The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index; 14 of the 41 sources its claims cite were checked for support.
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Open accessAbstract
Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
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Claims the paper makes
14 of 41 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies1–5.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005) source
- Supportedcites [2] Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006) source
The Abstract reports that TOR-pathway mutations and pharmacological inhibition increase chronological lifespan in yeast. The Conclusion says evidence from yeast, worms and flies indicates a central role for TOR in lifespan extension when signalling is reduced. The paper supports the collective claim, though it does not establish both intervention types in each species. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [3] Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004) source
- Partly supportedcites [4] Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004) sourceExperimental — accuracy not yet measured
The Abstract reports that genetic inhibition of TOR-pathway signalling extends lifespan in fruit flies, and the Introduction reports lifespan extension with TOR deficiency in nematodes. The paper does not report lifespan extension from TOR inhibition in yeast or from pharmacological inhibition; its mention of rapamycin describes a binding domain, not a drug intervention. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [5] Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“To document biochemical effects of rapamycin at the dose used for the lifespan studies, we evaluated the phosphorylation status of ribosomal protein subunit S6 (rpS6), a target substrate of S6 kinase 1 in the mTOR signalling pathway20, in visceral white adipose tissue (a sensitive indicator of mTOR inhibition by rapamycin treatment in vivo).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Partly supportedcites [20] Petroulakis, E., Mamane, Y., Le Bacquer, O., Shahbazian, D. & Sonenberg, N. mTOR signaling: implications for cancer and anticancer therapy. Br. J. Cancer 96 (Suppl.). R11–R15 (2007) sourceExperimental — accuracy not yet measured
The paper’s “Ribosomal protein S6 kinase” section places S6K1 downstream of mTOR, and its discussion of rapamycin says the drug inhibits mTOR. That supports the pathway rationale for measuring rpS6 phosphorylation, but the paper does not establish that it is a sensitive indicator of rapamycin-induced mTOR inhibition in vivo. (LLM, conf=0.83)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“At the cellular level, mTORC1 helps to coordinate growth and survival responses induced by alterations in nutrient availability, energy status, growth factor stimuli and exposure to potentially lethal cell stresses27–29; this strategic position at the nexus of nutrient/stress sensing pathways may contribute to the importance of TOR function in regulating lifespan in invertebrates and in mammals as”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Partly supportedcites [27] Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006) sourceExperimental — accuracy not yet measured
Figure 2 (p. 5) and Stress (p. 7) describe mTORC1 as responding to nutrients, energy status, growth factors, and stress. “TOR Influences Memory and Aging in Adults” (p. 3) reports lifespan effects in yeast, worms, and flies, but explicitly says links between mTOR signaling and mammalian longevity had not yet been reported. The attribution is therefore supported for the sensing pathways and invertebrate lifespan, but not for an established role in mammalian lifespan. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [28] Reiling, J. H. & Sabatini, D. M. Stress and mTORture signaling. Oncogene 25, 6373–6383 (2006) source
- Partly supportedcites [29] Sonenberg, N. & Hinnebusch, A. G. New modes of translational control in development, behavior, and disease. Mol. Cell 28, 721–729 (2007) sourceExperimental — accuracy not yet measured
The paper’s discussion of metabolism (indexed as Abstract; no page supplied) describes the PI3K/Akt/mTOR pathway as coupling nutrient and mitogen availability to cellular and organismal metabolic state. It also reports extended lifespan in C. elegans after loss of an eIF4E isoform, but does not link TOR function itself to lifespan regulation in either invertebrates or mammals, or establish the proposed nutrient/stress-sensing explanation. (LLM, conf=0.85)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Rapamycin may extend lifespan in old genetically heterogeneous mice through a combination of anti-neoplastic effects25,26 and effects on cellular stress resistance and response to nutrient dynamics27–29.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked — no full text of the sourcecites [25] Garber, K. Rapamycin’s resurrection: a new way to target the cancer cell cycle. J. Natl Cancer Inst. 93, 1517–1519 (2001) source
- Not matchedcites [26] Lorberg, A. & Hall, M. N. TOR: the first 10 years. Curr. Top. Microbiol. Immunol. 279, 1–18 (2004)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites [27] Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006) sourceExperimental — accuracy not yet measured
The Stress section (p. 6) describes TOR signaling in cellular responses to hypoxia, low energy, and other stresses; the aging section (p. 3) links TOR inhibition to longer lifespan in yeast, worms, and flies, possibly through calorie restriction. But it explicitly says links between mTOR signaling and mammalian longevity had not yet been reported, so it does not support this proposed mechanism for lifespan extension in old mice. The anti-neoplastic clause carries separate citations. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [28] Reiling, J. H. & Sabatini, D. M. Stress and mTORture signaling. Oncogene 25, 6373–6383 (2006) source
- Partly supportedcites [29] Sonenberg, N. & Hinnebusch, A. G. New modes of translational control in development, behavior, and disease. Mol. Cell 28, 721–729 (2007) sourceExperimental — accuracy not yet measured
The supplied Abstract passages link mTOR signaling to nutrient availability and report that reduced translation protects against oxidative stress and extends lifespan in C. elegans. They do not establish that rapamycin extends lifespan in old genetically heterogeneous mice through those mechanisms. The anti-neoplastic effects are attached to different citations (25–26) in the citing sentence. (LLM, conf=0.84)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Rapamycin's effect on lifespan is mediated by inhibition of mTOR.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We report here that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The genetically heterogeneous mouse population is representative enough that effects on lifespan are not genotype-specific.
- Rests on an assumption: Rapamycin's effect on lifespan is mediated by inhibition of mTOR.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Male mice at all three sites also had improved survival after rapamycin feeding (Figure 2).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we report that dietary encapsulated rapamycin increases mouse survival, including survival to the last decile, a measure of maximal lifespan.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Maximum lifespan was increased by rapamycin feeding.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Figure 3B shows that rapamycin reduced phosphorylated rpS6 4–5 fold when fed from 270 to about 800 days of age.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The genetically heterogeneous mouse population is representative enough that effects on lifespan are not genotype-specific.
- It may state two separate claims as one. 21
- Probably not a substantial claim. 14
Every source the paper cites for this claim was checked and supports it.
In the paper
“This coating increased the fraction of rapamycin that survived the food preparation process by 3- to 4-fold, and protected the agent from digestion in the stomach16.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Methods Summary > Diet preparation
What the sources say
- Supportedcites [16] Nadon, N. L. et al. Design of aging intervention studies: the NIA interventions testing program. AGE 30, 187–199 (2008) source
In “Issues unique to long-term intervention studies,” the paper reports a threefold higher rapamycin concentration in chow made with encapsulated rather than unencapsulated rapamycin, consistent with the claimed 3- to 4-fold range. The same passage says the enteric coating protects rapamycin from the stomach’s acidic conditions. (LLM, conf=0.90)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Median lifespan estimates of control females were consistent across sites (881–895 days), and were similar to values noted in Cohort 2004, which ranged from 858 to 909 days15.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Supportedcites [15] Miller, R. A. et al. An aging interventions testing program: study design and interim report. Aging Cell 6, 565–575 (2007) source
Table 1 (Discussion; page unavailable) gives female control medians of 858, 876, and 909 days across the three sites, matching the range attributed to the cited study. The Results report no significant difference in female control survival among sites. The 881–895-day range describes the citing document’s controls, not a result attributed to this source. (LLM, conf=0.91)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“At the cellular level, mTORC1 helps to coordinate growth and survival responses induced by alterations in nutrient availability, energy status, growth factor stimuli and exposure to potentially lethal cell stresses27–29; this strategic position at the nexus of nutrient/stress sensing pathways may contribute to the importance of TOR function in regulating lifespan in invertebrates and in mammals as”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Supportedcites [27] Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006) source
Figure 2 (p. 5) states that mTORC1 responds to growth factors, cellular energy status, nutrients, and stress while controlling pathways that determine cell growth. The Stress section (p. 6) describes responses to hypoxia and DNA damage, and Macroautophagy (p. 8) describes TOR-regulated recycling that helps starved cells survive. Together, these support the broad claim about coordinating growth and survival responses. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [28] Reiling, J. H. & Sabatini, D. M. Stress and mTORture signaling. Oncogene 25, 6373–6383 (2006) source
- Not checked yetcites [29] Sonenberg, N. & Hinnebusch, A. G. New modes of translational control in development, behavior, and disease. Mol. Cell 28, 721–729 (2007) source
Checked before — its earlier verdict is held back until a new check runs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The National Institute on Aging Interventions Testing Program (ITP) evaluates agents that may delay ageing and increase lifespan in genetically heterogeneous mice15–17.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked yetcites [15] Miller, R. A. et al. An aging interventions testing program: study design and interim report. Aging Cell 6, 565–575 (2007) source
Checked before — its earlier verdict is held back until a new check runs.
- Not checked yetcites [16] Nadon, N. L. et al. Design of aging intervention studies: the NIA interventions testing program. AGE 30, 187–199 (2008) source
Checked before — its earlier verdict is held back until a new check runs.
- Supportedcites [17] Strong, R. et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7, 641–650 (2008) source
The Introduction says the NIA developed the ITP to evaluate agents considered plausible candidates for delaying aging in laboratory mice. It also states that the protocol uses genetically heterogeneous mice and tests for effects on lifespan. (LLM, conf=0.92)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not checked yet
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Because incidences of most diseases rise rapidly with age6, interventions that delay ageing would greatly benefit health7–8.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Supportedcites [7] Miller, R. A. Extending life: scientific prospects and political obstacles. Milbank Q. 80, 155–174 (2002) source
In “Anti-geric Intervention: Slowing Aging in Laboratory Animals,” the paper says interventions that slow aging would delay late-life suffering and lengthen healthy adult life. It also argues that aging research could improve public health substantially more than research targeting one disease at a time. The claim reflects these projected benefits, not a demonstrated benefit in humans. (LLM, conf=0.93)
- Not matchedcites [8] Olshansky, S. J., Perry, D., Miller, R. A. & Butler, R. N. In pursuit of the longevity dividend. Scientist 20, 28–35 (2006)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:hedged· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Initial evidence that reduced TOR function can extend longevity came primarily from studies in yeast1,2 and invertebrates3–5.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005) source
- Supportedcites [2] Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006) source
The Abstract reports that decreased TOR signaling increases chronological life span in yeast. The Conclusion places this finding alongside evidence from worms and flies, supporting the sentence’s description of early evidence from yeast and invertebrates. Page numbers are not available in our copy. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [3] Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004) source
- Supportedcites [4] Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004) source
The Abstract reports that inhibiting TOR signaling extends lifespan in Drosophila, an invertebrate. This paper supports the invertebrate portion of the citing sentence; the yeast portion is attributed to other citations. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [5] Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003) source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When each site was evaluated separately, the beneficial effect of rapamycin for females was significant at each site (p < 0.005); for males, the effect was significant (p < 0.025) at UM and UT, but not at TJL.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rapamycin-fed and control mice were then compared separately for each combination of site and gender. Rapamycin had a consistent benefit, compared to controls, with p-values ranging from 0.03 to 0.0001 (Figure 2).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mean lifespan increases for females were 15%, 16%, and 7% (TJL, UM, UT), and life expectancy at 600 days increased by 45%, 48%, and 22% for females at the three sites.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The site-specific calculations documented a significant effect on females at both TJL (p = 0.0006) and UM (p = 0.0001); for males we noted a significant effect at both TJL (p = 0.008) and UT (p = 0.0001), with a marginal effect at UM (p = 0.07).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Summing across the three sites, 4.8% of the female control mice were alive at these ages, compared to 21.5% of the rapamycin-treated females (p < 0.0001). For males, the corresponding values were 5.9% of controls and 20.2% of rapamycin mice (p < 0.0001).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mean lifespan increases for males were 5%, 8%, and 15% (TJL, UM, UT), and male life expectancy at 600 days increased by 16%, 23% and 52%.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Blood levels of rapamycin in the treated mice were equivalent in males and females, between 60 and 70 ng/ml.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At the time of analysis, 51% of the females and 68% of the males had died, and a stratified log-rank test showed significantly lower mortality risk in the rapamycin-treated mice compared to controls, pooling across the three test sites (p = 0.0002 for males and p < 0.0001 for females).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice treated with other agents (enalapril and CAPE) evaluated in parallel did not differ from controls at the doses used (Supplemental Figure 1).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although rapamycin postpones death, it did not change the distribution of presumptive causes of death.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Strength:plain· not yet calibratedn = 40Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For data pooled across sites, a log-rank test rejected the null hypothesis that treatment and control groups did not differ (p < 0.0001); mice fed rapamycin were longer lived than controls (p < 0.0001) in both males and females.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
In the paper
“Because incidences of most diseases rise rapidly with age6, interventions that delay ageing would greatly benefit health7–8.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked yetcites [6] Kohn, R. R. Principles of Mammalian Aging 2nd edn 151 (Prentice-Hall, 1978)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sufficient mice are used to provide 80% power to detect a 10% increase (or decrease) in mean lifespan with respect to unmanipulated controls of the same sex, even if data from one of the three test sites were to be unavailable.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Beneficial effects of diet restriction (DR)21 and dwarf mutations, both of which extend lifespan in rodents, may to some degree result from repression of the mTOR complex 1 (mTORC1) pathway22,23.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked — no full text of the sourcecites [21] Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“The increase in both median and maximum lifespan seen in rapamycin-fed mice is consistent with the hypothesis that inhibiting the mTORC1 pathway retards mammalian ageing, but is not compelling proof that ageing rates are altered, which would require testing whether the intervention decelerates age-dependent changes in multiple organs, cell types, and intra-cellular and extra-cellular processes14.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
What the sources say
- Not checked — no full text of the sourcecites [14] Flurkey, K., Currer, J. M. & Harrison, D. E. in The Mouse in Biomedical Research 2nd edn, Vol. III (eds Fox, J. G. et al.) 637–672 (Academic, 2007) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Rapamycin's effect on lifespan is mediated by inhibition of mTOR.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data justify special attention to the role of the TOR pathway in control of ageing in mammals and in the pathogenesis of late-life illnesses.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, the significant benefits of rapamycin on male (and female) survival at TJL could not have been affected by diet prior to drug administration, because at TJL both control and rapamycin-fed mice received the same chow (Purina 5LG6) throughout this period.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Rapamycin's effect on lifespan is mediated by inhibition of mTOR.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
- Rests on an assumption: Rapamycin's effect on lifespan is mediated by inhibition of mTOR.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Control mice at UT and UM differed from those fed rapamycin, not only in exposure to rapamycin from 600 days of age, but also in specific formulation of the mouse chows (all based on the NIH-31 standard) used between weaning and 600 days.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rapamycin appears to reduce mid-life mortality risk when started at 270 days of age, but additional data are needed to provide an accurate estimate of effect size, and to evaluate effects on maximal longevity.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies are simultaneously replicated at three test sites: The Jackson Laboratory (TJL), the University of Michigan (UM), and the University of Texas Health Science Center (UT).”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Interpretation is somewhat complicated by differences among sites in survival of control males, and because mice assigned to the rapamycin-fed group at UT and perhaps at UM had lower mortality prior to 600 days than controls.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An effective anti-ageing intervention that could be initiated later than the midpoint of the lifespan could prove to be especially relevant to clinical situations, in which the efficacy of anti-ageing interventions would be particularly difficult to test in younger volunteers.”
§ Rapamycin fed late in life extends lifespan in genetically heterogeneous mice > Abstract
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
The paper relies on this without support.
Whether inhibition of mTOR signalling can extend life in a mammalian species was unknown.
“However, whether inhibition of mTOR signalling can extend life in a mammalian species was unknown.”
The paper relies on this without support.
The genetically heterogeneous mouse population is representative enough that effects on lifespan are not genotype-specific.
“The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility.”
The paper relies on this without support.
Rapamycin's effect on lifespan is mediated by inhibition of mTOR.
“Rapamycin reduces function of the rapamycin target kinase TOR and has anti-neoplastic activities, and genetic inhibition of TOR extends lifespan in short-lived model organisms.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Rapamycin and its analogs (so-called ‘rapalogs’) suppress the SASP by inhibiting mTOR and appear to extend healthspan and lifespan in mice105,108,109.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [108]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Additionally, rapamycin treatment increased lifespan and delayed certain ageing-related dysfunctions in mice234.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [234]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“which might explain its beneficial impact on longevity [121,122].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [122]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“marked increase in lifespan and enhance health-span in mice treated with rapamycin, a well-characterized inhibitor of mTOR (Harrison et al., 2009)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Harrison et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In mice, treatment with rapamycin also extends longevity in what is considered the most robust chemical intervention to increase lifespan in mammals”
From The Hallmarks of Aging (2013) · cites this paper as Harrison et al., 2009
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Interventions using chemical inducers of macroautophagy (another type of autophagy different from chaperone-mediated autophagy) have spurred extraordinary interest after the discovery that constant or intermittent administration of the mTOR inhibitor rapamycin can increase the lifespan of middle-aged mice (Blagosklonny, 2011; Harrison et al., 2009).”
From The Hallmarks of Aging (2013) · cites this paper as Harrison et al., 2009
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“When rapamycin is administered late in life, it extends lifespan (Harrison et al., 2009; Miller et al., 2011), slows aging in a dose-dependent manner, shows differential effects by sex (Wilkinson et al., 2012), and is synergistic with metformin.”
From Metformin as a tool to target aging (2016) · cites this paper as Harrison et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“starting with a landmark study by the National Institute on Aging Interventions Testing Program (NIA ITP) published in 2009 which demonstrated that rapamycin extended the lifespan of genetically heterogeneous mice 33.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [33]
The cited source says what the claim attributes to it.
In the citing paper
“Importantly, unlike caloric restriction, another well validated longevity intervention, which is less efficacious when begun later in life 34, rapamycin robustly extends lifespan when dosing was not initiated until late in life when the mice were 20 months of age (equivalent to about a 60 year old human) 33,35.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [33]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“a well-known inhibitor of mTOR, rapamycin, inhibits the production of SASP factors”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [122]
Experimental — accuracy not yet measuredIn the citing paper
“mTOR signaling has been demonstrated to be involved in regulating mammalian lifespan (Harrison et al., 2009).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Harrison et al., 2009
In the citing paper
“In 2009, rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, was shown to significantly extend the lifespan of mammals.58”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [58]
In the citing paper
“AMPK activators and the mTOR signalling pathway inhibitor rapamycin have considerable ramifications for longevity and managing age-related illnesses.58,402–404”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [58]
In the citing paper
“Animal models exploring the effect of rapamycin and rapalogs on longevity have determined their ability to extend lifespan167-169.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [169]
In the citing paper
“Moreover, it was recently shown that the TOR inhibitor rapamycin extends lifespan in mice even when treatment is initiated late in life (58).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [58]
In the citing paper
“Much of the literature suggests that the genetic regulation of mTOR signal transduction can slow the aging of many organisms [183–185].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [184]
In the citing paper
“For instance, inhibition of the mTOR pathway (using the drug rapamycin), which has been shown to extend lifespan in a variety of model organisms (de Magalhaes et al., 2012;Harrison et al., 2009), is an effective SASP suppressor (Correia-Melo et al., 2016;Herranz et al., 2015;Laberge et al., 2015).”
From Stress, cell senescence and organismal ageing (2018) · cites this paper as Harrison et al., 2009
In the citing paper
“Depletion of ribosome subunits or interference with the target of rapamycin/ribosomal protein S6 kinase pathway, which functions to activate protein translation, were found to alter the lifespan of a variety of species including mammals (54–56).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [54]
In the citing paper
“Additionally, rapamycin has earned great interest over the years to prolong lifespan (195, 280), even when administered to aged animals (281).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [281]
In the citing paper
“Middle-aged mice on a diet supplemented with rapamycin survived significantly longer (Harrison et al., 2009); however, reports of the potent immunosuppressive properties of rapamycin suggest that the drug is unsuitable for lifespan extension in humans.”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Harrison et al., 2009
In the citing paper
“Rapamycin selectively activates autophagy through inhibiting the mTOR pathway [60] and can extend the lifespan of mice [79].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [79]
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“40 Later, in 2009, Harrison et al. 41 suggested that when rapamycin, as an mTOR inhibitor drug, is administered to genetically heterogeneous mice from 600 days of age (relatively equivalent to 60 years of age in humans), it can prolong the median and maximal longevity.”
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Metadata
- Authors
- Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., Pahor, M., Javors, M. A., Fernandez, E., & Miller, R. A.
- Affiliations
- Jackson Laboratory (US)
- The University of Texas at San Antonio Health Science Center (US)
- National Institutes of Health (US)
- University of Michigan (US)
- NYU Langone Health (US)
- University of Florida (US)
- Corresponding author
- Harrison, David E.
- ORCID
- Venue
- Nature
- Published
- 2009-07
- Volume
- 460
- Issue
- 7253
- Pages
- 392-395
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2786175
- OpenAlex
- W2048376025
- Cited by
- 3,766
- References
- 32
- Citations by year
- 2026: 185 · 2025: 208 · 2024: 182 · 2023: 199 · 2022: 211 · 2021: 225 · 2020: 194 · 2019: 252 · 2018: 202 · 2017: 219 · 2016: 232 · 2015: 249 · 2014: 254 · 2013: 228 · 2012: 262
- FWCI
- 74.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institute on Aging (AG 022308, AG13319, P30AG025707, AG022307, AG022303, AG025707, P30AG013319, U01AG022307, P30AG028740, U01AG022308, U01AG022303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- rapamycin, mTOR signaling, TOR signaling, lifespan extension, aging, genetically heterogeneous mice, sex differences in longevity, age-related diseases, PI3K/AKT/mTOR pathway, cancer mortality, dietary restriction, autophagy, translational regulation, survival analysis
- MeSH terms
- Administration, Oral, Aging, Animals, Carrier Proteins, Diet, Disease Susceptibility, Female, Longevity, Male, Specific Pathogen-Free Organisms, Time Factors, Survival Analysis, Phosphotransferases (Alcohol Group Acceptor), Sirolimus, Mice, TOR Serine-Threonine Kinases
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