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Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway
Open accessAbstract
In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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“Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies1–5.”
From Rapamycin fed late in life extends lifespan in genetically heterogeneous mice (2009) · cites this paper as [4]
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.
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“In agreement with such a model, experiments in model organisms have shown that deletion or knockdown of ribosomal subunits, S6K1, or translation initiation factors results in increased lifespan 6,10.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [6]
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“Initial evidence that reduced TOR function can extend longevity came primarily from studies in yeast1,2 and invertebrates3–5.”
From Rapamycin fed late in life extends lifespan in genetically heterogeneous mice (2009) · cites this paper as [4]
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“Studies in yeast, worms and flies found that genetic inhibition of mTORC1 or signaling pathways downstream of mTORC1, including S6K and translation initiation factors, extends lifespan 5–11.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [6]
In the citing paper
“Of significance, TOR inactivation extends lifespan in yeast (Kaeberlein et al., 2005), flies (Kapahi et al., 2004), worms (Vellai et al., 2003) and mice (Harrison et al., 2009).”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Kapahi et al., 2004
In the citing paper
“Rapamycin is a strong inducer of autophagy and it extends lifespan in all organisms tested so far, including yeast, flies, worms and mice (Bjedov and Partridge, 2011; Kapahi et al., 2004).”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Kapahi et al., 2004
In the citing paper
“In many organisms, decreased TOR signalling is associated with the extension of life span 87, 88, 89 .”
From The common biology of cancer and ageing (2007) · cites this paper as [88]
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Citations
Cites
A C. elegans mutant that lives twice as long as wild type
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Extension of Life-Span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein
Clancy, D. J., Gems, D., Harshman, L. G., Oldham, S., Stocker, H., Hafen, E., Leevers, S. J., & Partridge, L. (2001) · Science · doi:10.1126/science.1057991 · Cited by 1,436
Genetic pathways that regulate ageing in model organisms
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The Endocrine Regulation of Aging by Insulin-like Signals
Tatar, M., Bartke, A., & Antebi, A. (2003) · Science · doi:10.1126/science.1081447 · Cited by 1,327
Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue
Blüher, M., Kahn, B. B., & Kahn, C. R. (2003) · Science · doi:10.1126/science.1078223 · Cited by 1,155
Influence of TOR kinase on lifespan in C. elegans
Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A. L., Orosz, L., & Müller, F. (2003) · Nature · doi:10.1038/426620a · Cited by 1,057
Extension of Life-Span with Superoxide Dismutase/Catalase Mimetics
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Autonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1–4
Böhni, R., Riesgo‐Escovar, J. R., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B. F., Beckingham, K., & Hafen, E. (1999) · Cell · doi:10.1016/s0092-8674(00)80799-0 · Cited by 840
Tissue-Specific Activities of C. elegans DAF-16 in the Regulation of Lifespan
Libina, N., Berman, J. R., & Kenyon, C. (2003) · Cell · doi:10.1016/s0092-8674(03)00889-4 · Cited by 820
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mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
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., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
“showed more than one of the following clinical signs: (1) inability to eat or to drink; (2) severe lethargy, as indicated by a lack of response such as a reluctance to move when gently prodded with a forceps; (3) severe balance or gait disturbance; (4) rapid weight loss over a period of 1 week or more; or (5) a severe…”
BackgroundExtending Healthy Life Span—From Yeast to Humans
Fontana, L., Partridge, L., & Longo, V. D. (2010) · Science · doi:10.1126/science.1172539 · Cited by 3,023
Metadata
- Authors
- Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., & Benzer, S.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Benzer, Seymour
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 14
- Issue
- 10
- Pages
- 885-890
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC2754830
- OpenAlex
- W2073701988
- Cited by
- 1,293
- References
- 45
- Citations by year
- 2026: 31 · 2025: 40 · 2024: 34 · 2023: 67 · 2022: 57 · 2021: 55 · 2020: 74 · 2019: 66 · 2018: 64 · 2017: 42 · 2016: 65 · 2015: 83 · 2014: 82 · 2013: 72 · 2012: 64
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3364 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institute on Aging (AG 16630, R01AG016630, R01AG024366)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- lifespan extension, TOR signaling, Drosophila, tuberous sclerosis complex, TSC1, TSC2, S6 kinase, dietary restriction, nutrient sensing, insulin signaling, adipose tissue, amino acid availability, growth regulation
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Adipose Tissue, Animals, Drosophila, Eating, Gene Expression Regulation, Longevity, Protein Kinases, Proteins, Repressor Proteins, Time Factors, Signal Transduction, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, Drosophila Proteins, TOR Serine-Threonine Kinases
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