest rapamycin intermittently (three times a week for 2 weeks, fol-into senescence in human cells.8-10,16 TOR accelerates aging in lowed by a 2 week break) starting from the age of 2 mo. 129/Sv diverse organisms, from worms to mammals.17-25 In mammals, mice have a normal lifespan and cancer incidence and are most mTOR (mammalian TOR) controls cellular mass growth, func- often used to produce knockout mice. We found that rapamycin tions and metabolism in response to nutrients, hormones, cyto- significantly increased lifespan and delayed spontaneous cancer. kines and growth factors.26-28 Rapamycin decelerates senescence This is the first report of extension of lifespan by rapamycin in in normal9 and progeric29 human cells. mTOR is also involved in normal inbred mice as well as the first report on lifelong admin-age-related diseases, such as atherosclerosis, metabolic syndrome, istration of rapamycin.
osteoporosis, neurodegeneration and macular degeneration.30-33 Thus, the mTOR pathway links cellular senescence, organismal aging and diseases of aging.34 Remarkably, rapamycin is a clinically approved drug that has Treatment with rapamycin significantly inhibited age-related been used for a decade in renal transplant patients. Therefore, weight gain in female mice (Fig. 1A). While in control, mice
it was suggested that rapamycin could be used for extension constantly gained weight during their lifespan; mice that received
of healthy lifespan and prevention of age-related diseases by rapamycin demonstrated a significantly smaller weight increase.
slowing down the aging process.3 This may become one of the As a result, from the 5th to 23rd months, body weight was increased
major breakthroughs in medicine since the discovery of antibi-
by 21.9% and by 12.4% in the control and rapamycin-treated otics. The main concern, however, is that rapamycin may exert group, respectively. The body weight in the rapamycin-treated *Correspondence to: Vladimir N. Anisimov and Mikhail V. Blagosklonny; Email: aging@mail.ru and blagosklonny@oncotarget.com Submitted: 09/15/11; Accepted: 10/18/11http://dx.doi.org/10.4161/cc.10.24.18486 Volume 10 Issue 24 2012 Landes Bioscience.
Do not distribute.
Figure 1. Effects of rapamycin weight gain, food consumption and body temperature in female 129/Sv mice. (A) Body weight. (B) Food consumption.
(C) Water consumption. (D) Body temperature.
animals was significantly less as compared with the control rapamycin survived the age of the death of the last mouse in the
between the age of 20 and 27 mo (Fig. 1A). Rapamycin slightly control group (22.9%).
affected food consumption in young mice and decreased food
Treatment with rapamycin shifted the survival curve to the consumption by 23% in old mice (Fig. 1B). Rapamycin did not right (Fig. 2A) and increased the mean lifespan by 7.8% of the
affect water consumption (Fig. 1C) and insignificantly decreased last 10% survivors. Rapamycin also increased the median lifespan
body temperature (Fig. 1D). There was no significant difference by 10.1% as well as the maximum lifespan by 9.3% by increas-
in age-related dynamics of the length of estrous cycle and in the ing the average lifespan of the long-lived mice, decreasing initial
ratio between the estrous cycle phases in the control and rapamy-
mortality (β) when treatment began in midlife and decreas- cin-treated groups. However, at the age of 18 mo, 46% and 65% ing the Gompertz parameter α (increases MRDT) (Table 4).
mice had regular estrous cycle in control and rapamycin-treated According to the Fischer exact test for count data, rapamycin sig-
groups, respectively (Table 1).
nificantly decreased the number of tumor-bearing mice (p-value The total incidence of chromosome aberrations (ChA) in bone = 0.0004578) (Table 5). Rapamycin also shifted the tumor-yield
marrow cells and fragments was increased in 26-mo-old treated curve to the right (Fig. 2B) and prolonged mean lifespan of long-
and non-treated mice compared with 4-mo-old controls. Levels lived tumor-bearing mice.
of total ChA were higher in old rapamycin-treated mice than in
According to the log-rank test for the conditional lifespan 26-mo-old controls (Table 2).
distributions (given all groups survived the age of 130 d), the Most importantly, in control, 11 mice survived until the age difference is significant between treated and untreated groups of of 800 d (35.5%) compared with 19 (54.3%) in the rapamycin- mice (Table 6). According to the estimated parameters of the
treated group (p > 0.05; Table 3), while survival until the age Cox regression model, rapamycin treatment decreases the rela-
of 900 d was 9.7% in control and 31.4% in the rapamycin-
tive risk of death compared with the control group (Table 7).
treated group (p < 0.01, t = 3.44). Eight female mice exposed to The log-rank test for the conditional lifespan distributions shows Table 1. Effect of rapamycin on parameters of estrous function in female 129/Sv mice
Length of estrous cycles
Rate of estrous cycles of various length
Fraction of mice with regular
Number of mice
< 5 days
5–7 days
> 7 days
estrous cycles (%)
Significant in comparison with control, *р<0,05.
Table 2. The incidenc
mo 2012 Lande
some aberrations (ChA) in bone marrow cel s
n female 129/S s
e treienc
ated or non-tre e.
ated with rapamycin Intact control (4 mo.)
Control (26 mo.)
Rapamycin (26 mo.)
Total incidence of ChA (%) 14.2 ± 1. di
.1 ± 1.6 e.
Incidence of single bridges (%) Incidence of multiple bridges (%) Incidence of fragments (%) aThe difference with the intact controls (4-month-old) is significant, p < 0.05. bThe difference with the controls (26-month-old) is significant, p < 0.05. There were four mice in each group.
Table 3. Effect of rapamycin on survival distribution in female 129/Sv mice
Number of survivors at the age of: (days)
*The first tumor detected in this interval. aThe difference with the controls of corresponding age is significant, p < 0.05; Fischer exact test.
the significant difference in tumor-bearing between treatment is significant between treated and control groups. According to and control groups. According to the estimated parameters of the estimated parameters of the Cox regression model, rapamycin the Cox regression model, rapamycin decreased risk of death in decreased the relative risk of death. According to the Fischer exact the group of tumor-bearing mice. The increase in lifespan was test for count data, the number of tumor-bearing mice under the observed only in the tumor-bearing cohort.
rapamycin treatment drops significantly (p-value = 0.0007602). Mice survived the age of 435 d (effective mice). Taking Mean lifespan of tumor-bearing mice (as well as long-lived mice)
into account the effective number of mice, we consider only increased under rapamycin treatment. Rapamycin treatment sig-
those who survived the age of 435 d (the age of the first tumor nificantly decreased the relative risk of death for tumor-bearing
detection). Rapamycin significantly increased the mean lifespan mice (Table 7).
of long-lived mice. As for the Gompertz model, the initial risk
of death (evaluated as parameter β) was 2.5 times lower in the
rapamycin-treated group as compared with the controls, whereas the rate of aging (α) was 1.4 times lower. According to the log- Evidence is emerging that mTOR is involved in cellular senes- rank test for the conditional lifespan distributions, the difference cence, organismal aging and age-related diseases.3 Rapamycin is Volume 10 Issue 24 Figure 2. Effects of rapamycin on lifespan and spontaneous carcinogenesis. (A) Effect of rapamycin on mice survival. (B) Effect of rapamycin on tumor
incidence.
Table 4. Parameters of the lifespan in female 129/Sv mice treated and non-treated with rapamycin
Mean lifespa n 2012 Lande
754 ± 43e.
Mean LS of last 10% survivors Maximum lifespan, daysDo not distrib
ute. 1038
Initial mortality rate (β), days-5 Aging rate (α), days-3 85.0 (75.9; 88.5) 118.2a (113.6; 139.4) The difference with the control of the same sex: ap < 0.05; bp < 0.001.
a clinically approved drug used in high doses in combinations Further investigations of a low-dose or an intermittent admin- with other immunosuppressants in patients after organ trans- istration of rapamycin starting from an older age are warranted. plantations. Here, we demonstrated that lifelong administra- Use of inbred strains of mice will allow one to compare results tion of rapamycin extends lifespan and postpones cancer in an and to choose the most beneficial schedules of rapamycin admin-inbred stain of female mice with normal lifespan. Cancer is an istration. Furthermore, combinations of rapamycin with metfor-age-related disease, and conditions that slow down the aging min, resveratrol, lipid-lowering agents, diet and physical exercise process are associated with decreased cancer incidence.36-40 In may afford additional benefits.
comparison, calorie restriction (CR), the proven modality that slows down aging, postpones cancer in mice.38-42 Since nutri- Material and Methods
ents activate the nutrient-sensing mTOR pathway, CR deacti-
vates mTOR.41 In this sense, rapamycin could be considered as Animals and experimental design. Inbred 129/Sv female mice,
"pharmacological CR." Also, metformin (an anti-diabetic drug originally obtained from Jackson Laboratory by the International
that is an indirect inhibitor of the mTOR pathway) moderately Agency for Research on Cancer (IARC), were housed and bred in
increased lifespan in female mice.43-45 In cancer-prone rodents, the Department of Carcinogenesis and Oncogerontology, N.N.
metformin delayed cancer, prolonged lifespan or both.43-48
Petrov Research Institute of Oncology.44 The animals were kept In our study, mice received high doses of rapamycin from the 5–7 in polypropylene cages (30 x 21 x 10 cm) under a standard age of 2 mo. Therefore, a certain overdose of rapamycin may mod- light/dark regimen (12 h light: 12 h darkness) at temperature erate a lifespan extension because of an increased mortality at a 22 ± 2°C and received standard laboratory chow43,50 and tap water young age. In theory, anti-aging agents should decrease fitness in ad libitum. Animals were checked daily by animal care person-young animals, especially in young males.49 Still, even taking this nel and weekly by a veterinarian. All studies were conducted in into account, our study demonstrated that lifelong administration accordance with ethical standards and according to national and of rapamycin significantly prolonged lifespan and dramatically international guidelines and have been approved by the authors' decreased spontaneous carcinogenesis in 129/Sv female mice.
institutional review board.
Table 5. Parameters of the tumorigenesis in female effective 129/Sv mice treated and non-treated with rapamycin
The age of the 1st tumor detection, days Effective number of mice Mean LS of effective mice, days 829 ± 27.0b (+10.5%) Initial mortality rate (β), days-5 44.9 (42.8; 46.2) 18.1 (15.3; 19.1)a Aging rate (α), days-3 85.0 (75.9; 88.5) 118.3a (113.6; 139.4) Number of tumor-bearing mice Number of tumors Mean LS of tumor-bearing mice, days Number of tumor-free mice Mean LS of tumor-free mice, days Localization of tumors
The difference with the control, ap < 0.05; bp < 0.001.
Table 6. Log-rank test estimation of differences in the lifespan distribu-
Longevity study.
Sixty si2012 Lande
x female 129/Sv mice at the age of tion between treated and non-treated with rapamycin female 129/Sv 2 mo were randomly divided into two groups. The first group of animals received 1.5 mg/kg rapamycin (LC Laboratories) sub- Mice survived
cutaneously (s.c.) three times a week for a period of 2 weeks, Groups of mice
the age of
followed by 2 weeks without rapamDo not
ycin. Mice in the s di
group received s.c. 0.1 of solvent without rapamycin and served as a control. Rapamycin was dissolved in 95% ethanol and then strib
130 days ute.
Tumor-bearing mice diluted with apyrogenic sterile water to a final concentration of 38 μg in 0.1 ml of 2% ethanol.
Once a month, simultaneously with weighing, the amount Tumor-bearing mice of drinking water and consumed food was measured and the rate of consumed food (grams) per mouse was calculated. Once every 3 mo, vaginal smears, taken daily for 2 weeks from the animals, were cytologically examined to estimate the phases of At autopsy, their skin and all internal organs were examined. their estrous function. In the same period, rectal body tempera- Revealed tumors were classified according to the recommenda- tures of the mice were measured with an electronic thermom- tion of the IARC as "fatal" (i.e., those, that directly caused the eter, TPEM-1 (KMIZ, Russia). The animals were observed until death of animal) or as "incidental" (for the cases in which animal their natural death or were sacrificed when moribund. The date died of a different cause). All tumors as well as the tissues and of each death was registered, and the mean lifespan, the age at organs with suspected tumor development were excised and fixed which 90% of the animals died, and the maximum lifespan were in 10% neutral formalin. After the routine histological process-estimated.
ing, the tissues were embedded into paraffin. Thin (5–7 μm) Cytogenetic study. Chromosome aberrations in bone marrow histological sections were stained with hematoxylin and eosine
cells were studied by the modified Ford method.51 Mice were sac- and were microscopically examined by a blind process. Tumors rificed with ether anesthesia. Both femurs of each mouse were were classified according to the IARC recommendations.
dissected, and bone marrow cells were flushed gently with 0.56% Statistics. Experimental results were statistically processed by
KCl solution into a centrifuge tube. Cells were treated for 20 the methods of variation statistics with the use of STATGRAPH min with hypotonic solution and fixed with ethanol:acetic acid statistic program kit. The significance of the discrepancies was mixture (3:1). Slides were stained with 4% acetoorseine. 20–30 defined according to the Student t-criterion, Fischer exact method, well-spread anaphases were analyzed for each animal, and cells χ2, non-parametric Wilcoxon-Mann-Whitney and Friedman with chromosome breaks, acentric fragments and other aberra- RM ANOVA on Ranks. Student-Newman-Keuls method was tions were evaluated on 1,000x magnification with a light micro- used for all pair-wise multiple comparisons. Coefficient of cor- scope (Leitz).
relation was estimated by the Spearman method, as previously Pathomorphological examination. All the animals that described. Differences in tumor incidence were evaluated by the
died or that were sacrificed when moribund were autopsied. Mantel-Hansel log-rank test. Parameters of the Gompertz model Volume 10 Issue 24 Table 7. Parameters of the Cox regression model for the relative risk of death compared to the control group in female 129/Sv mice
Mice survived the age:
Groups of mice
were estimated using the maximum likelihood method, a non- A semiparametric model of heterogeneous mortality was used linear optimization procedure and self-written code in "Matlab." to estimate the influence of the treatment on frailty distribution Confidence intervals for the parameters were obtained using the and baseline hazard.35bootstrap method.35 Disclosure of Potential Conflicts of Interest
For the experimental group, the Cox regression model was used to estimate relative risk of death and tumor develop- No potential conflicts of interest were disclosed.
ment under the treatment compared with the control group: h(t, z) = h (t) exp(zβ), where h(t, z) and h (t) denote the con- ditional hazard and baseline hazard rates, respectively; β is the The work was supported, in part, by the grant # 14.740.11.0115 unknown parameter for treatment group, and z takes values 0 from the Russian Federation Ministry of Education and Sciences and 1, being an indicator variable for two samples, the control and by the grant # 11-04-00317a from the Russian Foundation and treatment group.
Refere
nces 2012 Lande
10. Demidenko ZN, B lagosklonny MV. Q 19. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, macologic suppression of cellular senescence: pre- cienc
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MEK and PI-3K ut
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24. Bjedov I, Partridge L. A longer and healthier life with tion of Sch9p and involves increased mitochondrial 15. Leontieva OV, Gudkov AV, Blagosklonny MV. Weak TOR downregulation: genetics and drugs. Biochem OXPHOS complex density. Aging 2009; 1:131-45; p53 permits senescence during cell cycle arrest. Cell Soc Trans 2011; 39:460-5; PMID:21428920; http:// Cycle 2010; 9:4323-7; PMID:21051933; http:// Heeren G, Rinnerthaler M, Laun P, von Seyerl P, 25. Partridge L, Alic N, Bjedov I, Piper MD. Ageing Kossler S, Klinger H, et al. The mitochondrial ribosom- 16. Leontieva OV, Blagosklonny MV. DNA damaging in Drosophila: the role of the insulin/Igf and TOR al protein of the large subunit, Afo1p, determines cel- agents and p53 do not cause senescence in quiescent signalling network. Exp Gerontol 2011; 46:376- lular longevity through mitochondrial back-signaling cells, while consecutive re-activation of mTOR is via TOR1. Aging 2009; 1:622-36; PMID:20157544.
associated with conversion to senescence. Aging 2010; Demidenko ZN, Blagosklonny MV. Growth 26. Wullschleger S, Loewith R, Hall MN. TOR signaling stimulation leads to cellular senescence when the 17. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, in growth and metabolism. Cell 2006; 124:471- cell cycle is blocked. Cell Cycle 2008; 7:3355-61; Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426:620; PMID:14668850; 27. Blagosklonny MV, Hall MN. Growth and aging: a Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov 18. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, common molecular mechanism. Aging 2009; 1:357- VA, Pospelova TV, Blagosklonny MV. Rapamycin Benzer S. Regulation of lifespan in Drosophila by 62; PMID:20157523.
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TS, Popovich IG, Zabezhinski MA, et al. Effect of met-formin on lifespan and on the development of spontane- 33. Zhao C, Vollrath D. mTOR pathway activation in 42. Mostoslavsky R, Esteller M, Vaquero A. At the cross- ous mammary tumors in HER-2/neu transgenic mice. age-related retinal disease. Aging 2011; 3:346-7; road of lifespan, calorie restriction, chromatin and Exp Gerontol 2005; 40:685-93; PMID:16125352; disease: meeting on sirtuins. Cell Cycle 2010; 9:1907- 34. Blagosklonny MV. Aging and immortality: quasi- 12; PMID:20458180; http://dx.doi.org/10.4161/ programmed senescence and its pharmacologic inhibi- 49. Blagosklonny MV. Metformin and sex: Why suppres- sion of aging may be harmful to young male mice. tion. Cell Cycle 2006; 5:2087-102; PMID:17012837; 43. Anisimov VN, Berstein LM, Egormin PA, Piskunova Aging 2010; 2:897-9; PMID:21212463.
TS, Popovich IG, Zabezhinski MA, et al. Metformin 35. Anisimov VN, Zabezhinski MA, Popovich IG, slows down aging and extends lifespan of female SHR 50. Anisimov VN, Khavinson VK, Provinciali M, Alimova Piskunova TS, Semenchenko AV, Tyndyk ML, et mice. Cell Cycle 2008; 7:2769-73; PMID:18728386; IN, Baturin DA, Popovich IG, et al. Inhibitory effect of al. Rapamycin extends maximal lifespan in can- the peptide epitalon on the development of spontane-ous mammary tumors in HER-2/neu transgenic mice. cer-prone mice. Am J Pathol 2010; 176:2092- 44. Anisimov VN, Piskunova TS, Popovich IG, Int J Cancer 2002; 101:7-10; PMID:12209581; http:// 7; PMID:20363920; http://dx.doi.org/10.2353/ Zabezhinski MA, Tyndyk ML, Egormin PA, et al. Gender differences in metformin effect on aging, lifes- 36. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke pan and spontaneous tumorigenesis in 129/Sv mice. 51. Rosenfeld SV, Togo EF, Mikheev VS, Popovich A. Delayed occurrence of fatal neoplastic diseases in Aging 2010; 2:945-58; PMID:21164223.
IG, Khavinson V, Anisimov VN. Effect of epitha-lon on the incidence of chromosome aberrations ames dwarf mice: correlation to extended longev- 45. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski ity. J Gerontol A Biol
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in senescence-accelerated mice. Bull Exp Biol Med 37. Ikeno Y, Hubbard GB, Lee S, x.d2012 Lande
Sci 2003; 58:291- MA, Egormin PA, Piskuno S, et al. If started searly
in life, metformin treatment increases lifespan and postpones tumors in female SHR mice. Aging 2011; Cortez LA, Lew CM, 2002; 133:2 e.
74-6; PMID:12360351; http://dx.doi.
Webb CR, et al. Reduced incidence and delayed occur-rence of fatal neoplastic diseases in growth receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 2009; 64:522-9; PMID:19228785; http://dx.doi.org/10.1093/gerona/glp017.
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