Pharmacogenomic analysis indicates potential of 1,5-isoquinolinediol as a universal anti-aging agent for different...

Area of Science:

• Gerontology and Cellular Biology
• Pharmacology and Drug Discovery

Background:

• Multicellular organism aging involves progressive functional decline in cells and tissues.
• Accumulation of senescent cells is a key factor in host aging.
• Age-related functional decline is complex, involving diverse mechanisms and variable gene expression across tissues, posing challenges for anti-aging drug development.

Purpose of the Study:

• To identify a universal agent capable of counteracting age-related gene expression variations across different tissues.
• To evaluate the potential of the poly (ADP-ribose) polymerase (PARP) inhibitor 1,5-isoquinolinediol as a broad-acting anti-aging therapeutic.

Main Methods:

• Utilized a minimally modified connectivity map to screen for potential universal anti-aging agents.
• In vitro validation involved treating murine embryonic fibroblasts with 1,5-isoquinolinediol.
• Assessed the drug's effect on replicative senescence, cell viability, nuclear morphology, and β-galactosidase activity.
• Evaluated efficacy under conditions of hydroxyurea-induced oxidative stress.

Main Results:

• 1,5-isoquinolinediol effectively suppressed replicative senescence in murine embryonic fibroblasts at a concentration of 0.1 µM without causing cell death.
• The treatment inhibited the formation of abnormal nuclei and the cytoplasmic accumulation of β-galactosidase, key indicators of senescence.
• The anti-aging effects were more pronounced when senescence was accelerated by oxidative stress.

Conclusions:

• 1,5-isoquinolinediol demonstrates significant potential as a universal agent to combat cellular senescence across various tissues.
• This PARP inhibitor may be a promising candidate for developing novel anti-aging therapies aimed at promoting longevity.