PMID- 36959691
OWN - NLM
STAT- MEDLINE
DCOM- 20230517
LR  - 20230627
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 22
IP  - 5
DP  - 2023 May
TI  - Effect of peripheral cellular senescence on brain aging and cognitive decline.
PG  - e13817
LID - 10.1111/acel.13817 [doi]
LID - e13817
AB  - We examine similar and differential effects of two senolytic treatments, ABT-263 
      and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral 
      senescence, and markers of brain aging thought to underlie cognitive decline. 
      Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or 
      vehicle, and were compared to young (6 months). Both senolytic treatments rescued 
      memory, preserved the blood-brain barrier (BBB) integrity, and prevented the 
      age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function 
      associated with impaired cognition. Senolytic treatments decreased 
      senescence-associated secretory phenotype (SASP) and inflammatory 
      cytokines/chemokines in the plasma (IL-1beta, IP-10, and RANTES), with some markers 
      more responsive to D + Q (TNFalpha) or ABT-263 (IFNgamma, leptin, EGF). ABT-263 was more 
      effective in decreasing senescence genes in the spleen. Both senolytic treatments 
      decreased the expression of immune response and oxidative stress genes and 
      increased the expression of synaptic genes in the dentate gyrus (DG). However, 
      D + Q influenced twice as many genes as ABT-263. Relative to D + Q, the ABT-263 
      group exhibited increased expression of DG genes linked to cell death and 
      negative regulation of apoptosis and microglial cell activation. Furthermore, 
      D + Q was more effective at decreasing morphological markers of microglial 
      activation. The results indicate that preserved cognition was associated with the 
      removal of peripheral senescent cells, decreasing systemic inflammation that 
      normally drives neuroinflammation, BBB breakdown, and impaired synaptic function. 
      Dissimilarities associated with brain transcription indicate divergence in 
      central mechanisms, possibly due to differential access.
CI  - (c) 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & 
      Sons Ltd.
FAU - Budamagunta, Vivekananda
AU  - Budamagunta V
AD  - Department of Neuroscience, McKnight Brain Institute, University of Florida, 
      Gainesville, Florida, USA.
AD  - Genetics and Genomics Graduate Program, Genetics Institute, University of 
      Florida, Gainesville, Florida, USA.
AD  - Department of Pharmacodynamics, College of Pharmacy, University of Florida, 
      Gainesville, Florida, USA.
FAU - Kumar, Ashok
AU  - Kumar A
AUID- ORCID: 0000-0003-2541-8414
AD  - Department of Neuroscience, McKnight Brain Institute, University of Florida, 
      Gainesville, Florida, USA.
FAU - Rani, Asha
AU  - Rani A
AD  - Department of Neuroscience, McKnight Brain Institute, University of Florida, 
      Gainesville, Florida, USA.
FAU - Bean, Linda
AU  - Bean L
AD  - Department of Neuroscience, McKnight Brain Institute, University of Florida, 
      Gainesville, Florida, USA.
FAU - Manohar-Sindhu, Sahana
AU  - Manohar-Sindhu S
AD  - Genetics and Genomics Graduate Program, Genetics Institute, University of 
      Florida, Gainesville, Florida, USA.
FAU - Yang, Yang
AU  - Yang Y
AD  - Department of Pharmacodynamics, College of Pharmacy, University of Florida, 
      Gainesville, Florida, USA.
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center at San Antonio, San Antonio, Texas, USA.
FAU - Zhou, Daohong
AU  - Zhou D
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center at San Antonio, San Antonio, Texas, USA.
FAU - Foster, Thomas C
AU  - Foster TC
AD  - Department of Neuroscience, McKnight Brain Institute, University of Florida, 
      Gainesville, Florida, USA.
AD  - Genetics and Genomics Graduate Program, Genetics Institute, University of 
      Florida, Gainesville, Florida, USA.
LA  - eng
GR  - R21 AG068205/AG/NIA NIH HHS/United States
GR  - R01 AG063801/AG/NIA NIH HHS/United States
GR  - R01 AG037984/AG/NIA NIH HHS/United States
GR  - R01 AG052258/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230323
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - XKJ5VVK2WD (navitoclax)
RN  - 0 (Senotherapeutics)
RN  - RBZ1571X5H (Dasatinib)
RN  - 9IKM0I5T1E (Quercetin)
SB  - IM
MH  - Rats
MH  - Animals
MH  - Male
MH  - *Senotherapeutics
MH  - Rats, Inbred F344
MH  - Cellular Senescence
MH  - Aging
MH  - Hippocampus
MH  - Dasatinib/pharmacology
MH  - *Cognitive Dysfunction/genetics
MH  - Quercetin/pharmacology
PMC - PMC10186609
OTO - NOTNLM
OT  - aging
OT  - cognition
OT  - inflammation
OT  - oxidative stress
OT  - senolytic NMDA receptor
OT  - transcription
COIS- Daohong Zhou is an inventor of two pending patent applications for use of Bcl-xL 
      PROTACs, synthesized using ABT-263, as senolytic and antitumor agents. Daohong 
      Zhou is a co-founder of and has equity in Dialectic Therapeutics, which develops 
      Bcl-xL PROTACs to treat cancer.
EDAT- 2023/03/25 06:00
MHDA- 2023/05/17 06:42
PMCR- 2023/03/23
CRDT- 2023/03/24 00:43
PHST- 2023/02/22 00:00 [revised]
PHST- 2022/12/23 00:00 [received]
PHST- 2023/02/24 00:00 [accepted]
PHST- 2023/05/17 06:42 [medline]
PHST- 2023/03/25 06:00 [pubmed]
PHST- 2023/03/24 00:43 [entrez]
PHST- 2023/03/23 00:00 [pmc-release]
AID - ACEL13817 [pii]
AID - 10.1111/acel.13817 [doi]
PST - ppublish
SO  - Aging Cell. 2023 May;22(5):e13817. doi: 10.1111/acel.13817. Epub 2023 Mar 23.