Table 1 Mitochondrial-targeted anti-senescence interventions and their biological outcomes
From: Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease
Mitochondrial dysfunction | Anti-senescence intervention | Mitochondrial target | Model | Biological outcome | Reference |
|---|---|---|---|---|---|
ETC | Temporal antimycin A treatment | Transient complex III inhibition | SIS human fetal lung fibroblasts (MRC-5) | • Reduced SA-β-gal activity • Increased Ki-67-positive cells • Reduced intracellular ROS • Increased ΔΨm • Decreased ATP levels • Increased mitochondrial biogenesis • Reduced mitophagy | |
ROS | Mitoquinone mesylate (MitoQ) | Mitochondrial antioxidant | Doxorubicin-induced senescent human umbilical vein endothelial cells (HUVECs) | • Increased proliferation • Reduced p16 • Reduced mitochondrial superoxide • Reduced IL-8, IL-6, and MCP-1 • Reduced 53BP1 DNA damage marker | |
Superoxide dismutase 3 overexpression | Antioxidant | Human fetal lung fibroblasts (MRC-5) | • Increased replicative lifespan under normoxia and hyperoxia • Decreased intracellular peroxides • Slowed telomere shortening under normoxia and hyperoxia | ||
α-phenyl-t-butyl-nitrone | Antioxidant | Human fetal lung fibroblasts (MRC-5) | • Increased replicative lifespan • Decreased intracellular peroxides under normoxia, hyperoxia, and in SIS • Slowed telomere shortening | ||
Carnosine | Antioxidant | Human foreskin fibroblasts (HFF-1); human fetal lung fibroblasts (MRC-5) | • Increased replicative lifespan • Maintenance of non-senescent morphology | ||
Aminoguanidine | Antioxidant | Progeroid mice-derived dermal fibroblasts | • Increased replicative lifespan • Maintenance of non-senescent morphology • Reduced lipid peroxides | ||
Human fetal lung diploid fibroblasts (2BS) | • Increased replicative lifespan • Slowed telomere shortening • Maintenance of non-senescent morphology • Reduced DNA damage after H2O2 exposure | ||||
ROS/Metabolism | Nicotinamide | Antioxidant, increased NAD+ levels, increased sirtuin activity | Human foreskin fibroblasts | • Increased replicative lifespan • Reduced SA-β-gal activity • Decreased p53 and p21 protein levels • Decreased ROS • Slowed telomere shortening • Decreased ATP levels • Increased ΔΨm | |
Metabolism | Cyanidin-3-O-glucoside or CD38 siRNA | Inhibition or knockdown of CD38 increasing the NAD+/NADH ratio leading to SIRT6 activation | D-galactose-induced senescent rat myocardial cells (H92C) | • Reduced SA-β-gal activity • Increased proliferation • Increased telomerase reverse transcriptase mRNA levels • Decreased ROS • Increased NAD+/NADH ratio • Decreased CD38 mRNA and protein levels • Increased SIRT6 mRNA and protein levels | |
Cyanidin-3-O-glucoside | Inhibition of CD38 increasing the NAD+/NADH ratio leading to SIRT6 activation | Myocardial tissue of 16-week-old D-galactose acute aging mouse model | • Increased NAD+/NADH ratio • Decreased CD38 mRNA and protein levels • Increased SIRT6 mRNA and protein levels • Decreased collagen • Improved fiber morphology • Decreased SASP factors (IL-1α, IL-1β, IL-6, IL-10, IL-17A, TNF-α) in peripheral blood • Improved oxygen consumption | ||
Metformin | AMPK activation inducing autophagy | Hydrogen peroxide-induced senescent human lens epithelial cells (HLE-B3) | • Reduced p16 mRNA levels • Reduced p21 mRNA and protein levels • Reduced p53 protein levels • Reduced SA-β-gal activity • Reduced IL-6 and IL-8 mRNA levels • Improved autophagic flux • mTOR inhibition | ||
Metformin or berberine | AMPK activation increasing NAD+/NADH ratio through NAMPT expression and activating SIRT1 and autophagy | Hydrogen peroxide-induced senescent mouse embryonic fibroblasts (NIH/3T3) | • Reduced SA-β-gal activity • Increased NAMPT mRNA and protein levels • Increased NAD+/NADH ratio • Increased SIRT1 activity • Improved autophagic flux | ||
Licochalcone D | AMPK activation inducing autophagy | Oxidative stress-induced senescent human bone marrow-mesenchymal stem cells (hBM-MSCs) | • Reduced p16, p21, and p53 protein levels • Reduced SA-β-gal activity • Increased autophagic flux | ||
AMPK activation | 17-week-old D-galactose acute aging mouse model | • In heart and hippocampus: reduced p21 and p53 protein levels, increased phosphorylated AMPK • In heart: increased autophagy markers • In hippocampus: reduced receptor for advanced glycation end-products expression | |||
Nifedipine | Calcium channel block leading to AMPK activation and increased autophagy | Hydrogen peroxide-induced senescent primary rat vascular smooth muscle cells (VSMCs) | • Reduced p53 and p21 protein levels • Reduced SA-β-gal activity • Decreased intracellular calcium • mTOR inhibition • Increased autophagic flux | ||
Increased mitochondrial biogenesis/ROS | Rapamycin | mTORC1 inhibition-mediated reduction in PGC-1β-dependent mitochondrial biogenesis | Irradiation-induced senescent human fetal lung fibroblasts (MRC-5) | • Reduced SA-β-gal activity • Decreased p21 mRNA and protein levels • Reduced ROS, reduced γH2AX DNA damage marker • Reduced IL-6 mRNA | |
15 to 16-month-old C57/BL6 mouse liver | • Reduced SA-β-gal levels • Reduced p21 protein levels • Reduced telomere-associated foci • Reduced SASP (CXCL-1 and inhibin A mRNA levels) | ||||
Increased mitochondrial biogenesis | Resveratrol, salidroside | Increased mitochondrial biogenesis without concomitant ROS increase via SIRT1 upregulation | Replicative senescent human fetal lung fibroblasts (MRC-5) | • Reduced SA-β-gal activity • Reduced intracellular ROS • Increased ΔΨm • Increased ATP levels | |
Mitochondrial elongation | FIS1 upregulation | Increased mitochondrial fission | RNAi-mediated FIS1-depleted cervical cancer cells (HeLa) | • Reduced SA-β-gal activity | |
Mitochondrial elongation and impaired mitophagy | siRNA-mediated p53 knockdown | Increased mitochondrial fission via decreased expression of OPA1 and increased expression and phosphorylation of DRP1 | Calcified mouse vascular smooth muscle cells (VSMCs) | • Reduced p53 and p21 protein levels • Reduced SA-β-gal activity • Increased ΔΨm • Reduced mitochondrial ROS | |
Impaired mitophagy | Rapamycin, nicotinamide (NAM), or nicotinamide riboside (NR) | PINK1/Parkin-dependent mitophagy activation | Irradiation-induced senescent primary neonatal human diploid fibroblasts (HDFs) | • Reduced p16 and p21 levels • SA-β-gal activity • Reduced cell size • Did not rescue proliferation or suppress IL-6 and IL-8 mRNA levels | |
IGF-1 | Mitophagy upregulation via the NRF2/SIRT3 pathway activation | Replicative senescent mouse vascular smooth muscle cells (VSMCs) | • Reduced p16 and p21 protein levels • Reduced SA-β-gal activity • Increased ΔΨm • Maintained telomere length • Reduced mtDNA damage | ||
Generalized mitochondrial dysfunction | Methylene blue | Redox cycling | Human fetal lung fibroblasts (IMR90) | • Extended replicative lifespan • Extended replicative lifespan under exposure to hydrogen peroxide or cadmium • Increased oxygen consumption • Increased complex IV expression • Increased heme synthesis • Increased NADH oxidation | |
Human fetal lung fibroblasts (IMR90) | • Increased PGC-1α expression • Increased NAD+/NADH ratio • Increased complex IV activity • Decreased intracellular oxidants • Extended replicative lifespan • Slowed telomere erosion | ||||
Human primary skin fibroblasts | • Decreased mitochondrial ROS • Decreased p16 levels • Decreased SA-β-gal activity • Increased expression of NRF2 pathway • Increased proliferation | ||||
Cholestatic livers of Sprague-Dawley rats (bile duct ligation model) | • Mitigated splenomegaly and hepatomegaly • Increased ΔΨm • Decreased mitochondrial lipid peroxidation • Increased mitochondrial dehydrogenase activity • Increased ATP | ||||
C57/BL6 mice multiple sclerosis model (cuprizone-fed) | • Decreased demyelinated neurons in the corpus callosum • Increased locomotor activity • Increased ΔΨm • Decreased mitochondrial lipid peroxidation • Increased mitochondrial dehydrogenase activity • Increased ATP levels | ||||
Klotho upregulation | Senescence-associated mitochondrial dysfunction | Unilateral ischemia-reperfusion (UIRI) mouse kidney | • Increased mitochondrial mass • Decreased mitochondrial ROS • Improved mitochondrial morphology • Reduced p16 protein levels • Reduced SA-β-gal activity • Reduced p19 and γH2AX mRNA and protein levels | ||
Prolong cultured human cortical brain organoids | • Reduced p16 mRNA levels • Reduced p21 protein levels • Reduced SA-β-gal activity • Reduced IL-8, IL-1α, and IL-1β mRNA levels | ||||
Lifelong 40% caloric restriction | Age-related mitochondrial dysfunction | 24-month-old B6D2F1 mice isolated mitochondria and permeabilized fibers from gastrocnemius muscle | • Increased respiratory function • Increased mitochondrial efficiency • Decreased uncoupling • No change in mitochondrial abundance or biogenesis | ||
60% caloric restriction from 14 weeks of age | Age-related mitochondrial dysfunction | 22-24-month-old C57BL/6 mice adipose-derived stem cells | • Reduced mitochondrial activity • Reduced SA-β-gal activity | ||
Mitochondrial transplantation from mesenchymal stem cells to senescent cells | Senescence-associated mitochondrial dysfunction | Replicative senescent human retinal pigment epithelial cells (ARPE-19) | • Decreased mitochondrial and intracellular ROS • Increased mitochondrial fission markers • Increase in Parkin and decrease in PINK1 protein levels • Reduced p16 and p21 protein levels • Reduced SA-β-gal activity • Reduced cell size • Reduced NF-κB phosphorylation • Reduced IL-8 and TNF-α mRNA levels | ||
CCCP-induced Parkin-mediated mitochondrial clearance | Elimination of mitochondria from the cell | Irradiation-induced senescent human fetal lung fibroblasts (MRC-5) | • Reduced p16 and p21 protein levels • Reduced SA-β-gal activity • Reduced cell size • Reduced ROS • Reduced senescence-associated heterochromatin foci • Reduced SASP factor secretion (IL-6, IL-8, GRO and MCP-1) • Decreased mTOR activity • Initial small increase in proliferation followed by proliferative arrest | ||
DAMP release | CRISPR-Cas9 deletion of BAX and BAK macropores | Blocking mtDNA release | Irradiation-induced senescent BAX−/−BAK−/− human fetal lung fibroblasts | • Reduced expression of SASP factors • No impact on other senescence markers (p16, p21, SA-β-gal activity, γH2A.X foci, Lamin B1, HMGB1, or proliferation) | |
BAX channel inhibitor BAI1 | Blocking miMOMP-mediated mtDNA release | Irradiation-induced senescent human fetal lung fibroblasts (MRC-5 and IMR-90) | • Reduced mtDNA release • Reduced IL-6, IL-8, and IL-1β expression | ||
23-month-old C57BL/6 mice | • Reduced frailty score • Improved neuromuscular coordination • Improved grip strength • Improved spine and femur trabecular bone microarchitecture • In bone, reduced SASP factor expression with no change in p16, p21, or p53 • In brain, reduced p16-positive cells • Decrease in the senescence gene panel SenMayo374 in microglia and oligodendrocytes |
