Targeting the biology of aging with mTOR inhibitors

In the paper

“Studies in mice have likewise shown that genetic depletion of mTORC1 subunits, deletion of S6K1 or downstream substrates, or expression of dominant negative 4E-BP1 in specific tissues extends the lifespan and healthspan of mice 13–16.”

What the sources say

• Partly supported

  The lifespan results report that S6K1 deletion increased longevity in female mice and was associated with resistance to age-related pathologies. They also report no effect on median or maximum lifespan in male mice, so the unqualified lifespan claim for mice overstates this source’s finding. This paper supports the S6K1-deletion part of the multi-citation sentence, not the other listed interventions. (LLM, conf=0.88)

  cites [13] Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper reports increased lifespan in S6K1-knockout mice (Extended Data Figure 5) and in mice carrying a phosphorylation-deficient mutation in the downstream effector EPRS (main text, page unavailable). It also reports improved glucose homeostasis and reduced adiposity, but does not establish an extension of healthspan. Its EPRS mutation is not described as a tissue-specific deletion, and the paper does not report lifespan extension from dominant-negative 4E-BP1. (LLM, conf=0.86)

  cites [14] Arif, A. et al. EPRS is a critical mTORC1–S6K1 effector that influences adiposity in mice. Nature 542, 357–361 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) states that reduced S6K signaling extends lifespan in mice, and the Discussion reports lifespan extension after S6k1 deletion. But the Introduction says the lifespan outcome for mice with activated 4E-BP was unknown; this paper reports metabolic benefits of muscle-specific 4E-BP1 activation, not extended mouse lifespan. It also does not establish that tissue-specific depletion of mTORC1 subunits extends both lifespan and healthspan in mice. (LLM, conf=0.88)

  cites [15] Tsai, S. et al. Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. J. Clin. Invest. 125, 2952–2964 (2015). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports lifespan extension in female S6K1-knockout mice and protection from aging-related metabolic decline in mice overexpressing wild-type 4E-BP1. The Discussion reports metabolic benefits from tissue-specific expression of activated 4E-BP1, but the paper does not report lifespan extension from that intervention or from depletion of mTORC1 subunits. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [16] Tsai, S. Y. et al. Increased 4E-BP1 expression protects against diet-induced obesity and insulin resistance in male mice. Cell Rep. 16, 1903–1914 (2016). sourceExperimental — accuracy not yet measured

In the paper

“In the subset of 6 animals treated with rapamycin or vehicle for nine months, 2 rapamycin-treated animals showed an increase in fasting blood glucose, and 2 rapamycin-treated animals shown an increase in triglycerides suggesting the possibility of some inhibition of TORC2 at this dose level 47.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [47] Sills, A. M., Artavia, J. M., DeRosa, B. D., Ross, C. N. & Salmon, A. B. Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. Am. J. Primatol. 81, e22927 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Rapamycin is an acute inhibitor of mTORC1 but not mTORC2 28.”

What the sources say

• Supported

  The Results and Discussion (page unavailable) report that FKBP12-rapamycin binds the raptor-containing mTOR complex but not the rictor-containing complex. The paper describes the rictor complex as rapamycin-insensitive while allowing that long-term treatment might eventually disrupt its assembly, consistent with the claim's acute-treatment qualifier. (LLM, conf=0.90)

  cites [28] Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004). source

In the paper

“Both rapamycin and complete mTOR inhibition preferentially inhibit translation of mRNAs with 5′ terminal oligopyrimidine (TOP) motifs, suggesting a potential role for these genes in longevity 55,56.”

What the sources say

• Partly supported

  The passage on Torin1 treatment (section labelled Abstract; page unavailable) reports selective suppression of TOP mRNA translation under complete mTOR inhibition. The passage on rapamycin says TOP mRNA translation is inhibited less by rapamycin than by other forms of mTOR suppression, but does not establish that rapamycin preferentially inhibits TOP mRNAs. The longevity suggestion is the citing authors’ inference, not a finding assessed here. (LLM, conf=0.86)

  cites [55] Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (page unavailable) reports that rapamycin selectively suppresses translation of 5′TOP mRNAs. The paper does not report the effect of complete mTOR inhibition, so it supports only the rapamycin portion of the attributed comparison. The proposed longevity role appears to be the citing authors’ inference, not a finding tested here. (LLM, conf=0.87)

  cites [56] Jefferies, H. B. et al. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 16, 3693–3704 (1997). sourceExperimental — accuracy not yet measured

In the 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.”

What the sources say

• Supported

  The paper reports that feeding rapamycin from 600 days of age—about 20 months—extended median and maximum lifespan in male and female mice (Abstract, passage 7; Methods Summary, passage 5). It also describes a 600-day-old mouse as roughly equivalent to a 60-year-old person (Abstract, passage 1). The caloric-restriction comparison has a separate citation in the citing sentence. (LLM, conf=0.94)

  cites [33] Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). source
• Partly supported

  The Diet Restriction section reports that dietary restriction markedly increased lifespan in the studied mice, supporting its description as a longevity intervention. It says restriction began at 4–5 weeks of age but does not compare its efficacy when begun later in life. The rapamycin finding is attached to other citations in the citing sentence, not this one. (LLM, conf=0.84)

  cites [35] Flurkey, K., Astle, C. M. & Harrison, D. E. Life extension by diet restriction and N-acetyl-l-cysteine in genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 65, 1275–1284 (2010). sourceExperimental — accuracy not yet measured

In the paper

“Many of the side effects of rapamycin, which include immunosuppression, hyperlipidemia and hyperglycemia, have raised concerns about the feasibility of using rapamycin to promote healthy longevity in humans and slowed clinical evaluation of mTOR inhibitors for diseases of aging 26.”

What the sources say

• Supported

  In “Rapamycin side effects” (page not available), the paper identifies immune suppression as a major concern and reports hyperlipidemia, glucose intolerance, and increased new-onset diabetes among rapamycin’s metabolic effects. The latter findings support the claim’s reference to hyperglycemia. (LLM, conf=0.89)

  cites [26] Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980–989 (2013). source

In the paper

“Further, neither mTOR inhibition by rapamycin or deletion of S6K1 significantly slows protein translation in mice or cells 52–54.”

What the sources say

• ?Not checked — no full text of the sourcecites [52] Mieulet, V. et al. S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover. Am. J. Physiol. Cell Physiol. 293, C712–C722 (2007). source
• Partly supported

  In the section on Torin1 and mTOR, the paper reports that rapamycin had very little effect on total protein synthesis in wild-type and Rictor-null mouse embryonic fibroblasts. It does not report that deleting S6K1 leaves translation unchanged, nor does this cell experiment establish the claim in mice. The paper also distinguishes rapamycin treatment from more complete mTOR inhibition. (LLM, conf=0.88)

  cites [53] Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [54] Pedersen, S., Celis, J. E., Nielsen, J., Christiansen, J. & Nielsen, F. C. Distinct repression of translation by wortmannin and rapamycin. Eur. J. Biochem. 247, 449–456 (1997). source

In the paper

“A small pilot study found that treatment with 0.05 mg/kg or 0.1 mg/kg rapamycin three times per week did not cause statistically significant side effects but did improve measurements of cardiac function (fractional shortening and diastolic function) 48.”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [48] Urfer, S. R. et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience 39, 117–127 (2017). sourceExperimental — accuracy not yet measured

In the paper

“In mammals, autophagy is reportedly upregulated in CR mice and in the cells of long-lived Snell dwarf mice, and is required for some of the beneficial effects of a CR diet on the heart, kidney, and liver 69–72.”

What the sources say

• Partly supported

  In “Restorative Efforts: A Multi-Front Attack?” (page unavailable), the paper reports that caloric restriction preserves autophagic regulation and liver-protein proteolysis in rats. It does not establish upregulation in CR mice or Snell dwarf mice, or that autophagy is required for CR benefits in the heart, kidney, and liver. (LLM, conf=0.86)

  cites [69] Cuervo, A. M. et al. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1, 131–140 (2005). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (‘Effect of caloric restriction on myocardial autophagy’; page unavailable) reports increased autophagy markers in the hearts of calorie-restricted mice. The Discussion says further study is needed to establish whether autophagy helps preserve cardiac function; it does not show that autophagy is required for the diet’s benefits. This paper also does not address Snell dwarf mice or benefits to the kidney and liver. (LLM, conf=0.89)

  cites [70] Han, X. et al. Influence of long-term caloric restriction on myocardial and cardiomyocyte contractile function and autophagy in mice. J. Nutr. Biochem. 23, 1592–1599 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“CR enhances autophagy in aged kidney,” page unavailable) reports greater autophagy markers in kidneys of calorie-restricted mice than in mice fed ad libitum. The Discussion links Sirt1-mediated autophagy and adaptation to hypoxia to kidney protection. This paper does not establish the claim about Snell dwarf mice or the heart and liver. (LLM, conf=0.86)

  cites [71] Kume, S. et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest. 120, 1043–1055 (2010). sourceExperimental — accuracy not yet measured
• Supported

  The Results section reports greater autophagy in fibroblasts from Snell dwarf mice than in control cells after amino acid deprivation, and the Discussion reports the same pattern after oxidative stress. This supports the Snell-dwarf-cell portion of the multiply cited sentence; the finding is specific to fibroblasts under those conditions. (LLM, conf=0.88)

  cites [72] Wang, M. & Miller, R. A. Fibroblasts from long-lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress. Aging Cell 11, 668–674 (2012). source

In the paper

“Low doses of the mTOR inhibitor BEZ235 were observed to be well-tolerated and to decrease the incidence of laboratory-confirmed RTIs (the Phase 2b primary endpoint; OR 0.601 [90% CI 0.39, 0.92]; p-value 0.025) but not the incidence of clinically symptomatic respiratory illness”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [84] Mannick, J. B. et al. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2, e250–e262 (2021). source

In the paper

“Autophagy is normally impaired with age in multiple types of mouse cells, and genetic activation of autophagy in the aged mouse liver rejuvenates the liver histologically and improves function 76–78.”

What the sources say

• Partly supported

  The paper reports that aged transgenic mouse livers more closely resembled young livers ultrastructurally and performed better on a liver-function assay (both passages labeled Abstract; page unavailable). It also describes age-related autophagy decline broadly, but its mouse experiments focus on liver, not multiple types of mouse cells. The genetic intervention maintained or restored chaperone-mediated autophagy rather than generally activating autophagy. (LLM, conf=0.85)

  cites [76] Zhang, C. & Cuervo, A. M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, 959–965 (2008). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [77] Hua, Y. et al. Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res. Cardiol. 106, 1173–1191 (2011). source
• Partly supported

  In Results and Discussion, “Periodic FMD in aged mice” (page unavailable), the paper reports an age-dependent increase in the autophagy-related marker p62 in mouse muscle, supporting an age-related change in that tissue. It does not establish impairment across multiple mouse cell types or report genetic activation of autophagy rejuvenating the aged liver histologically or functionally. (LLM, conf=0.88)

  cites [78] Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015). sourceExperimental — accuracy not yet measured

In the paper

“A study by Neff and colleagues found that rapamycin significantly reduced the proportion of 16 month old mice with cancer and/or precancerous lesions 87, and suggested that this indicated that the effects of rapamycin on lifespan was driven by its anti-cancer effects.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [87] Neff, F. et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 123, 3272–3291 (2013). source

In the paper

“However, the NIA ITP has shown that the overall prevalence of cancer at death, as well as the spectrum of cancers observed, was very similar between rapamycin-treated mice and controls 36.”

What the sources say

• Supported

  The Results (Table 3; page unavailable) report non-neoplastic causes of death in 11% of rapamycin-treated mice and 7% of controls, indicating similar overall cancer prevalence. The same three cancers were the most common in both groups, and the authors conclude that rapamycin did not dramatically change the range of illnesses observed at death, although lung carcinoma was more common in treated mice. (LLM, conf=0.88)

  cites [36] Miller, R. A. et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191–201 (2011). source

In the paper

“Mice expressing EPRS S999A, which is non phosphorylatable, have reduced body weight and adipose mass, and increased lifespan, similar to mice lacking S6K1 14.”

What the sources say

• Supported

  The Abstract identifies S999A as a phospho-deficient EPRS mutation and reports that homozygous S999A mice had lower body weight, reduced adipose tissue mass, and increased lifespan, with notable similarities to S6K1-deficient mice. The detailed lifespan and adiposity passages further support the comparison. (LLM, conf=0.95)

  cites [14] Arif, A. et al. EPRS is a critical mTORC1–S6K1 effector that influences adiposity in mice. Nature 542, 357–361 (2017). source

In the paper

“While rapamycin itself is not a strong inducer of autophagy compared to mTOR kinase inhibitors 53, the effects of rapamycin on the pathology of mouse models of Alzheimer’s disease has been attributed in part to increased autophagy 79,80.”

What the sources say

• Supported

  Citation 53 is attached to the comparison of rapamycin with mTOR kinase inhibitors, not to the Alzheimer’s disease claim, which has separate citations. In “Torin1 Is a Potent and Selective mTOR” (page not provided), the paper reports strong autophagy-marker changes with Torin1 but only a minor change with rapamycin. (LLM, conf=0.94)

  cites [53] Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009). source
• Supported

  The Results section reports that rapamycin induced autophagy in 3xTg-AD mice and that prophylactic treatment reduced Aβ pathology. It attributes the benefit to facilitating autophagy, while noting that inducing autophagy after plaques and tangles were established did not rescue the pathology. The comparison with mTOR kinase inhibitors is attached to a different citation, not this source. (LLM, conf=0.91)

  cites [79] Majumder, S., Richardson, A., Strong, R. & Oddo, S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE 6, e25416 (2011). source
• Supported

  The Introduction and Results and Discussion report that rapamycin reduced Aβ42 and cognitive deficits in PDAPP mice and suggest that increased autophagy contributed to those effects. The comparison with mTOR kinase inhibitors is attached to a different citation, not this source. Page numbers were not supplied. (LLM, conf=0.93)

  cites [80] Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS ONE 5, e9979 (2010). source

In the paper

“The study confirmed that 6 weeks of treatment with a low dose of mTOR inhibitors was safe and was associated with a dose-dependent significant improvement in influenza vaccination response.”

What the sources say

• Partly supported

  The trial description reports 264 adults aged ≥65 treated for six weeks, and the safety passage says the regimens were generally well tolerated. The results report a significant vaccination-response improvement for the low-dose RAD001–BEZ235 combination, but not a dose-dependent improvement: neither RAD001 dose met the primary endpoint alone, and BEZ235 alone showed no increase. The paper's dose-dependent statement concerns pharmacodynamic effects, not vaccination response (indexed section labeled Abstract; page unavailable). (LLM, conf=0.88)

  cites [83] Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Several studies have been conducted on hematopoietic stem cells (HSCs); aged mice have elevated mTORC1 activity in their HSCs, as well as functional deficits similar to those observed in a mouse model of hyperactive mTORC1 activity 39.”

What the sources say

• Supported

  In the Results section, HSCs from old mice had increased phosphorylation of the mTORC1 substrate S6K and its substrate S6 compared with HSCs from young mice. The Results also report that Tsc1 deletion constitutively activated mTOR in young-mouse HSCs and produced functional deficits resembling those of aged HSCs. (LLM, conf=0.93)

  cites [39] Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009). source

In the paper

“In worms, mTORC2 inhibition has most often been associated with reduced lifespan, while in flies increasing mTORC2 activity through overexpression of Rictor extends lifespan 21,111–113.”

What the sources say

• Partly supported

  The Results section reports that rict-1 mutants have reduced lifespan on OP50 food, supporting a condition-specific instance of the worm claim. But it also reports that TORC2 inhibition extends lifespan under other conditions, so it does not establish that reduced lifespan is the most common outcome. Our copy does not report lifespan extension from Rictor overexpression in flies (no page numbers available). (LLM, conf=0.86)

  cites [21] Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s ‘RICT-1 regulates life span in a diet-dependent manner’ section reports that rict-1 mutant worms were short-lived on the standard OP50 diet, supporting the worm portion of the claim. It also reports extended lifespan on HB101 and HT115 and concludes that the effect depends on diet, so this paper does not establish that inhibition ‘most often’ reduces lifespan. The fly portion is not a finding of this worm study. (LLM, conf=0.87)

  cites [111] Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496–511 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and discussion section (page unavailable) reports that loss of the mTORC2 component rict-1 shortened worm lifespan under several conditions, supporting the worm portion. It also reports lifespan extension after rict-1 RNAi, so the effect depends on conditions; our copy does not support the claim about Rictor overexpression extending lifespan in flies. (LLM, conf=0.85)

  cites [112] Mizunuma, M., Neumann-Haefelin, E., Moroz, N., Li, Y. & Blackwell, T. K. mTORC2–SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13, 869–878 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that heart-specific rictor overexpression prolongs lifespan in flies. The Discussion describes the lifespan findings in C. elegans as conflicting, so it does not support the claim that mTORC2 inhibition in worms has most often been associated with reduced lifespan. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [113] Chang, K. et al. TGFB–INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 16, 1807–1822 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Altered mTORC1 signaling with age has also been reported in other tissues of mice, with most studies reporting increased mTORC1 activity with age 39,97,106–108.”

What the sources say

• Supported

  The Results section (‘Dysregulation of the mTOR Pathway in HSC from aged mice’) reports increased phosphorylation of mTORC1 substrates in hematopoietic stem cells from old versus young mice. This paper supports the cited sentence as an example of age-related increased mTORC1 activity in mice; the sentence cites several studies for its broader ‘most studies’ characterization. (LLM, conf=0.88)

  cites [39] Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009). source
• Supported

  The Discussion states that numerous studies reported age-related changes in mTOR signaling, with the majority suggesting increased mTORC1 signaling across tissues and cell types. Table 1 in the Introduction lists several mouse-tissue studies reporting increases. The paper distinguishes those earlier reports from its own finding that increases are not universal. (LLM, conf=0.94)

  cites [97] Baar, E. L., Carbajal, K. A., Ong, I. M. & Lamming, D. W. Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell 15, 155–166 (2016). source
• Partly supported

  The Results (‘Signaling pathways in aging’) support altered mTOR signaling in old mouse liver and muscle. They report markedly decreased p70 S6 kinase phosphorylation, reflecting decreased mTOR activity—not increased activity. The paper does not establish that most studies report an increase. (LLM, conf=0.86)

  cites [106] Houtkooper, R. H. et al. The metabolic footprint of aging in mice. Sci. Rep. 1, 134 (2011). sourceExperimental — accuracy not yet measured
• Supported

  The paper’s opening summary reports higher mTOR activity in the livers of 28-month-old female mice than in middle-aged mice after overnight fasting. It supports this citation’s role as an example of increased mTOR signaling with age in a mouse tissue. (LLM, conf=0.88)

  cites [107] Leontieva, O. V., Paszkiewicz, G. M. & Blagosklonny, M. V. Fasting levels of hepatic p-S6 are increased in old mice. Cell Cycle 13, 2656–2659 (2014). source
• ?Not checked — no full text of the sourcecites [108] Calhoun, C. et al. Senescent cells contribute to the physiological remodeling of aged lungs. J. Gerontol. A Biol. Sci. Med. Sci. 71, 153–160 (2016). source

In the paper

“Another side effect of doses of rapamycin that extend lifespan in mice is testicular degeneration 25,144, and reduced male fertility has been observed in humans treated with rapalogs 145,146.”

What the sources say

• Supported

  The Introduction states that the study tested a 14 ppm rapamycin dose previously shown to extend lifespan in mice. The section ‘Rapamycin increases testicular degeneration in male mice’ reports degeneration in 30/36 treated males versus 2/15 controls, including at the lowest dose. The human-fertility clause has separate citations and is not attributed to this paper. (LLM, conf=0.94)

  cites [25] Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012). source
• Supported

  The Results section (page unavailable) calls testicular degeneration a known side effect of rapamycin in mice and reports substantially reduced testes mass with both daily and intermittent treatment. The Introduction states that rapamycin extends lifespan in mice. The separate claim about reduced fertility in humans is attributed to other citations, not this paper. (LLM, conf=0.86)

  cites [144] Arriola Apelo, S. I. et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15, 28–38 (2016). source
• Supported

  The citation to this paper is attached to the human-fertility portion of the sentence, not the claim about mice. In the ‘Fathered pregnancy rate in SRL-treated patients’ section, the fathered pregnancy rate was significantly lower in sirolimus-treated kidney transplant recipients than in the comparison group. The paper concludes that sirolimus may reduce male fertility. (LLM, conf=0.92)

  cites [145] Zuber, J. et al. Sirolimus may reduce fertility in male renal transplant recipients. Am. J. Transplant. 8, 1471–1479 (2008). source
• ?Not checked — no full text of the sourcecites [146] Huyghe, E. et al. Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transpl. Int. 20, 305–311 (2007). source

In the paper

“Whole body deficiency of mTORC2 signaling, or tissue-specific inhibition of mTORC2 signaling in the brain, liver, or adipose tissue, reduces lifespan in C57BL/6J mice 114–117.”

What the sources say

• Partly supported

  The Discussion reports reduced male lifespan after whole-body, liver-specific, or hypothalamic mTORC2 loss. The Results report a 7% reduction in median female lifespan with adipose-specific loss, but no significant effect on male lifespan. The Animals section specifies a C57BL/6 background, not specifically C57BL/6J; the claim omits the sex-specific limits of the findings. (LLM, conf=0.88)

  cites [114] Yu, D. et al. Calorie-restriction-induced insulin sensitivity is mediated by adipose mTORC2 and not required for lifespan extension. Cell Rep. 29, 236–248 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section ('mTORC2 signaling is essential for healthspan and lifespan'; page unavailable) reports that hypothalamic Rictor deletion shortened lifespan in both female and male mice. The Introduction also reports reduced male lifespan after whole-body RICTOR depletion or hepatic Rictor deletion. The paper does not establish reduced lifespan from adipose-specific inhibition, and its Materials and Methods say the experimental mice were backcrossed to C57BL/6N, not C57BL/6J. (LLM, conf=0.90)

  cites [115] Chellappa, K. et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell 18, e13014 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports that whole-body Rictor deletion and deletion in several tissues negatively affect survival, but it does not identify brain and adipose tissue as lifespan-reducing sites. The Results show reduced lifespan after hepatic Rictor deletion in male C57BL/6J mice; the Introduction explicitly says liver-specific deletion has no lifespan effect in females. The claim therefore overgeneralizes the liver finding to mice of both sexes. (LLM, conf=0.88)

  cites [116] Arriola Apelo, S. I. et al. Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging. eLife 9, e56177 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that whole-body or liver-specific Rictor depletion decreased male, but not female, lifespan. The paper does not report lifespan effects from brain- or adipose-specific inhibition. Its Experimental Procedures identify the mice as C57BL/6, not specifically C57BL/6J. (LLM, conf=0.90)

  cites [117] Lamming, D. W. et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13, 911–917 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Rapamycin may be particularly beneficial against cancer stem cells, and has been shown to deplete leukemia-initiating cells and inhibit both self-renewal and differentiation of stem cells derived from infantile hemangioma 91,92.”

What the sources say

• Supported

  In “Rapamycin depletes leukaemia-initiating cells,” transplantation experiments show that rapamycin inhibited the generation or maintenance of leukaemia-initiating cells in Pten-deleted mice. This supports the leukaemia finding attributed to this source; the infantile-haemangioma finding appears to be covered by the other citation in the sentence. (LLM, conf=0.91)

  cites [91] Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006). source
• Partly supported

  The Results section, “HemSC Self-renewal and Multi-lineage Differentiation are Disrupted by Rapamycin” (page unavailable), reports reduced self-renewal and inhibited adipogenic differentiation in stem cells from infantile hemangioma. It does not support an unqualified inhibition of differentiation: endothelial differentiation was unaffected, and another Results section reports increased smooth-muscle markers. The leukemia-initiating-cell claim appears alongside a second citation and is not attributed specifically to this paper. (LLM, conf=0.88)

  cites [92] Greenberger, S. et al. Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma. J. Invest. Dermatol. 131, 2467–2476 (2011). sourceExperimental — accuracy not yet measured

In the paper

“Inhibition of mTORC2 signaling extends the lifespan of C. elegans under certain temperatures and dietary conditions111,112, has anti-tumor effects 128–131, is beneficial in mouse models of mitochondrial disease132,133, and has been shown to inhibit or reverse senescence in human cells 134,135.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [111] Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496–511 (2009). source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [112] Mizunuma, M., Neumann-Haefelin, E., Moroz, N., Li, Y. & Blackwell, T. K. mTORC2–SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13, 869–878 (2014). source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [128] Guertin, D. A. et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15, 148–159 (2009). sourceExperimental — accuracy not yet measured
• Supported

  This source is cited among references 128–131 for the anti-tumor-effects clause, not for the lifespan, mitochondrial-disease, or senescence clauses. In the Results (‘LINC00998 inhibits AML cell survival and induces apoptosis in vivo’), tumors with reduced mTORC2 levels were smaller than controls; the ‘mTORC2 is the downstream target’ results also report that mTORC2 overexpression rescued the reduced malignant behavior of AML cells. (LLM, conf=0.88)

  cites [129] Fang, X. et al. LINC00998 functions as a novel tumor suppressor in acute myeloid leukemia via regulating the ZFP36 ring finger protein/mammalian target of rapamycin complex 2 axis. Bioengineered 12, 10363–10372 (2021). source
• Partly supported

  Only the anti-tumor clause is attributed to this source; the other clauses have separate citations. The Results section, “Targeting mTORC2 sensitize NSCLC to gemcitabine in vivo” (page unavailable), reports anti-tumor effects when mTORC1/2 inhibition was combined with gemcitabine in NSCLC xenografts. It does not establish the unqualified claim that mTORC2 inhibition has anti-tumor effects on its own. (LLM, conf=0.84)

  cites [130] Tian, L. et al. mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer. Neoplasia 23, 643–652 (2021). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [131] Ding, Y. et al. Vimentin loss promotes cancer proliferation through up-regulating Rictor/AKT/β-catenin signaling pathway. Exp. Cell Res. 405, 112666 (2021). source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [132] Johnson, S. C. et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342, 1524–1528 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [133] Martin-Perez, M. et al. PKC downregulation upon rapamycin treatment attenuates mitochondrial disease. Nat. Metab. 2, 1472–1481 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [134] Walters, H. E., Deneka-Hannemann, S. & Cox, L. S. Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging 8, 231–244 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [135] Chung, C. L. et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. GeroScience 41, 861–869 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Specifically, a short 6-week course of rapamycin has been shown to rejuvenate the function of hematopoietic stem cells, increase production of naïve lymphocytes and improve the response to influenza vaccination in old mice 39.”

What the sources say

• Partly supported

  The Results sections on HSC function and immunity report that six weeks of rapamycin improved HSC regenerative capacity, increased B-cell and pre-B-cell production, and improved old mice’s response to influenza vaccination. They do not establish an increase in naïve lymphocytes specifically; the immunity section also says the percentage of T cells did not increase. (LLM, conf=0.85)

  cites [39] Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009). sourceExperimental — accuracy not yet measured

In the paper

“In elderly humans, 6 weeks of mTOR inhibitor treatment (a rapalog alone or in combination with a catalytic site mTOR inhibitor) also improved the response to influenza vaccination and was associated with a decrease in the percentage of exhausted PD1+ T cells in peripheral blood 82,83.”

What the sources say

• ?Not checked — no full text of the sourcecites [82] Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014). source
• Partly supported

  In the indexed section “TORC1 inhibition as an immunotherapy to reduce infections in the elderly” (page not provided), the trial reports six weeks of treatment and an improved influenza-vaccine response, strongest for RAD001 plus BEZ235. The same section attributes the decrease in exhausted PD1+ T cells to a previous RAD001-monotherapy study; it does not report that decrease for the combination treatment. (LLM, conf=0.87)

  cites [83] Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Genetic inhibition of mTORC2 in one or more tissues of a mouse can result in frailty, hyperphagia, insulin resistance, hyperlipidemia, hypercholesterolemia, hyperglycemia, kyphosis, and/or obesity depending upon the specific tissues in which mTORC2 is inhibited 114–117, 68.”

What the sources say

• Partly supported

  The Results (pages unavailable in our copy) report insulin resistance and elevated triglycerides after adipose Rictor deletion, plus elevated cholesterol in calorie-restricted female knockout mice. The Discussion reports increased frailty after hypothalamic Rictor deletion. The paper does not establish hyperphagia, hyperglycemia, kyphosis, or obesity as outcomes of mTORC2 inhibition; kyphosis appears only as an item in the frailty assessment, and the studied adipose knockout mice had normal glucose tolerance and no increased adiposity. (LLM, conf=0.88)

  cites [114] Yu, D. et al. Calorie-restriction-induced insulin sensitivity is mediated by adipose mTORC2 and not required for lifespan extension. Cell Rep. 29, 236–248 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [115] Chellappa, K. et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell 18, e13014 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [116] Arriola Apelo, S. I. et al. Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging. eLife 9, e56177 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“Male and female L-RKO mice are glucose intolerant”; page unavailable) reports hepatic insulin resistance and hyperglycemia after liver-specific Rictor deletion, supporting those tissue-dependent effects. It does not report hyperphagia, hyperlipidemia, hypercholesterolemia, kyphosis, or obesity from genetic mTORC2 inhibition in mice. Its report that aged male L-RKO mice had normal rotarod performance also does not establish frailty. (LLM, conf=0.88)

  cites [117] Lamming, D. W. et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13, 911–917 (2014). sourceExperimental — accuracy not yet measured
• ?Could not verify

  Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

  cites [68] Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4, e24 (2008). sourceExperimental — accuracy not yet measured

In the paper

“While autophagy thus seems to be very important from this description alone, studies in yeast, worms, and flies have shown that inactivation of autophagy shortens lifespan, while promotion of autophagy extends lifespan 65–67.”

What the sources say

• Supported

  The cited paper supports the yeast portion of the claim: the section “Autophagy is Required for Rapamycin to Extend CLS” reports shorter chronological life span in autophagy-deficient yeast grown in SD minimal medium. “Rapamycin Promotes Autophagy during Chronological Aging” reports that low-dose rapamycin both upregulates autophagy and extends yeast life span. The paper notes that autophagy-deficient yeast are not necessarily short-lived under other growth conditions; the other citations in the group bear on worms and flies. (LLM, conf=0.88)

  cites [65] Alvers, A. L. et al. Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5, 847–849 (2009). source
• Partly supported

  The paper reports that knocking down atg-7 or atg-12 shortened lifespan in wild-type and daf-2 mutant C. elegans (results in the indexed copy; article pp. 93–95). It does not report that promoting autophagy extends lifespan, or present lifespan experiments in yeast or flies. (LLM, conf=0.88)

  cites [66] Hars, E. S. et al. Autophagy regulates ageing in C. elegans. Autophagy 3, 93–95 (2007). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper reports that autophagy-gene mutations shorten lifespan in flies (p. 10) and that autophagy knockdown shortens lifespan in wild-type worms (section 3.1, p. 4). It also reports lifespan extension associated with autophagy promotion in yeast, worms, and flies (section 5, p. 12). But the claim is too categorical: the Concluding remarks (p. 12) report that suppressing autophagy after development extends lifespan in worms and that inhibiting it in adult flies does not affect lifespan; the cited passages also do not establish that inactivation shortens baseline lifespan in yeast. (LLM, conf=0.86)

  cites [67] Lionaki, E., Markaki, M. & Tavernarakis, N. Autophagy and ageing: insights from invertebrate model organisms. Ageing Res. Rev. 12, 413–428 (2012). sourceExperimental — accuracy not yet measured

In the paper

“Indeed, rapamycin has been shown to inhibit the accumulation of senescent cells in mice as well as suppress the senescence associated secretory phenotype (SASP) 110.”

What the sources say

• Partly supported

  The Results section, “Rapamycin decreases β-gal staining and the SASP in Nrf2KO mice” (page unavailable), reports reduced senescence-associated staining in mouse fat tissue and reduced inflammatory cytokines, supporting SASP suppression in mice. It does not establish that rapamycin inhibits the accumulation of senescent cells: p16 was not significantly reduced in Nrf2KO fat tissue, and the Discussion distinguishes SASP suppression from removal of senescent cells. (LLM, conf=0.88)

  cites [110] Wang, R. et al. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell 16, 564–574 (2017). sourceExperimental — accuracy not yet measured

In the paper

“In addition, low dose mTOR inhibitor treatment significantly decreased the rate of infections, the majority of which were respiratory tract infections.”

What the sources say

• Supported

  The infection-rate results (passage 7) report statistically significant reductions versus placebo with low-dose BEZ235 alone and with RAD001 plus BEZ235. The same passage states that the majority of infections reported during the trial were respiratory tract infections. RAD001 alone did not significantly reduce infection rates, but the claim does not attribute the result to every regimen. (LLM, conf=0.94)

  cites [83] Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). source

In the paper

“Interestingly, whole body overexpression of 4E-BP1 also has positive effects on healthspan, protecting male mice from diet-induced obesity 16.”

What the sources say

• Supported

  The Introduction reports that transgenic 4E-BP1 expression protects male mice from diet-induced obesity and that aging male transgenic mice are protected from metabolic decline. The Discussion describes the model as whole-body overexpression and confirms protection from diet-induced obesity, supporting the sentence’s healthspan framing. (LLM, conf=0.92)

  cites [16] Tsai, S. Y. et al. Increased 4E-BP1 expression protects against diet-induced obesity and insulin resistance in male mice. Cell Rep. 16, 1903–1914 (2016). source

In the paper

“Treatment of aged mice with rapamycin restored the functional capacity of their HSCs, and boosted the immune response to influenza virus.”

What the sources say

• Supported

  The Results section, “Rapamycin restores HSC function in the old mice,” reports improved regenerative capacity of HSCs from rapamycin-treated aged mice. The Results section, “Short-term rapamycin treatment boosts immunity of the old mice,” reports increased influenza-specific IgG after immunization and protection against influenza challenge; the Discussion describes restored HSC function and a protective antibody response. (LLM, conf=0.94)

  cites [39] Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009). source

In the paper

“Rapamycin inhibits cell proliferation, epithelial-mesenchymal transition and cancer stem cell characteristics of lung cancer stem cells and colorectal cancer stem cells 93,94”

What the sources say

• ?Not checked — no full text of the sourcecites [93] Xie, L. X. et al. Rapamycin inhibited the function of lung CSCs via SOX2. Tumour Biol. 37, 4929–4937 (2016). source
• Partly supported

  Results §3.4 reports that rapamycin suppressed FBXW7-loss-associated migration, invasion, and tumor-sphere formation in colon cancer cell lines; the Abstract also describes suppression of EMT and stemness. The paper does not report that rapamycin inhibited cell proliferation. It studies colorectal, not lung, cancer cells; the sentence’s other citation may be intended to support the lung-cancer portion. (LLM, conf=0.87)

  cites [94] Wang, Y. et al. Rapamycin inhibits FBXW7 loss-induced epithelial–mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem. Biophys. Res. Commun. 434, 352–356 (2013). sourceExperimental — accuracy not yet measured

In the paper

“Finally, lifespan-extending doses of rapamycin in mice also promote the formation of cataracts 25, although cataracts have not been associated with rapalog treatment in humans.”

What the sources say

• Supported

  The citation is attached to the claim about mice. The Abstract reports a significantly higher incidence of cataracts in mice treated with rapamycin starting at 9 months, and ‘Rapamycin increases cataract severity’ reports a dose-dependent increase at 20 months. The separate statement about human rapalog treatment is not attached to this citation. (LLM, conf=0.92)

  cites [25] Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012). source

In the paper

“One of the best described systems for regulating the nucleotide binding status of the Rag GTPases is the activity of the GATOR complexes. GATOR1 functions as a GAP for RagA and RagB, while GATOR2 acts to inhibit the activity of GATOR1 167,168.”

What the sources say

• ?Not checked — no full text of the sourcecites [167] Panchaud, N., Peli-Gulli, M. P. & De Virgilio, C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6, ra42 (2013). source
• Supported

  The paper states that GATOR2 functions upstream of GATOR1 and calls it “an inhibitor of an inhibitor (GATOR1)” in the passage discussing Fig. 2G–H. Its abstract also says GATOR2 negatively regulates DEPDC5, a GATOR1 subunit. (LLM, conf=0.93)

  cites [168] Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013). source

In the paper

“The localization of TSC has also been reported to be sensitive to amino acids, including arginine, although the mechanism by which this takes place is unclear 181.”

What the sources say

• Supported

  The Results section reports that arginine deprivation promotes TSC2 localization to lysosomes, while replenishing arginine or all amino acids redistributes it to the cytoplasm. The Introduction says whether arginine acts directly or indirectly remains unresolved, consistent with the citing sentence’s qualification about the mechanism. (LLM, conf=0.94)

  cites [181] Carroll, B. et al. Control of TSC2–Rheb signaling axis by arginine regulates mTORC1 activity. eLife 5, e11058 (2016). source

In the paper

“The regulation of RagC and RagD is somewhat less well understood, but the FLCN complex has been shown to act as a GAP for these GTPases 174–177.”

What the sources say

• Supported

  In Results (‘FLCN-FNIP2 is a GAP for RagC and RagD’), purified FLCN-FNIP2 stimulated GTP hydrolysis by both RagC and RagD. The same section concludes that the intact complex has GAP activity for these GTPases. (LLM, conf=0.95)

  cites [174] Tsun, Z. Y. et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52, 495–505 (2013). source
• Supported

  The Introduction states that FLCN–FNIP serves as a GAP for RagC/D. The Discussion and Figure 9 likewise describe its GAP activity toward RagC/D. Page numbers are not provided in the supplied passages. (LLM, conf=0.95)

  cites [175] Meng, J. & Ferguson, S. M. GATOR1-dependent recruitment of FLCN–FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. J. Cell Biol. 217, 2765–2776 (2018). source
• Partly supported

  The Introduction says the FLCN–FNIP complex interacts with and regulates Rag GTPases. It does not identify RagC and RagD as its targets or say the complex acts as a GAP, so the specific mechanism attributed to this paper is unsupported. (LLM, conf=0.76)

  cites [176] Martinez-Carreres, L. et al. CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival. Cancer Res. 79, 5245–5259 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion states that FLCN:FNIP2 stimulates GTP hydrolysis of RagC, supporting its role as a RagC GAP. The passages retrieved for RagD do not establish GAP activity toward RagD, so this source supports only the RagC part of the claim. No page numbers are available in our copy. (LLM, conf=0.88)

  cites [177] Jansen, R. M. et al. Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation. Sci. Adv. 8, eadd2926 (2022). sourceExperimental — accuracy not yet measured

In the paper

“A number of different factors have been reported to control the lysosomal localization of TSC, most notably insulin/PI3K/AKT signaling, which acts to phosphorylates TSC on multiple residues, causing TSC to depart from the lysosome and permitting Rheb to be loaded by GTP 180.”

What the sources say

• Supported

  The Introduction states that insulin activates PI3K–Akt signaling, which phosphorylates multiple residues on TSC2. The Results section on PI3K–Akt shows that this phosphorylation is required for the TSC complex to dissociate from the lysosome, and the Discussion states that its release from lysosomal Rheb allows Rheb-GTP loading. (LLM, conf=0.94)

  cites [180] Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771–785 (2014). source

In the paper

“Briefly, mTORC1 is recruited to the lysosome by interacting with heterodimeric pairs of the Rag family of small GTPases 165,166.”

What the sources say

• Supported

  The paper reports that Rag heterodimers interact with mTORC1 through raptor and that Rag proteins are required for amino-acid-induced mTOR relocalization. It finds that a significant fraction of mTOR moves to late endosomal and lysosomal compartments, supporting the claim of Rag-mediated recruitment to the lysosome. The indexed passages are labeled Abstract and provide no page number. (LLM, conf=0.88)

  cites [165] Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008). source
• Partly supported

  The Introduction describes RagA/B–RagC/D heterodimers, and the Discussion says their dimer formation is important for TORC1 activation. But the Discussion presents regulation of TORC1-component localization only as a possibility; our copy does not establish that Rag heterodimers recruit mTORC1 to the lysosome through a physical interaction. (LLM, conf=0.86)

  cites [166] Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008). sourceExperimental — accuracy not yet measured

In the paper

“Several studies have shown that restriction of protein or specific restriction of either methionine or one or more of the branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) reduces mTORC1 activity and extends lifespan in preclinical species 24,150–152.”

What the sources say

• Partly supported

  The Results and Discussion (page numbers unavailable) associate lower protein relative to carbohydrate with lower hepatic mTOR activation and longer lifespan in mice. The paper does not test restriction of methionine or individual BCAAs, and it measures mTOR activation rather than specifically establishing reduced mTORC1 activity. (LLM, conf=0.86)

  cites [24] Solon-Biet, S. M. et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 19, 418–430 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that methionine restriction extends maximum lifespan in rats and mice, supporting the methionine-and-lifespan portion of the claim. It does not report reduced mTORC1 activity; instead, it describes the mechanisms as unknown and discusses changes in protein synthesis as a possibility. This paper does not test protein or branched-chain amino acid restriction. (LLM, conf=0.87)

  cites [150] Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119–125 (2005). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports that low-protein diets promote longevity in rodents and that restricting all three BCAAs extends lifespan in male mice; the paper also reports lifespan extension from isoleucine restriction. It does not establish that these restrictions reduce mTORC1 activity. The Discussion instead suggests that isoleucine restriction may act largely through mTORC1-independent mechanisms (page numbers unavailable in our copy). (LLM, conf=0.89)

  cites [151] Green, C. L. et al. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Preprint at https://doi.org/10.1101/2022.10.06.511051 (2022). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that lifelong BCAA restriction extended lifespan in male mice and reduced skeletal-muscle mTORC1 signaling in males. It also reports no lifespan extension in females and no corresponding mTORC1 changes in females. The Introduction describes lifespan benefits of protein and methionine restriction, but this paper does not establish that those restrictions also reduce mTORC1 activity. (LLM, conf=0.89)

  cites [152] Richardson, N. E. et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice. Nat. Aging 1, 73–86 (2021). sourceExperimental — accuracy not yet measured

In the paper

“High-resolution structures have also been generated of the complexes that regulate mTORC1 activity, including the TSC complex 158, the Rag GTPases in complex with mTORC1 and Ragulator 159–161, and the binding of leucine by Sestrin2 162.”

What the sources say

• Supported

  The “Structure of leucine-bound Sestrin2” section reports a crystal structure of leucine-bound Sestrin2 resolved to 2.7 Å. Electron-density analysis identified a leucine molecule bound in its C-terminal domain, directly supporting the attributed claim. (LLM, conf=0.94)

  cites [162] Saxton, R. A. et al. Structural basis for leucine sensing by the sestrin2–mTORC1 pathway. Science 351, 53–58 (2016). source

In the paper

“Other potentially mTORC1-lowering diets include a ketogenic diet, which has been shown to extend the lifespan of mice while reducing mTORC1 activity 154.”

What the sources say

• Partly supported

  The Abstract reports increased median lifespan and survival in ketogenic-diet mice. The Results section on mTORC1 signaling reports decreased signaling in liver but increased p-4E-BP1 in skeletal muscle, so the unqualified claim that the diet reduced mTORC1 activity omits an important tissue-specific distinction. Page numbers are not provided in our copy. (LLM, conf=0.88)

  cites [154] Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546 (2017). sourceExperimental — accuracy not yet measured

In the paper

“The Rag GTPases have also been reported to recruit TSC to lysosomes in response to amino acid restriction, possibly via a GATOR2 or Sestrin2-dependent mechanism 182.”

What the sources say

• Supported

  The Discussion states that the Rag GTPase helps recruit TSC to lysosomes in response to amino acid starvation. It also describes Rag-dependent cycling of TSC on and off lysosomes under amino acid depletion. The cited claim accurately paraphrases that finding. (LLM, conf=0.92)

  cites [182] Yang, S. et al. The Rag GTPase regulates the dynamic behavior of TSC downstream of both amino acid and growth factor restriction. Dev. Cell 55, 272–288 (2020). source

In the paper

“In contrast to the subjects in the above trials, who tolerated everolimus or BEZ235 quite well, a small, 8-week long randomized clinical trial of 25 older adults between 70 and 95 years of age treated with 1 mg/day of rapamycin experienced more side effects than placebo including a small increase in glycated hemoglobin (within-group p=0.03), and a 40% rise in triglyceride levels (within-group p=0.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [149] Kraig, E. et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: immunological, physical performance, and cognitive effects. Exp. Gerontol. 105, 53–69 (2018). sourceExperimental — accuracy not yet measured

In the paper

“One of the best described systems for regulating the nucleotide binding status of the Rag GTPases is the activity of the GATOR complexes. GATOR1 functions as a GAP for RagA and RagB, while GATOR2 acts to inhibit the activity of GATOR1 167,168.”

What the sources say

• ?Not checked — no full text of the sourcecites [167] Panchaud, N., Peli-Gulli, M. P. & De Virgilio, C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6, ra42 (2013). source
• Supported

  The paper explicitly states that GATOR1 has GAP activity for RagA and RagB (Abstract). It also reports that purified GATOR1 increased GTP hydrolysis by RagA or RagB in vitro. The supplied passages do not give page numbers. (LLM, conf=0.95)

  cites [168] Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013). source

In the paper

“mTORC1 activity drives a wide variety of anabolic processes through phosphorylation of substrates including ribosomal protein S6 kinase beta-1 (S6K1) and the eukaryotic translation initiation factor 4E-binding proteins (4E-BPs).”

In the paper

“Every study observed an extension of lifespan in one or more dosing groups, with females typically benefiting more than males at equivalent doses of rapamycin.”

In the paper

“Initial studies suggested that rapamycin, dosed at ~1 mg/kg of body weight via the diet, was well tolerated, with only minor effects of rapamycin on hematological parameters, and no statistically significant changes in blood glucose, cholesterol, or triglyceride levels47.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [47] Sills, A. M., Artavia, J. M., DeRosa, B. D., Ross, C. N. & Salmon, A. B. Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. Am. J. Primatol. 81, e22927 (2019). source

In the paper

“A number of lessons can be drawn from this set of studies, primarily that rapamycin is an extraordinarily robust geroprotective intervention, extending lifespan in multiple wild-type mouse strains handled by multiple teams, and including inbred, outbred, and genetically heterogenous male and female mice.”

In the paper

“The mechanistic Target of Rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase found in diverse species including mice and humans.”

In the paper

“In contrast to mTORC1, which is responsive to many different environmental cues, mTORC2 primarily acts as an effector of PI3K signaling by tuning the activity of substrates including AKT, serum/glucocorticoid regulated kinase (SGK), and protein kinase C alpha (PKCα).”

In the paper

“but also as we detail below, in both wild-type mice and in many disease models.”

In the paper

“The mTOR kinase forms the catalytic core of two distinct protein complexes, mTOR Complex 1 (mTORC1) and mTORC2, each of which are composed of shared as well as unique protein subunits and phosphorylate different substrates.”

In the paper

“In this review, we will discuss data generated over the past decade suggesting that the beneficial effects of rapamycin on healthspan and lifespan are mediated by inhibition of mTORC1 whereas the negative effects of rapamycin on glucose and lipid metabolism are mediated by inhibition of mTORC2.”

In the paper

“Conversely, the lifespan of male mice is extended by acarbose and 17-α estradiol, and these compounds increased hepatic mTORC2 activity 118.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [118] Garratt, M. et al. Male lifespan extension with 17-α estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice. Aging Cell 17, e12786 (2018). source

In the paper

“Immunophenotyping revealed that low or intermittent doses of everolimus decreased the percentage of PD-1+ exhausted T cells in the peripheral blood of older adults and this may have been a mechanism underlying their improved immune function.”

What the sources say

• ?Not checked — no full text of the sourcecites [82] Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014). source

In the paper

“The clinical trial demonstrated that 6 weeks of treatment with either 0.5 mg once daily or 5 mg once weekly everolimus was well tolerated and significantly improved the response of older adults to an influenza vaccination.”

What the sources say

• ?Not checked — no full text of the sourcecites [82] Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014). source

In the paper

“Specific inhibition of mTORC1 in mice using a mTORC1-speicific inhibitor did not result in hyperglycemia, impaired glucose tolerance, hyperlipidemia or hypercholesterolemia, again demonstrating that these negative effects are mediated at least in part by inhibition of mTORC2 120.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [120] Schreiber, K. H. et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat. Commun. 10, 3194 (2019). source

In the paper

“Thus, lower or intermittent doses of rapamycin, or treatment with rapalogs that more specifically target mTORC1, are predicted to reduce mTORC2-associated side effects such as hyperlipidemia and hyperglycemia without impairing the lifespan-extending benefits of mTORC1 inhibition.”

In the paper

“While cancer prevention clearly plays a role in the benefits of rapamycin in mice, cancer is itself an age-related disease, and thus prevention of cancer is an expected consequence of geroprotective therapies.”

In the paper

“The approved doses of rapalogs also inhibit immune function and therefore the FDA-approved prescribing information notes that taking rapalogs may increase the risk of infection and certain cancers associated with immunosuppression 137,138.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [137] Novartis. Full Prescribing Information Zortress https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021560s000lbl.pdf (2010).
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [138] Pfizer. Full Prescribing Information Rapamune https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf (2017).

In the paper

“In mice, rapamycin has been shown to be immunomodulatory, improving CD8+ T cell immunological memory while at the same time impairing defenses against acute viral and bacterial infections 85.”

What the sources say

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  cites [85] Goldberg, E. L., Smithey, M. J., Lutes, L. K., Uhrlaub, J. L. & Nikolich-Zugich, J. Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J. Immunol. 193, 757–763 (2014). source

In the paper

“However, given the balance of the evidence, particularly the genetic studies showing that mTORC2 activity is associated with lifespan and that inhibition of mTORC1 alone can extend lifespan, we believe that inhibition of mTORC2 is “off-target” with respect to the beneficial effects of rapamycin and rapalogs on healthspan and longevity.”

In the paper

“Trelinska and colleagues observed hyperlipidemia in 66% of TSC patients taking high daily doses of everolimus for 15 months; hyperglycemia was observed in 22% of subjects 139.”

What the sources say

• ?Not checked — no full text of the sourcecites [139] Trelinska, J. et al. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anticancer Drugs 26, 437–442 (2015). source

In the paper

“Rapalogs are approved for use in transplant and cancer patients at high doses that strongly suppress mTORC1 activity 136and have significant side effects including mouth ulcers similar to canker sores, gastrointestinal side effects, hyperlipidemia and hyperglycemia, and impaired wound healing.”

What the sources say

• ?Not checked — no full text of the sourcecites [136] Tabernero, J. et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol. 26, 1603–1610 (2008). source

In the paper

“Of interest, clinical trials to date suggest that low or intermittent doses of mTOR inhibitors enhance rather than suppress immune function and decrease infection risk in older adults.”

In the paper

“In contrast to its actions of cancer stems cells, rapamycin has been shown to have beneficial effects on self-renewal and function in normal stem cells, which may contribute to the benefits of rapamycin on tissue function.”

In the paper

“It is possible that lower doses of rapamycin, intermittent treatment with rapamycin, or treatment with everolimus would be better tolerated than the daily dose of 1 mg/day examined here, but this has not been directly tested.”

In the paper

“Lessons learned from the combined Phase 2b and 3 trial results suggest that upregulation of antiviral immunity by low dose mTOR inhibitor therapy may have a greater impact on 1) severity than incidence of viral RTIs, 2) RTIs caused by coronaviruses, rhinoviruses and influenza viruses as opposed to other respiratory viruses; 3) the incidence and severity of viral RTIs in older adults ≥ 75 years of”

In the paper

“The leucyl-tRNA synthetase (LRS) has been shown to function as a leucine sensor for mTORC1, acting as a GAP for RagD 178.”

What the sources say

• ?Not checked — no full text of the sourcecites [178] Han, J. M. et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012). source

In the paper

“As highlighted in Figure 3, in both humans and mice, treatment with low or intermittent doses of rapamycin or everolimus, or treatment of mice with the mTORC1-selective inhibitor DL001, is much better tolerated than the high doses of mTOR inhibitors currently approved for organ transplant and oncology indications, with fewer metabolic side effects and less immunosuppression.”

In the paper

“The mitochondrial threonyl-tRNA synthetase TARS2 functions as a threonine sensor, interacting with GTP-RagC to promote the GTP loading of RagA, likely via the recruitment of an unidentified RagA GEF 179.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [179] Kim, S. H. et al. Mitochondrial threonyl-tRNA synthetase TARS2 is required for threonine-sensitive mTORC1 activation. Mol. Cell 81, 398–407 (2021). source