Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice
Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75492 |
| _version_ | 1828108668875309056 |
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| author | Edward Fielder Tengfei Wan Ghazaleh Alimohammadiha Abbas Ishaq Evon Low B Melanie Weigand George Kelly Craig Parker Brigid Griffin Diana Jurk Viktor I Korolchuk Thomas von Zglinicki Satomi Miwa |
| author_facet | Edward Fielder Tengfei Wan Ghazaleh Alimohammadiha Abbas Ishaq Evon Low B Melanie Weigand George Kelly Craig Parker Brigid Griffin Diana Jurk Viktor I Korolchuk Thomas von Zglinicki Satomi Miwa |
| author_sort | Edward Fielder |
| collection | DOAJ |
| description | Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sublethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations, metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial reactive oxygen species production via NADPH oxidase 4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions. |
| first_indexed | 2024-04-11T10:49:22Z |
| format | Article |
| id | doaj.art-f0753cffc75f40b89161b517a1c14968 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:49:22Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f0753cffc75f40b89161b517a1c149682022-12-22T04:28:57ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.75492Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in miceEdward Fielder0https://orcid.org/0000-0003-2834-8706Tengfei Wan1Ghazaleh Alimohammadiha2Abbas Ishaq3Evon Low4B Melanie Weigand5George Kelly6Craig Parker7Brigid Griffin8Diana Jurk9Viktor I Korolchuk10Thomas von Zglinicki11https://orcid.org/0000-0002-5939-0248Satomi Miwa12Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomNewcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United KingdomCancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sublethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations, metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial reactive oxygen species production via NADPH oxidase 4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.https://elifesciences.org/articles/75492ageingsenescencesenolyticmetforminfrailty |
| spellingShingle | Edward Fielder Tengfei Wan Ghazaleh Alimohammadiha Abbas Ishaq Evon Low B Melanie Weigand George Kelly Craig Parker Brigid Griffin Diana Jurk Viktor I Korolchuk Thomas von Zglinicki Satomi Miwa Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice eLife ageing senescence senolytic metformin frailty |
| title | Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice |
| title_full | Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice |
| title_fullStr | Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice |
| title_full_unstemmed | Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice |
| title_short | Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice |
| title_sort | short senolytic or senostatic interventions rescue progression of radiation induced frailty and premature ageing in mice |
| topic | ageing senescence senolytic metformin frailty |
| url | https://elifesciences.org/articles/75492 |
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