Targeting cellular senescence prevents age-related bone loss in mice
Open accessAbstract
Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.
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The introduction argues that senescent cells and their SASP products contribute to deficits in cognition and mobility.
“Recent evidence suggests that the accumulation of senescent cells, which can release a variety of pro-inflammatory, apoptotic, and toxic by-products, called the senescence-associated secretory phenotype (SASP), is one of the drivers of deficits in both cognition11, 12, 13, 14, 15, 16 and mobility.7,17, 18, 19, 20, 21, 22”
From A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease (2025) · cites this paper as [17]
The paper’s introductory discussion says senescent cells can produce harmful SASP factors, and its concluding discussion notes that targeting senescent cells or their SASP has reduced frailty in old mice. That offers indirect support for the mobility portion of the citing sentence, but this paper studies bone loss, does not measure mobility, and does not address cognitive deficits. The supplied copy provides no page numbers for these passages. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThis sterile inflammatory state can impair neighboring and distant non-senescent cells, including progenitors, reducing tissue function and regenerative capacity.
“This sterile inflammatory state can provoke dysfunction of neighboring and distant non-senescent cells, such as progenitor cells, contributing to impaired tissue function and reduced regenerative capacity18,21,24,26,34.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [21]
The paper’s Abstract says the inflammatory senescence-associated secretory phenotype has harmful paracrine and systemic effects and can cause tissue dysfunction. It also reports that senescent-cell-conditioned medium impaired osteoblast mineralization and altered osteoclast progenitor survival. It does not establish reduced regenerative capacity or show that progenitor cells themselves become dysfunctional. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIntermittent senolytic administration appears as effective as continuous treatment for reducing senescent cell burden.
“With senolytics, intermittent administration appears to be as effective as continuous treatment for attenuating senescent cell burden21.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [21]
The treatment passage (indexed as Abstract; page unavailable) reports that once-monthly dasatinib plus quercetin reduced markers of senescent-cell burden in old mice. The Online Methods report similar effects with weekly and biweekly dosing, but the paper does not compare intermittent senolytic dosing with continuous senolytic treatment. The claimed equivalence to continuous treatment is therefore unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn aged osteoporotic mice, D+Q reduces bone-resorbing osteoclasts, increases bone-forming osteoblasts, and restores bone mass.
“In age-related osteoporosis linked to senescent-like osteocytes and bone marrow cells in mice, D + Q reduced development of bone-resorbing osteoclasts, while increasing differentiated bone-forming osteoblasts, with restoration of bone mass21.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [21]
The D+Q results (Abstract; page unavailable in our copy) report improved bone microarchitecture and fewer osteoclasts in aged mice. Osteoblast numbers increased on the endocortical surface, but did not change in trabecular bone. The reported osteoclast counts do not establish that D+Q reduced osteoclast development. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAnimal data also provide a justification for using P1NP as the primary outcome.
“although as noted earlier, P1NP could also justifiably have been chosen as our primary outcome based on our animal data13,14.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [13]
The paper reports that clearing senescent cells in old mice maintained trabecular bone formation and increased cortical bone formation (Abstract; page not provided). Those animal findings could motivate a bone-formation outcome, but our copy does not mention P1NP or assess its suitability as a primary outcome. (LLM, conf=0.78)
Experimental — accuracy not yet measured
SASP activation in osteocytes promotes osteoclast activity and impairs bone strength, and senolytic drugs reduce bone loss in this setting.
“SASP activation in osteocytes was shown to promote osteoclast activity, thus impairing bone strength. In this context, senolytic drugs reduced bone loss139.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [139]
The passages labeled Abstract (no page supplied) report that senescent osteocytes develop the SASP, that senescent-cell conditioned medium promotes osteoclastogenesis, and that senolytic treatment improves bone mass and strength in old mice. They do not establish that osteocyte-derived SASP specifically caused the increased osteoclast activity or impaired bone strength; the conditioned-medium experiment concerns senescent cells generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOsteocytes in old mice show telomeric dysfunction markers and accumulate p16.
“In old mice, osteocytes show markers of telomeric dysfunction and accumulate p16.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [139]
The paper reports that p16Ink4a expression in mouse osteocytes increases markedly after about 18 months of age (Abstract; page unavailable). It also measures senescence-associated distention of satellites in osteocytes, but the Online Methods identify these as decondensed or elongated centromeres, not markers of telomeric dysfunction. The telomeric-dysfunction part of the claim is therefore unsupported by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome projects using dasatinib and quercetin in aged mice with established bone loss observed a reduction in senescent osteoclasts, contributing to treatment of osteoporosis.
“Some projects that used senolytics (dasatinib and quercetin) in aged mice with established bone loss have observed a reduction in senescent osteoclasts [111], contributing to the treatment of osteoporosis.”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [111]
The paper’s Abstract (page not supplied) reports that dasatinib and quercetin improved bone outcomes in old mice with established bone loss and reduced osteoclast numbers. It reports fewer senescent osteocytes, not fewer senescent osteoclasts; the osteoclast finding concerns total numbers. The osteoporosis treatment implication is therefore supported as preclinical potential, but the specific claim about senescent osteoclasts is not. (LLM, conf=0.91)
Experimental — accuracy not yet measuredDepletion of cells expressing the senescence marker p16INK4A in genetically modified mice prolongs median lifespan and improves overall health.
“depletion of cells expressing the senescence marker cyclin-dependent kinase inhibitor p16INK4A in genetically modified mice prolongs median lifespan and improves overall health (Baker et al. 2016; Farr et al. 2017; Baker et al. 2011; Jeon et al. 2017; Abdul-Aziz et al. 2019; Kim et al. 2019; Patil et al. 2019; Xu et al. 2015; Roos et al. 2016; Baar et al. 2017)”
From Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain (2020) · cites this paper as Farr et al. 2017
The passage labeled Abstract (page not provided) says that eliminating p16Ink4a-expressing cells in INK-ATTAC mice extends healthspan and prevents multiple age-related morbidities, supporting the improved-health portion. It does not say that median lifespan is prolonged; the Online Methods state that the old mice in this study were sacrificed at 24 months. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCentromere FISH has been used to detect senescence-associated distension of satellites (SADS) in multiple tissues.
“Centromere FISH has also been used to detect senescence-associated distension of satellites (SADS), also a senescence-associated marker, in multiple tissues28–30.”
From Spatial mapping of cellular senescence: emerging challenges and opportunities (2023) · cites this paper as [29]
The Online Methods section, “SADS analysis of senescent osteocytes” (page not provided), describes using centromere-targeted FISH to measure SADS in mouse bone osteocytes. It does not show SADS detection by FISH in multiple tissues; the paper assesses adipose tissue with other senescence markers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe study was designed to examine whether findings in aged mice showing anabolic and antiresorptive effects of intermittent senolytic therapy applied to humans.
“Therefore, the aim of this phase 2 RCT was to examine whether our findings in aged mice demonstrating both anabolic and antiresorptive effects of intermittent senolytic therapy on bone metabolism13,14, were applicable to humans.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [13]
Genetic removal of senescent cells in mouse models improves several age-related conditions, including vascular reactivity, atherosclerotic plaques, pulmonary function, osteoarthritis, fatty liver disease, pulmonary fibrosis, and bone loss.
“Clearance of Sncs in INK-ATTAC or p16-3MR mice restores vascular reactivity (12), stabilizes atherosclerotic plaques (13), improves pulmonary function (14), alleviates osteoarthritis (10), improves fatty liver disease (15), improves lung function in a pulmonary fibrosis model (14), and prevents age-related bone loss (16).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [16]
Experimental — accuracy not yet measuredSenolytics remove postmitotic cells that have senescent features, producing health benefits and supporting the idea that senescent cells cause disease.
“Senolytics do clear postmitotic cells with senescent features, resulting in beneficial health outcomes (16, 34, 35) and reinforcing Sncs’ role in causing disease.”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [16]
Dasatinib plus quercetin reduces aortic calcification in atherosclerotic ApoE−/− mice, improves lung function in a mouse model of idiopathic pulmonary fibrosis, reduces hepatic steatosis, and prevents age-related bone loss.
“D+Q also reduces aortic calcification of atherosclerotic ApoE−/− mice (12), improves lung function in a murine model of idiopathic pulmonary fibrosis (14), reduces hepatic steatosis (15), and prevents age-related bone loss (16).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [16]
Genetically removing p16-expressing senescent cells from old INK-ATTAC mice reduces senescent osteocytes by 46% and significantly improves trabecular bone, cortical thickness, and bone strength in the spine and femur.
“Genetic clearance of p16-expressing Sncs from old INK-ATTAC mice results in a 46% reduction in senescent osteocytes, as assessed by measuring SADS, and significantly improves trabecular bone, thicker cortices, and bone strength in the spine and femur (16).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [16]
In old mice, Sost mRNA levels drop in osteocyte-enriched bone samples after senescent cells are cleared.
“Sost mRNA levels are reduced in osteocyte-enriched bone samples in old mice following senescent cell clearance13,14”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [13]
Preclinical studies showed that senescent osteocytes remained reduced in mice after 4 months of monthly D+Q, with similar findings in genetic clearance models.
“the observation from our preclinical studies that senescent osteocytes remained reduced in mice following 4 months of monthly D + Q administration, with similar findings noted in our genetic clearance models13,14.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [13]
D+Q dosing every 4 weeks was used based on previous mouse studies where this regimen prevented age-related bone loss.
“we used D + Q dosing every 4 weeks based on our previous studies in mice where this dosing regimen was effective in preventing age-related bone loss13.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [13]
Senolytics may be as effective if given intermittently as continuously, despite the elimination half-lives of D and Q being <11 h.
“Indeed, as we reported in old mice treated for age-related osteoporosis with D + Q [5], these findings suggest senolytics may be as effective if given intermittently as continuously, despite the elimination half-lives of D and Q being <11 h.”
Mouse experiments for a genetic targeting approach of senescent cells have been described by our group earlier.
“Mouse experiments for a genetic targeting approach of senescent cells have been described by our group earlier37.”
From A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues (2022) · cites this paper as [37]
Elimination of senescent cells or inhibition of their produced SASPs had a protective and preventative effect on age-related bone loss.
“Further studies conducted by Farr et al. (2017) suggest a causal link between cellular senescence and age-related bone loss by showing that the elimination of senescent cells or the inhibition of their produced SASPs had a protective and preventative effect on age-related bone loss [38].”
From Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics (2023) · cites this paper as [38]
Clearance of p16-expressing cells improves multiple parameters of physical health and function within ageing mice.
“it has previously been shown that clearance of p16‐expressing cells improves multiple parameters of physical health and function within ageing mice”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Farr et al, 2017
γH2AX+ BMAds are substantially increased in both AD mice and old mice compared to their respective controls.
“Immunofluorescence using the DNA damage marker γH2AX, a robust marker of senescent cells50–52, also revealed a substantial increase in γH2AX+ BMAds in both AD mice (Fig. 3q,r) and old mice (Fig. 3s,t) compared with their respective controls.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [51]
The citation is attached to the description of γH2AX as a robust marker of senescent cells, not to the citing authors’ reported increase in γH2AX+ BMAds. The cited paper discusses DNA damage and senescence in its main text and measures other senescence markers (Online Methods, SADS analysis), but searches for γH2AX and bone marrow adipocytes found no passage validating that marker or reporting the stated comparison in AD and old mice. (LLM, conf=0.76)
Experimental — accuracy not yet measuredAdministration of dasatinib and quercetin (D+Q) in subjects with diabetic kidney disease reduced senescent cell numbers and circulating levels of SASP factors, such as IL-1α and IL-6.
“Consistent with this notion, the administration of dasatinib and quercetin (D+Q), a well-studied senolytic cocktail, in subjects with diabetic kidney disease reduced senescent cell numbers and circulating levels of SASP factors, such as IL-1α and IL-6 (20, 40–45).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [42]
In aged mice, SASP promotes decreased BMD by inhibiting osteoblast-mediated bone mineralisation and stimulating osteoclast differentiation.
“In aged mice, the SASP promotes decreased BMD from inhibition of osteoblasts‐mediated bone mineralisation and stimulation of osteoclast differentiation from progenitor cells (Farr et al, 2017).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Farr et al, 2017
Senescent cells play an important role in skeletal aging in part by decreasing osteoprogenitor cell number and the generation of osteoblasts that produce the bone matrix, and by stimulating osteoclastogenesis to resorb the bone.
“Recent studies by us and others have shown that SCs play an important role in skeletal aging in part by decreasing osteoprogenitor cell number and the generation of osteoblasts that produce the bone matrix; stimulate osteoclastogenesis to resorb the bone42,43.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [43]
Senolytic drugs include quercetin, navitoclax, and fisetin.
“Senolytic drugs include quercetin, navitoclax, and fisetin”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [102]
In preclinical aging models, senescent cell accumulation is associated with chronic diseases, geriatric syndromes, multimorbidity, and accelerated aging phenotypes.
“In pre-clinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multi-morbidity, and accelerated aging phenotypes.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [4]
In animals, genetic and pharmacologic reduction of senescent cell burden prevents, delays, or alleviates various aging-related diseases and sequelae.
“In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [4]
Senolytics have been used to prevent, delay, or alleviate many age-onset diseases and syndromes in preclinical models.
“Senolytics have been used to prevent, delay, or alleviate a plethora of age-onset diseases and syndromes in pre-clinical models.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [4]
Minimizing the SASP using JAK/STAT inhibition is very similar to eliminating or reducing senescent cell burden genetically or pharmacologically with senolytics.
“In terms of alleviating age-related phenotypes, minimizing the SASP using Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibition is very similar to eliminating or reducing the burden of senescent cells genetically (e.g., using INK-ATTAC mice) or pharmacologically with senolytic agents [4, 11, 13, 60].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [4]
Targeting senescent cells in aged mice (20-24 months) with established bone loss by dasatinib (5 mg/kg) plus quercetin (50 mg/kg) once monthly for 4 months, or by ABT263 (41 μmol/kg) daily for 5 days, lowered bone resorption, with maintained trabecular bone formation and enhanced cortical bone formation.
“Some studies have shown that targeting senescent cells in aged mice (aged 20-24 months) with established bone loss by use of dasatinib (5 mg/kg) plus quercetin (50 mg/kg) by oral gavage once monthly for 4 months, 31 or by ABT263 (41 μmol/kg) daily for 5 days, 105 lowered bone resorption, with maintained trabecular bone formation and enhanced cortical bone formation.31,32”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [31]
Monthly administration of D+Q is as effective as daily administration for osteoporosis in mice.
“This notion is supported by monthly administration of D+Q being as effective as daily administration for osteoporosis in mice (Farr et al., 2017).”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Farr et al., 2017
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Senolytics improve physical function and increase lifespan in old age
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Self-citationLength-independent telomere damage drives post-mitotic cardiomyocyte senescence
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Self-citationVascular senescence in cardiovascular and metabolic diseases
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Self-citationReducing Senescent Cell Burden in Aging and Disease
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Self-citationConnecting aging biology and inflammation in the omics era
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Self-citationAutoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging
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Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss
Chandra, A., Lagnado, A. B., Farr, J. N., Monroe, D. G., Park, S., Hachfeld, C., Tchkonia, T., Kirkland, J. L., Khosla, S., Passos, J. F., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3978 · Cited by 138 · see citing works
Self-citationVi, L., Baht, G. S., Soderblom, E. J., Whetstone, H., Wei, Q., Furman, B., Puviindran, V., Nadesan, P., Foster, M., Poon, R., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07666-0 · Cited by 140 · see citing works
Poblocka, M., Bassey, A. L., Smith, V. M., Falcicchio, M., Manso, A. S., Althubiti, M., Sheng, X., Kyle, A., Barber, R., Frigerio, M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-99852-2 · Cited by 137 · see citing works
Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes
Eckhardt, B. A., Rowsey, J. L., Thicke, B. S., Fraser, D. G., O’Grady, K. L., Bondar, O. P., Hines, J. M., Singh, R. J., Thoreson, A. R., Rakshit, K., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.135236 · Cited by 130 · see citing works
Self-citationSpatial mapping of cellular senescence: emerging challenges and opportunities
Gurkar, A. U., Gerencser, A. A., Mora, A. L., Nelson, A. C., Zhang, A. R., Lagnado, A. B., Enninful, A., Benz, C., Furman, D., Beaulieu, D., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00446-6 · Cited by 139 · see citing works
The costs and benefits of senotherapeutics for human health
Raffaele, M., & Vinciguerra, M. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00300-7 · Cited by 140 · see citing works
Lozano-Torres, B., Estepa-Fernández, A., Rovira, M., Orzáez, M., Serrano, M., Martínez-Máñez, R., & Sancenón, F. (2019) · Nature Reviews Chemistry · doi:10.1038/s41570-019-0108-0 · Cited by 140 · see citing works
Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis
Khosla, S., Farr, J. N., & Kirkland, J. L. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-02694 · Cited by 130 · see citing works
Self-citationSharma, A. K., Roberts, R. L., Benson, R. D., Pierce, J. L., Yu, K., Hamrick, M. W., & McGee-Lawrence, M. E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00354 · Cited by 131 · see citing works
“Accordingly, senolytic therapies that target and remove these cells hold enormous promise for the treatment of age-related diseases, including osteoporosis (Baker et al., 2011; Chang et al., 2016; Farr et al., 2017; Grezella et al., 2018; Khosla et al., 2018; Geng et al., 2019; Kim and Kim, 2019).”
BackgroundTargeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
Song, S., Tchkonia, T., Jiang, J., Kirkland, J. L., & Sun, Y. (2020) · Advanced Science · doi:10.1002/advs.202002611 · Cited by 129 · see citing works
Self-citationExercise reduces circulating biomarkers of cellular senescence in humans
Englund, D. A., Sakamoto, A. E., Fritsche, C. M., Heeren, A. A., Zhang, X., Kotajarvi, B. R., Lecy, D. R., Yousefzadeh, M. J., Schafer, M. J., White, T. A., et al. (2021) · Aging Cell · doi:10.1111/acel.13415 · Cited by 125 · see citing works
Self-citationAli, D., Tencerova, M., Figeac, F., Kassem, M., & Jafari, A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.981487 · Cited by 122 · see citing works
“Furthermore genetic depletion of senescent cells, using the inducible INKATTAC ‘suicide’ transgene that eliminates the p16 expressing cells, in a murine pre-clinical model of age-related osteoporosis, exhibited anti-resorptive and anabolic impact on bone, leading to decreased BMAT and increased bone mass (32).”
BackgroundFarr, J. N., Atkinson, E. J., Achenbach, S. J., Volkman, T. L., Tweed, A. J., Vos, S. J., Ruan, M., Sfeir, J., Drake, M. T., Saul, D., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03096-2 · Cited by 127 · see citing works
“…that our previous studies in aged mice had demonstrated a reduction in bone resorption and increase in bone formation following seno-lytic treatment 13,14 , the choice of whether to assign CTx or P1NP as the primary endpoint was entirely arbitrary, particularly in the absence of any previous human…”
InfluentialSelf-citationChandra, A., Lagnado, A. B., Farr, J. N., Doolittle, M., Tchkonia, T., Kirkland, J. L., LeBrasseur, N. K., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13602 · Cited by 120 · see citing works
Self-citationOsteocyte RANKL is required for cortical bone loss with age and is induced by senescence
Kim, H.-N., Xiong, J., MacLeod, R. S., Iyer, S., Fujiwara, Y., Cawley, K. M., Han, L., He, Y., Thostenson, J. D., Ferreira, E., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.138815 · Cited by 117 · see citing works
Aquino-Martinez, R., Rowsey, J. L., Fraser, D. G., Eckhardt, B. A., Khosla, S., Farr, J. N., & Monroe, D. G. (2020) · Bone · doi:10.1016/j.bone.2019.115220 · Cited by 114 · see citing works
“Since senescent osteocytes in the murine skeleton usually do not appear until ~18 months of age [23, 32], it was curious that a significant 30% of osteocytes from young, 6 month-old alveolar bone exhibit senescent qualities, as evidenced by SADS (Fig.”
BackgroundSelf-citationAge-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice
Liu, J., Zhang, J., Lin, X., Boyce, B. F., Zhang, H., & Xing, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148073 · Cited by 112 · see citing works
Cellular senescence in the lung across the age spectrum
Parikh, P., Wicher, S., Khandalavala, K., Pabelick, C. M., Britt, R. D., & Prakash, Y. S. (2019) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00424.2018 · Cited by 112 · see citing works
Expansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence
Ogrodnik, M., Salmonowicz, H., Jurk, D., & Passos, J. F. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.06.011 · Cited by 104 · see citing works
Self-citationTargeting senescent cells for a healthier longevity: the roadmap for an era of global aging
Sun, Y., Li, Q., & Kirkland, J. L. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac030 · Cited by 105 · see citing works
Self-citationOrally-active, clinically-translatable senolytics restore α-Klotho in mice and humans
Zhu, Y., Prata, L. G. P. L., Gerdes, E. O. W., Netto, J. M. E., Pirtskhalava, T., Giorgadze, N., Tripathi, U., Inman, C. L., Johnson, K. O., Xue, A., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103912 · Cited by 96 · see citing works
Self-citationEnglund, D. A., Zhang, X., Aversa, Z., & LeBrasseur, N. K. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111595 · Cited by 94 · see citing works
Self-citationHsp90 inhibitors as senolytic drugs to extend healthy aging
Fuhrmann-Stroissnigg, H., Niedernhofer, L. J., & Robbins, P. D. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1475828 · Cited by 92 · see citing works
Musculoskeletal senescence: a moving target ready to be eliminated
Baar, M. P., Perdiguero, E., Muñoz-Cánoves, P., & de Keizer, P. L. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.05.007 · Cited by 83 · see citing works
Local senolysis in aged mice only partially replicates the benefits of systemic senolysis
Farr, J. N., Saul, D., Doolittle, M. L., Kaur, J., Rowsey, J. L., Vos, S. J., Froemming, M. N., Lagnado, A. B., Zhu, Y., Weivoda, M., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162519 · Cited by 81 · see citing works
Self-citationMitochondria and cellular senescence: Implications for musculoskeletal ageing
Habiballa, L., Salmonowicz, H., & Passos, J. F. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.417 · Cited by 82 · see citing works
Millar, C. L., Iloputaife, I., Baldyga, K., Norling, A. M., Boulougoura, A., Vichos, T., Tchkonia, T., Deisinger, A., Pirtskhalava, T., Kirkland, J. L., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105612 · Cited by 88 · see citing works
Self-citationAquino‐Martinez, R., Eckhardt, B. A., Rowsey, J. L., Fraser, D. G., Khosla, S., Farr, J. N., & Monroe, D. G. (2021) · Journal of Periodontology · doi:10.1002/jper.20-0529 · Cited by 78 · see citing works
Self-citationThe implications of bone marrow adipose tissue on inflammaging
Aaron, N., Costa, S., Rosen, C. J., & Qiang, L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.853765 · Cited by 74 · see citing works
- Authors
- Farr, J. N., Xu, M., Weivoda, M. M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., LeBrasseur, N. K., Drake, M. T., Pignolo, R. J., Pirtskhalava, T., Tchkonia, T., Oursler, M. J., Kirkland, J. L., & Khosla, S.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Kirkland, James L
- Khosla, Sundeep
- ORCID
- Venue
- Nature Medicine
- Published
- 2017-08-21
- Volume
- 23
- Issue
- 9
- Pages
- 1072-1079
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5657592
- OpenAlex
- W2750509325
- Cited by
- 1,182
- References
- 46
- Citations by year
- 2026: 138 · 2025: 140 · 2024: 151 · 2023: 159 · 2022: 135 · 2021: 136 · 2020: 143 · 2019: 105 · 2018: 66 · 2017: 9
- FWCI
- 65.33
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-11-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (1369828)
- National Institute on Aging (R01AG048792, P01AG004875, R01AG013925, R21AG049182, R37AG013925)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR068275, R01AR065402, K01AR070281, K01AR070241, R01AR067129, T32AR056950)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- cellular senescence, age-related bone loss, osteoporosis, senolytics, senolytic therapy, caspase-8, JAK inhibitors, senescence-associated secretome, bone resorption, osteoclastogenesis, osteoblast mineralization, bone microarchitecture, bone strength, aging
- MeSH terms
- Cortical Bone, Cancellous Bone, Animals, beta-Galactosidase, Bone and Bones, Cell Differentiation, Flow Cytometry, Mice, Transgenic, Nitriles, Osteoblasts, Osteoclasts, Osteocytes, Osteoporosis, Pyrazoles, Pyrimidines, Absorptiometry, Photon, Weight-Bearing, Cellular Senescence, Culture Media, Conditioned, Apoptosis, Gene Expression Profiling, Mice, Caspase 8, Janus Kinases, Real-Time Polymerase Chain Reaction, In Vitro Techniques
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