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

Abstract

The natural aging of multicellular organisms is marked by a progressive decline in the function of cells and tissues. The accumulation of senescent cells in tissues seems to eventually cause aging of the host. Nevertheless, gene expression that influences aging is unlikely to be conserved between tissues, and age-related loss of function seems to depend on a variety of mechanisms. This is a concern when developing anti-aging drugs in geriatric clinical pharmacology. We have sought a universal agent to redundantly cover gene expression despite the variation in differentially expressed genes between tissues. Using a minimally modified connectivity map, the poly (ADP-ribose) polymerase (PARP) inhibitor 1,5-isoquinolinediol was selected as a potent candidate, simultaneously applicable to various tissues. This choice was validated in vitro. Treatment of murine embryonic fibroblasts with 1,5-isoquinolinediol appeared to efficiently suppress the rate of replicative senescence at a concentration of 0.1 μM without resulting in cell death. The appearance of abnormal nuclei and accumulation of β-galactosidase in the cytoplasm were inhibited by daily treatment with the agent. When the aging process was accelerated by hydroxyurea-induced oxidative stress, the effect was even more noticeable. Thus, 1,5-isoquinolinediol may potentially be developed as an agent to prolong life.

Adjudin delays cellular senescence through Sirt3‑mediated attenuation of ROS production

“…Cells were treated with HU, which inhibits ribonucleotide reductase activity (26,27), to produce an in vitro senescence model. HU-induced senescence has been widely used to mimic cell aging (28)(29)(30)(31)(32)(33)(34). MEFs were pretreated with adjudin for 1 h, followed by a 24-h incubation period with 6 mM HU.…”

Mechanisms of Hydroxyurea‐Induced Cellular Senescence: An Oxidative Stress Connection?

“…Similarly, 1,5-isoquinolinediol (IQD), a poly (ADP-ribose) polymerase (PARP1) inhibitor, protects MEF cells from HU-induced senescence [ 185 ]. PARPs perform poly(ADP-ribosyl)ation of proteins as an immediate cellular response to genotoxic insults induced by ionizing radiation, alkylating agents, and oxidative stress [ 186 ].…”

“…PARPs perform poly(ADP-ribosyl)ation of proteins as an immediate cellular response to genotoxic insults induced by ionizing radiation, alkylating agents, and oxidative stress [ 186 ]. HU accelerates the MEF replicative senescence rate by inducing oxidative stress paralleled to increasing PARP1 and lamin A expression, while IQD effectively suppresses the senescence rate by decreasing the activity of PARP1 [ 185 ]. Noticeably, the increased expression and activity of PARP1 rapidly consume the NAD+ necessary for Sirt-1 function, so the decreased Sirt-1 activity results in increased oxidative stress.…”

The crystal structure of 2,2,2-trifluoro-1-(isoquinolin-1-yl)ethane-1,1-diol, C11H8F3NO2

“…In this application the collagenase can be inhibited to improve the wrinkles of the skin. It is also the main component of the synthesis of poly (ADP-ribose) polymerase (PARP) inhibitors [4]. In particular, the introduction of a CF 3 group into a drug candidate enhances the chemical and metabolic stability of the compound, improves lipophilicity and bioavailability, and even increases protein binding affinity [5][6][7].…”