Caloric restriction and cellular senescence
Open accessAbstract
Cellular senescence is a state of irreversible growth arrest characterized by hypertrophy and secretion of various bioactive molecules, a phenomenon defined the Senescence-Associated Secretory Phenotype (SASP). Senescent cells are implicated in a number of biological functions, from embryogenesis to aging. Significantly, excessive accumulation of senescent cells is associated to a decline of regenerative capacity and chronic inflammation. In accordance, the removal of senescent cells is sufficient to delay several pathologies and promote healthspan. Calorie restriction (CR) without malnutrition is currently the most effective non-genetic intervention to delay aging phenotypes. Recently, we have shown that CR can prevent accumulation of senescent cells in both mice and humans. Here, we summarize the current knowledge on the molecular and cellular events associated with CR, and define how these events can interfere with the induction of cellular senescence. We discuss the potential side effects of preventing senescence, and the possible alternative dietary interventions with potential senolytic properties.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Caloric restriction extends lifespan in many organisms and decreases the burden of senescent cells.
“an intervention which has been shown to extend lifespan in a plethora of organisms and decrease the burden of senescent cells (Fontana et al., 2018; Mercken et al., 2012).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Fontana et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · see citing works
Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239 · see citing works
Extending 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 · see citing works
Self-citationNaturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,891 · see citing works
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,562 · see citing works
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · see citing works
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232 · see citing works
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045 · see citing works
Self-citationChemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801 · cited 1× · see citing works
“Importantly, some SASP components can reinforce senescence 25 and induce senescence in neighboring cells (paracrine senescence) 26 .”
BackgroundmTOR is a key modulator of ageing and age-related disease
Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013) · Nature · doi:10.1038/nature11861 · Cited by 1,676 · see citing works
Jeon, O. H., Kim, C., Laberge, R.-M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., et al. (2017) · Nature Medicine · doi:10.1038/nm.4324 · Cited by 1,515 · see citing works
Self-citationInk4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486 · see citing works
Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation
Qiu, X., Brown, K., Hirschey, M. D., Verdin, E., & Chen, D. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.015 · Cited by 1,310 · see citing works
Senescent cells: an emerging target for diseases of ageing
Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R.-M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.116 · Cited by 1,284 · see citing works
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype
Wiley, C. D., Velarde, M. C., Lecot, P., Liu, S., Sarnoski, E. A., Freund, A., Shirakawa, K., Lim, H. W., Davis, S. S., Ramanathan, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.11.011 · Cited by 1,275 · see citing works
Laberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3195 · Cited by 1,160 · see citing works
Self-citationImpact of caloric restriction on health and survival in rhesus monkeys from the NIA study
Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., Longo, D. L., Allison, D. B., Young, J. E., Bryant, M., et al. (2012) · Nature · doi:10.1038/nature11432 · Cited by 1,145 · see citing works
Cellular senescence drives age-dependent hepatic steatosis
Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., Day, C. P., Burt, A., Palmer, A., Anstee, Q. M., et al. (2017) · Nature Communications · doi:10.1038/ncomms15691 · Cited by 1,044 · see citing works
Unmasking Transcriptional Heterogeneity in Senescent Cells
Hernandez-Segura, A., de Jong, T. V., Melov, S., Guryev, V., Campisi, J., & Demaria, M. (2017) · Current Biology · doi:10.1016/j.cub.2017.07.033 · Cited by 972 · cited 1× · see citing works
“It is clear now that the composition of SASP factors is dependent on the type of cells and senescence inducers 27 .”
BackgroundSelf-citationKurz, D. J., Decary, S., Hong, Y., & Erusalimsky, J. D. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.20.3613 · Cited by 899 · see citing works
Caloric restriction improves health and survival of rhesus monkeys
Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., Ingram, D. K., Weindruch, R., de Cabo, R., & Anderson, R. M. (2017) · Nature Communications · doi:10.1038/ncomms14063 · Cited by 838 · cited 1× · see citing works
“Accumulating data indicate that CR extends lifespan also in non-human primates 38 .”
BackgroundmTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3225 · Cited by 788 · see citing works
Jurk, D., Wang, C., Miwa, S., Maddick, M., Korolchuk, V., Tsolou, A., Gonos, E. S., Thrasivoulou, C., Jill Saffrey, M., Cameron, K., et al. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00870.x · Cited by 598 · see citing works
Spatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes
Narita, M., Young, A. R. J., Arakawa, S., Samarajiwa, S. A., Nakashima, T., Yoshida, S., Hong, S., Berry, L. S., Reichelt, S., Ferreira, M., et al. (2011) · Science · doi:10.1126/science.1205407 · Cited by 594 · see citing works
Chinta, S. J., Woods, G., Demaria, M., Rane, A., Zou, Y., McQuade, A., Rajagopalan, S., Limbad, C., Madden, D. T., Campisi, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.092 · Cited by 530 · see citing works
Self-citationNOTCH1 mediates a switch between two distinct secretomes during senescence
Hoare, M., Ito, Y., Kang, T.-W., Weekes, M. P., Matheson, N. J., Patten, D. A., Shetty, S., Parry, A. J., Menon, S., Salama, R., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3397 · Cited by 522 · see citing works
Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice
Mitchell, S. J., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., González-Reyes, J. A., Cortassa, S., Kaushik, S., Gonzalez-Freire, M., Patel, B., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.027 · Cited by 451 · see citing works
Amino acids and mTORC1: from lysosomes to disease
Efeyan, A., Zoncu, R., & Sabatini, D. M. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.05.007 · Cited by 436 · cited 1× · see citing works
“Energy and amino acids restriction cause an inhibition of mTORC1 activity, which in turn enhances autophagy, improves proteostasis and stem cell function 61 .”
BackgroundCalorie restriction and cancer prevention: metabolic and molecular mechanisms
Longo, V. D., & Fontana, L. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.11.004 · Cited by 378 · see citing works
Self-citationMeydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., Gupta, A. K., Villareal, D. T., Bhapkar, M., Huang, M., et al. (2016) · Aging · doi:10.18632/aging.100994 · Cited by 228 · see citing works
Self-citationSenescence as a mode of tumor suppression.
Sager, R. (1991) · Environmental Health Perspectives · doi:10.1289/ehp.919359 · Cited by 213 · see citing works
“Social Life” of Senescent Cells: What Is SASP and Why Study It?
Borodkina, A. V., Deryabin, P. I., Giukova, А. А., & Nikolsky, N. N. (2018) · Acta Naturae · doi:10.32607/20758251-2018-10-1-4-14 · Cited by 170 · see citing works
Insulin‐like growth factor‐1 regulates the <scp>SIRT</scp> 1‐p53 pathway in cellular senescence
Tran, D., Bergholz, J., Zhang, H., He, H., Wang, Y., Zhang, Y., Li, Q., Kirkland, J. L., & Xiao, Z. (2014) · Aging Cell · doi:10.1111/acel.12219 · Cited by 161 · cited 1× · see citing works
“Notably, prolonged exposure of cells to IGF-1 can induce premature senescence through the regulation of SIRT1-p53 pathway 82 .”
BackgroundAdult-onset, short-term dietary restriction reduces cell senescence in mice
Wang, C., Maddick, M., Miwa, S., Jurk, D., Czapiewski, R., Saretzki, G., Langie, S. A. S., Godschalk, R. W. L., Cameron, K., & von Zglinicki, T. (2010) · Aging · doi:10.18632/aging.100196 · Cited by 142 · see citing works
Senescent cells communicate via intercellular protein transfer
Biran, A., Perelmutter, M., Gal, H., Burton, D. G. A., Ovadya, Y., Vadai, E., Geiger, T., & Krizhanovsky, V. (2015) · Genes & Development · doi:10.1101/gad.259341.115 · Cited by 139 · see citing works
Sardeli, A. V., Komatsu, T. R., Mori, M. A., Gáspari, A. F., & Chacon-Mikahil, M. P. T. (2018) · Nutrients · doi:10.3390/nu10040423 · Cited by 138 · cited 1× · see citing works
“Indeed, in contrast to the scientifically unsupported opinion that long-term CR promotes frailty 41-43 , recent data from the Wisconsin CR Primate study clearly show that the levels of weakness, poor endurance, slowness, low physical activity and frailty were significantly lower in the CR than in…”
ResultFontana, L., Mitchell, S. E., Wang, B., Tosti, V., van Vliet, T., Veronese, N., Bertozzi, B., Early, D. S., Maissan, P., Speakman, J. R., et al. (2018) · Aging Cell · doi:10.1111/acel.12746 · Cited by 81 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 9
- [2]McHugh, D. & Gil, J. Senescence and aging: Causes, consequences, and therapeutic avenues. The Journal of cell biology 217 , 65-77 (2018).
- [5]Dimri, G.P. , et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America 92 , 9363-9367 (1995).
- [19]Rodier, F. , et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. Journal of cell science 124 , 6881 (2011).
- [42]Miller, S.L. & Wolfe, R.R. The danger of weight loss in the elderly. The journal of nutrition, health & aging 12 , 487-491 (2008).
- [48]Weiss, E.P. , et al. Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. The American journal of clinical nutrition 84 , 1033-1042 (2006).
- [78]Linn, S., Kairis, M. & Holliday, R. Decreased fidelity of DNA polymerase activity isolated from aging human fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 73 , 2818-2822 (1976).
- [80]SHIMOKAWA, I. , et al. Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction. The FASEB Journal 17 , 1108-1109 (2003).
- [86]Patterson, R.E. & Sears, D.D. Metabolic Effects of Intermittent Fasting. Annual review of nutrition 37 , 371-393 (2017).
- [87]Mattson, M.P. , et al. Meal frequency and timing in health and disease. Proceedings of the National Academy of Sciences of the United States of America 111 , 16647-16653 (2014).
Cited by
Sorted by citations
Cytoplasmic DNA: sources, sensing, and role in aging and disease
Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D. (2021) · Cell · doi:10.1016/j.cell.2021.09.034 · Cited by 288 · see citing works
Obesity May Accelerate the Aging Process
Salvestrini, V., Sell, C., & Lorenzini, A. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00266 · Cited by 260 · see citing works
Meal timing, aging, and metabolic health
Kessler, K., & Pivovarova-Ramich, O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081911 · Cited by 95 · see citing works
Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review
Amaya-Montoya, M., Pérez-Londoño, A., Guatibonza-García, V., Vargas-Villanueva, A., & Mendivil, C. O. (2020) · Advances in Therapy · doi:10.1007/s12325-020-01287-0 · Cited by 82 · see citing works
Basisty, N., Kale, A., Patel, S., Campisi, J., & Schilling, B. (2020) · Expert Review of Proteomics · doi:10.1080/14789450.2020.1766976 · Cited by 69 · see citing works
Yang, Y., & Zhang, L. (2020) · Food & Function · doi:10.1039/c9fo02611h · Cited by 57 · see citing works
Blast Exposure Leads to Accelerated Cellular Senescence in the Rat Brain
Arun, P., Rossetti, F., Wilder, D. M., Sajja, S., Van Albert, S. A., Wang, Y., Gist, I. D., & Long, J. B. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00438 · Cited by 30 · see citing works
Early ageing after cytotoxic treatment for testicular cancer and cellular senescence: Time to act
Lubberts, S., Meijer, C., Demaria, M., & Gietema, J. A. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.102963 · Cited by 19 · see citing works
Self-citation
- Authors
- Fontana, L., Nehme, J., & Demaria, M.
- Affiliations
- The University of Sydney (AU)
- University Medical Center Groningen (NL)
- Corresponding author
- Fontana, Luigi
- Demaria, Marco
- Venue
- Mechanisms of Ageing and Development
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 176
- Pages
- 19-23
- ISSN
- 0047-6374 (ISSN-L)
- OpenAlex
- W2899505251
- Cited by
- 104
- References
- 37
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 16 · 2023: 19 · 2022: 11 · 2021: 19 · 2020: 16 · 2019: 10 · 2018: 1
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- green
- research.rug.nl
- Licence
- Locations
- Mechanisms of Ageing and Development (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Bakewell Foundation, the Longer Life Foundation (an RGA/Washington University Partnership)
- National Center for Research Resources
- Italian Federation of Sport Medicine (FMSI)
- National Council for Scientific Research-Lebanese University (CNRS-L) scholarship
- Dutch Cancer Foundation (KWF)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- caloric restriction, cellular senescence, senescence-associated secretory phenotype, senolytics, aging, healthspan, regenerative capacity, chronic inflammation, dietary intervention, senescent cell accumulation
- MeSH terms
- Aging, Animals, Humans, Cellular Senescence, Caloric Restriction, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
