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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TOR inactivation extends lifespan in yeast, flies, worms and mice.
“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
Rapamycin is a strong inducer of autophagy and extends lifespan in all organisms tested so far, including yeast, flies, worms and mice.
“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 many organisms, decreased TOR signalling is associated with extension of lifespan.
“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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“…of dietary restriction do not exhibit an additive increase on lifespan with mTOR inhibition, implying the underlying mechanisms for how they exert their influence on longevity are shared and likely driven by reduced TOR signaling (Kapahi et al., 2004; Kaeberlein et al., 2005; Hansen et al., 2007).”
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- 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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