Senolytic treatment alleviates doxorubicin‐induced chemobrain

Aging Cell, Journal Year: 2024, Volume and Issue: 23(2)

Published: Jan. 15, 2024

Abstract Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy‐induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox has also been as model of However, it unclear if induces brain changes that observed during aging since does not readily enter the brain. Rather, mechanism chemobrain likely involves induction peripheral cellular senescence release senescence‐associated secretory phenotype (SASP) factors these SASP disrupt cognition. We examined effect on markers In addition, we employed senolytic, ABT‐263, which limited access The results indicate plasma brain, activating microglia, increasing stress, altering gene transcription. turn, synaptic function required memory was reduced response altered redox signaling. ABT‐263 prevented or most Dox‐induced effects. emphasize link between decline from senescent cells some differences well similarities advanced age treatment.

Language: Английский

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The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr−/−;hApoB100+/+ mice

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

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Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: May 15, 2024

There are sex differences in vulnerability and resilience to the stressors of aging subsequent age-related cognitive decline. Cellular senescence occurs as a response damaging or stress-inducing stimuli. The includes state irreversible growth arrest, development senescence-associated secretory phenotype, release pro-inflammatory cytokines associated with diseases. Senolytics compounds designed eliminate senescent cells. Our recent work indicates that senolytic treatment preserves function male F344 rats. current study examined effect on female Female rats (12 months) were treated dasatinib (1.2 mg/kg) + quercetin ABT-263 vehicle for 7 months. Examination estrus cycle indicated females had undergone estropause during treatment. Senolytic may have increased behavioral stress responsivity, particularly initial training cued version watermaze. However, pre-training cue task reduced responsivity spatial all groups learned discrimination. In contrast preserved memory observed senolytic-treated males, older exhibited impaired episodic relative young (6-month) females. We suggest not been able compensate loss estradiol, which can act mechanisms anxiety independent cellular senescence.

Language: Английский

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Sex, senescence, senolytics, and cognition

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 4, 2025

This review focuses on sexual dimorphism in cellular senescence and senolytic treatment relation to brain health age-related cognitive decline. The stressors of aging, DNA damage, inflammation, oxidative stress induce cell senescence, a hallmark aging. Senescent cells change their function molecular profile are primed release pro-inflammatory cytokines. functional changes include the activation signals prevent death. cytokines from peripheral senescent during middle age induces neighbor heightens level systemic contributing neuroinflammation. In response neuroinflammation stress, some neurons alter physiology, decreasing neuronal excitability synaptic transmission. neurophysiology is protective against death due excitotoxicity, at expense loss normal function, inflammation may underlie prevalence, symptoms, pathogenesis diseases, including neurodegenerative diseases. Sex differences have been observed for astrocytes, microglia, cells, those involved innate adaptive immune responses. Interventions that remove such as drugs, can reduce or ameliorate aging-related function. Similarities responses males females depend system examined, regimen, burden, when initiated. Estrogen impacts several these factors influences transcription genes promoting growth, proliferation, survival programs manner opposite drugs. addition, estrogen has anti-aging effects independent rapidly modifying neurophysiology. Thus, it important recognize that, addition sex there other sexually dimorphic mechanisms contribute aging process. results indicate senolytics interact with fundamental biology, hormones.

Language: Английский

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The chemotherapy agent doxorubicin induces CNS expression of Ascl1, a regulator of adult neurogenesis and differentiation

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 21, 2025

Cancer-related cognitive impairment (CRCI) is a common side effect of cancer and its treatments. Cancer chemotherapy has been associated with hippocampal dysfunction memory impairment. We investigated the effects one agent, doxorubicin, on transcription factor Ascl1 proliferation stem cells in brain. used an inducible mouse model designed to express TdTomato Ascl1-lineage cells. Five six-month-old Ascl1-CreERT2:ROSA mice were treated peripherally single dose either doxorubicin (10 mg/kg) or DMSO control (n = 9 per group, n 4–5 sex). analyzed brains that had exposed for 2 weeks induced expression after first week. immunostaining neurogenesis stage specific markers evaluate neuronal differentiation dentate gyrus hippocampus. Overall, significantly increased by 81% at this time point. As measured double stains Sox2, GFAP, NeuroD1, doxorubicin-treated experienced increase Ascl1-mediated neural compared control. A similar significant number Ascl1-expressing (by 146%) treatment was observed gray matter cerebral cortex. Thus, rather than leading loss developing neurons, we found their appearance progression, suggesting losses from chemotherapies may require greater more sustained damage.

Language: Английский

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A Conversation with ChatGPT on Contentious Issues in Senescence and Cancer Research

Molecular Pharmacology, Journal Year: 2024, Volume and Issue: 105(5), P. 313 - 327

Published: March 8, 2024

Artificial intelligence (AI) platforms, such as Generative Pretrained Transformer (ChatGPT), have achieved a high degree of popularity within the scientific community due to their utility in providing evidence-based reviews literature. However, accuracy and reliability information output ability provide critical analysis literature, especially with respect highly controversial issues, has generally not been evaluated. In this work, we arranged question/answer session ChatGPT regarding several unresolved questions field cancer research relating therapy-induced senescence (TIS), including topics reversibility, its connection tumor dormancy, pharmacology newly emerging drug class senolytics. provided responses consistent available although occasionally overlooking essential components current understanding role TIS biology treatment. Although ChatGPT, similar AI an accurate review outputs should still be considered carefully, issues biology.

SIGNIFICANCE STATEMENT

Intelligence platforms great for researchers investigate biomedical literature prompt manner. arise when it comes certain biological questions, field. This work discussion some yet-to-be-fully-elucidated conundrums treatment highlights strengths weaknesses utilizing analyzing on topic.

Language: Английский

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Ohwia caudata aqueous extract attenuates senescence in aging adipose-derived mesenchymal stem cells

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e29729 - e29729

Published: April 16, 2024

Stem cells exhibit pluripotency and self-renewal abilities. Adipose-derived mesenchymal stem can potentially be used to reconstruct various tissues. They possess significant versatility alleviate aging-related diseases. Unfortunately, aging leads senescence, apoptosis, a decline in regenerative capacity adipose-derived cells. These changes necessitate strategy mitigate the effects of on

Language: Английский

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Therapy-induced senescence is finally escapable, what is next?

Cell Cycle, Journal Year: 2024, Volume and Issue: 23(6), P. 713 - 721

Published: March 18, 2024

Several breakthrough articles have recently confirmed the ability of tumor cells to escape stable cell cycle arrest imposed by Therapy-Induced Senescence (TIS). Subsequently, accepting hypothesis that TIS is escapable should encourage serious reassessments fundamental roles senescence in cancer treatment. The potential for from undermines well-established suppressor function senescence, proposes it as a mechanism dormancy leading disease recurrence and invites further investigation its unfavorable contribution therapy outcomes. Moreover, escaping strongly indicates elimination senescent cells, primarily through pharmacological means, suitable approach increasing efficacy treatment, one still requires exploration. This commentary provides an overview recent evidence unequivocally demonstrated therapy-induced overcoming terminal growth fate future perspectives on biology.

Language: Английский

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Can senolysis be used to overcome tumor immune evasion?

Journal of Stem Cell Research & Therapeutics, Journal Year: 2024, Volume and Issue: 9(1), P. 26 - 32

Published: Jan. 1, 2024

Tumor escape from immunologically mediated destruction is a well-studied phenomena and has been shown to utilize several pathways in common with physiological conditions such as pregnancy, well ocular or testicular immune privilege. Recent interest senescence revealed that senescent cells surrounding tumors contribute development of specific microenvironment may allow for escape. Senescent have reported possess “senescence associated secretory phenotype” (SASP) which produces inflammatory agents directly indirectly suppression T cell NK function. Exosomes secreted by can suppress activation, downregulate activity dendritic cells, are needed initiation immunity. Studies demonstrated reduction load increases tumor sensitivity variety therapies. We will overview supportive evidence use senolytics potentiate the efficacy immunotherapy cancer, discuss our preliminary findings regarding SenoVax™ (IND #30745), an autologous, polyvalent senolytic vaccine being developed treatment advanced non-small lung cancer.

Language: Английский

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