An attempt to prevent senescence: a mitochondrial approach

Area of Science:

• Mitochondrial biology and gerontology
• Antioxidant chemistry and pharmacology

Background:

• Aging is associated with increased oxidative stress and mitochondrial dysfunction.
• Developing targeted antioxidants for mitochondria could decelerate organismal senescence.
• A collaborative international project aimed to synthesize and evaluate novel mitochondrial antioxidants.

Purpose of the Study:

• To synthesize and characterize novel mitochondria-targeted antioxidants (SkQs).
• To evaluate the anti- and prooxidant properties of SkQs in various biological systems.
• To assess the efficacy of SkQs in decelerating aging and treating age-related diseases.

Main Methods:

• Synthesis of plastoquinone-based compounds (SkQs) with varying linkers and cations.
• Selection of highly permeable SkQ derivatives (SkQ1, SkQR1, SkQ3) using planar bilayer phospholipid membranes.
• Testing antioxidant/prooxidant activity in vitro (solutions, micelles, liposomes, BLM) and in vivo (mitochondria, cell cultures, whole organisms).

Main Results:

• SkQ1, SkQR1, and SkQ3 demonstrated antioxidant activity at sub-micromolar concentrations, with SkQ1 being rechargeable by the mitochondrial respiratory chain.
• SkQ1 specifically prevented cardiolipin oxidation and SkQR1 localized to mitochondria in cell cultures.
• SkQ1 and SkQR1 inhibited apoptosis and necrosis, prolonged lifespan in various species, and ameliorated numerous age-related conditions including retinopathy, glaucoma, and osteoporosis.

Conclusions:

• SkQs, particularly SkQ1, are effective mitochondria-targeted antioxidants with significant anti-aging and therapeutic potential.
• SkQ1 demonstrated remarkable efficacy in restoring vision in animal models of retinopathy and preventing sight loss.
• SkQs show promise for treating senescence and a wide range of age-related diseases, including cardiovascular and oncological conditions.