Table 1.
Preclinical studies investigating cellular senescence in relation to AD risk factors and AD neuropathology.
| Citation | Aging/Neurodegenerative Disease Model | Senotherapeutic Treatment and Dosing Strategy | Senescent Cell Types Investigated | Brief Summary of Outcomes |
|---|---|---|---|---|
| (Streit et al., 2009) | Human postmortem AD brain tissue | None | Microglia | Morphologically senescent-like, not activated, microglia were found near Aβ plagues and preceded tau tangles in human brains. |
| (Geng et al., 2010) | Male Sprague-Dawley rats (6-, 18-, 24-month old) & in vitro hippocampal neurons | None | Neurons | SA β-gal staining increased in the CA3, but not DG of the hippocampus with aging (51 % by 24 months) |
| (Bhat et al., 2012) | Postmortem human brain & in vitro astrocytes | None | Astrocytes | p16 positive astrocytes were increased with age and in AD brain tissue. |
| (Jurk et al., 2012) | Male C57Bl/6 mice (4- & 32-month old) | None | Neurons | Age and telomerase-related senescent phenotypes in neurons were mediated by the DNA damage response, slightly attenuated by caloric restriction, and fully rescued by the knockout of Cdkn1a. |
| (He et al., 2013) | Male C57BL/6 and APP/PS1 (9-month-old) | None | Neural stem cells | Aβ42 exposure increased senescent phenotypes in NSCs in the dentate gyrus of APP/PS1 mice. |
| (Al-Mashhadi et al., 2015) | Postmortem human brains with or without white matter lesions | None | Oligodendrocytes | Senescent phenotypes were identified in oligodendrocytes of aged brains, but were not associated with white matter lesions. |
| (Kang et al., 2015) | Postmortem human brain tissue from young and aged adults without neuropathology | None | Astrocytes; neurons; oligodendrocytes | Gata4, a SASP regulator, was highly associated with age and p16 expression in astrocytes, pyramidal neurons, and oligodendrocytes in humans. |
| (Turnquist et al., 2016) | Postmortem brain tissues from AD and ALS patients | None | Astrocytes | Greater senescent cell burden in AD and ALS tissue compared to non-diseased, age-matched and pediatric control tissue |
| (Bussian et al., 2018) | Male and female PS19;ATTAC mice (weanling to 12-month-old) | 2 mg/kg AP20187 twice weekly from weaning (long term) or 10 mg/kg for five consecutive days at 6 months of age (short-term) | Astrocytes; microglia | Clearance of senescent cells prevented gliosis, hyperphosphorylation of tau, and neuronal degeneration |
| 50 mg/kg ABT263 for 5 consecutive days followed by 16 days of rest from weaning until 6 months | ||||
| (Musi et al., 2018) | Male and female rTg4510Mapt+/+, rTg4510Mapt0/0, rTg21221 Mapt+/+, 3xTgAD mice (2- to 23-month-old) | 5 mg/kg dasatinib and 50 mg/kg quercetin for 5 consecutive days followed by 9 days rest for 6 treatment cycles | Neurons | Dasatinib + quercetin treatment reduced total NFT density, SASP gene expression, neuron loss, and ventricular enlargement. |
| Postmortem human brain: Alzheimer’s disease (AD) Progressive Supranuclear Palsy (PSP) | None | Neurons | AD: Elevated senescent gene expression in NFT-bearing neurons compared to neurons without NFTs. | |
| PSP: Elevated CDKN2D expression compared to age-matched controls that negatively correlated with cognition. | ||||
| (Chow et al., 2019) | Male and female C57BL/6 J mice (3- and 22–24 month old) +/− insulin resistance | None | Neurons | Chronic insulin exposure led to senescence phenotype in neurons via dysregulation of hexokinase 2 |
| (Moreno-Blas et al., 2019) | Male Wistar rat brains (4- or 25-month-old) | None | Astrocytes; neurons | Astrocytes and neurons showed a wide range of senescent phenotypes, which were attenuated or exacerbated in vitro via stimulation and inhibition of autophagy, respectively. |
| (Norton et al., 2019) | Postmortem human brain without AD and with or without cerebral small vessel disease | None | Mural cells | Senescent phenotypes were observed in mural cells of aged individuals, but were less prevalent in patients with cerebral small vessel disease. |
| (Ogrodnik et al., 2019) | Male C57BL/6 INK-ATTAC mice (8-month-old) +/− high fat diet; INK-ATTAC; db/db mice | 10 mg/kg AP20187 for 3 days every 2weeks for a total of 8–10 weeks | Astrocytes; microglia | Clearing obesity-induced senescent glial cells improved neurogenesis and alleviated anxiety-related behavior. |
| db/db mice | 5 mg/kg dasatinib and 50 mg/kg quercetin for 5 days every 2 weeks for 8 weeks | |||
| (Ritzel et al., 2019) | Male C57BL/6 mice (3- & 18-month-old) +/− TBI | None | Microglia | Aging and TBI increased microglia senescent phenotypes including Bcl-2, p16INK4a, p21CIP1a, lipofuscin, and H2AX. |
| (Schwab et al., 2019) | Postmortem human brains with or without a history of TBI | None | Astrocytes; ependymal cells; neurons; oligodendrocytes | Brains from patients with a history of TBI showed extensive dysfunction, DNA damage, and other cellular senescence phenotypes in a variety of cell types. |
| (Stojiljkovic et al., 2019) | Male C57BL/6J mice (3- & 24-month-old) | None | Microglia | Various markers of microglial senescence distinct from microglial activation increased with age, although aged microglia in vivo may have been quiescent rather than senescent. |
| (Tominaga et al., 2019) | Male C57BL/6 mice (10-weeks-old) +/− TBI | None | Astrocytes; microglia; neurons | Cell cycle initiation increased for the first four days post-TBI, while markers of senescence were elevated on days 4, 7, and 14 with some cell type-specific differences in expression of senescence. |
| (Turnquist et al., 2019) | Postmortem human brain tissue from patients that had received radiation and age-matched controls | None | Astrocytes | Astrocyte senescence was the most prominent cell type in radiation exposed human tissues. |
| (Zhang et al., 2019) | Male and female APP/PS1, WT mice and APP/PS1/ZsGreen mice (2.5- to 8-month-old) | 12 mg/kg dasatinib and 50 mg/kg quercetin, once daily for 9 days (short-term) or 11 weeks (long-term) | Oligodendrocyte progenitor cells | Aβ induced senescence in oligodendrocyte progenitor cells and senolytic treatment reduced neuroinflammation, Aβ burden, and cognitive deficits. |
| ( Arun et al., 2020 ) | Male Sprague-Dawley rats (9–10-week-old to 1-year +/−TBI) | None | Did not investigate | Single and repeated blast exposures increased markers of cellular senescence, particularly at 1 month, in several neuroanatomical structures. |
| (Bryant et al., 2020) | Intact microvessels from postmortem human AD brain tissue | None | Endothelial cells | Senescence-related genes were significantly upregulated in endothelial cells. |
| ( Gao et al., 2020 ) | Neural stem cell spheroids from 3-week-old and 23-month-old C57BL/6 mice | 100 pg/mL Ribes meyeri anthocyanins extract | Neural stem cells (NSCs) | NSCs of aged mice showed increased senescence phenotypes and treatment with Ribes meyeri anthocyanins or Nar reduced senescence and improved cognition. |
| Female C57BL/6 mice (12-mo-old) | 100 mg/kg Ribes meyeri anthocyanins extract for 2 months or 20 mg/kg Nar for 1 month | |||
| ( Hu et al., 2021 ) | Male SAMP8 mice (2-, 6-, 12-month-old) | 1010 embryonic stem cell-derived extracellular vesicles (ESC-sEVs) twice weekly for 6 months | NSCs | ESC-sEV treatment alleviated senescence in hippocampal NSCs and improved age-related declines in cognition. |
| ( Ogrodnik et al., 2021 ) | Male INK-ATTAC and WT mice (4- & 24-month-old) | 10 mg/kg AP20187 for 3 consecutive days once every two weeks for 8 weeks | Microglia; oligodendrocyte progenitor cells | Senolysis reduced p16INK4a expression, microglial activation, and SASP factors and improved cognitive function. |
| 5 mg/kg dasatinib and 10 mg/kg quercetin for 3 consecutive days once every two weeks for 8 weeks | ||||
| ( Schwab et al., 2021 ) | Male C57BL/6 mice (7–9-week-old) +/− repeated mild TBI | None | Did not investigate | Following an initial DNA damage response at 24 h, senescent cell phenotypes were observed in the brain 7 days after traumatic brain injury. |
| ( Yousefzadeh et al., 2021a ) | Male and female mice with hematopoietic cell Ercc1 knockout (2- to 24-months old) | None | Did not investigate | Whole-body immune senescence increased p16 expression in the brain, but showed no differences in p21 expression or age-associated lesions via H&E staining. |
Abbreviations: amyloid-beta (Aβ); Alzheimer’s disease (AD); Amyotrophic lateral sclerosis (ALS); embryonic stem cell derived small embryonic vesicles (ESC-sEV); lipopolysaccharide (LPS); neural stem cell (NSC); neurofibrillary tangle (NFT); senescence-associated β-galactosidase (SA-βgal); senescence-associated heterochromatin foci (SAHF); senescence-associated secretory phenotype (SASP); traumatic brain injury (TBI).