Effect of peripheral cellular senescence on brain aging and cognitive decline

Budamagunta, Vivekananda; Kumar, Ashok; Rani, Asha; Bean, Linda A.; Manohar-Sindhu, Sahana; Yang, Yang; Zhou, Daohong; Foster, Thomas C.

doi:10.1111/acel.13817

Cited by 28 publications

(59 citation statements)

References 133 publications

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“…No statistically significant change in body weight from baseline was seen in either group (Figure 9B). In line with previous studies (39,43), we observed significant age-related improvements in forelimb grip strength after ABT-263 treatment (Figure 9C). Moreover, ABT-263 prevented worsening in rotarod performance weeks later (Figure 9D), and markedly improved gait performance from baseline compared to the vehicle control group (Figure 9E-H).…”

Section: The Senolytic Agent Abt-263 Improves Behavioral Performance ...supporting

confidence: 93%

The brain-bone marrow axis and its implications for chronic traumatic brain injury

Ritzel,

Li,

Jiao

et al. 2023

Preprint

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Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBIàWT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBIàWT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.

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Section: The Senolytic Agent Abt-263 Improves Behavioral Performance ...supporting

confidence: 93%

The brain-bone marrow axis and its implications for chronic traumatic brain injury

Ritzel,

Li,

Jiao

et al. 2023

Preprint

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“…Furthermore, Dox treatment increased systemic cytokines/chemokines, which were reduced by ABT-263 treatment. Several cytokines/chemokines, which were increased in the current study, have been reported to increase with aging and are associated with impaired cognition of aging(Budamagunta et al, 2023;Scheinert et al, 2015;Serre- Miranda et al, 2020;Speisman et al, 2013;Yegla & Foster, 2019).However, several differences between aging and Dox treatment are likely important when considering Dox treatment as a model of aging. Cognitive deficits may arise due to a variety of cytokines/ chemokines.…”

mentioning

confidence: 59%

“…These cytokines can disrupt the BBB and induce morphological characteristics of activated microglia. Similar to ABT-263 treatment of aging animals(Budamagunta et al, 2023), ABT-263 was effective at preserving the BBB and mitigated morphological changes of microglial soma size, loss of branches, and loss of branch length.…”

mentioning

confidence: 86%

“…As plasma cytokines/chemokines can cross the BBB to impact CNS functioning (Aluise et al, 2010a;Budamagunta et al, 2023), with a significant interaction between treatment and training [F (10, 230) = 2.13; p < 0.05] due to a slower swim speed for Doxtreated animals relative to the other groups (Figure 2e). A repeated measures ANOVA on the distance to platform yielded a significant effect across training blocks [F (5, 230) = 22.24; p < 0.0001] and a treatment effect [F (2, 46) = 3.54; p < 0.05] in the absence of an interaction.…”

Section: Behavioral Impairment Following Dox Treatment Was Attenuated...mentioning

confidence: 99%

“…Thus, it is likely that much of the influence of Dox treatment was mediated by peripheral changes, particularly the increase in systemic cytokines, which then influence synaptic memory mechanisms through oxidative stress. and cognitive decline (Budamagunta et al, 2023). For the two groups receiving Dox treatment, 2 mg/kg dose of Dox was administered once a week for 4 weeks while the group receiving the senolytic treatment received a 12 mg/kg dose of ABT-263 for 5 consecutive days every other week (as depicted in Figure 1a).…”

Section: Con Clus Ionmentioning

confidence: 99%

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Senolytic treatment alleviates doxorubicin‐induced chemobrain

Budamagunta,

Kumar,

Rani

et al. 2024

Aging Cell

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

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Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice

Fang,

Peck,

Quinn

et al. 2024

GeroScience

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Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer’s disease (AD). The APPNL−F/NL−F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL−F/NL−F mice. Thus, 4-month-old male and female APPNL−F/NL−F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APPNL−F/NL−F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-β (Aβ)42 and senescence-associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL−F/NL−F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine. Graphical Abstract

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Effect of peripheral cellular senescence on brain aging and cognitive decline

Cited by 28 publications

References 133 publications

The brain-bone marrow axis and its implications for chronic traumatic brain injury

The brain-bone marrow axis and its implications for chronic traumatic brain injury

Senolytic treatment alleviates doxorubicin‐induced chemobrain

Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice

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