Resveratrol activates SIRT1 in a Lamin A-dependent manner

Abstract

Human sirtuin1 (SIRT1), the closest homolog of the yeast sir2 protein, functions as an NAD+-dependent histone and non-histone protein deacetylase in several cellular processes, like energy metabolism, stress responses, aging, etc. In our recent study, we have shown that lamin A (a major nuclear matrix protein) directly binds with and activates SIRT1. Resveratrol, a natural phenol, has long been known as an activator of SIRT1. However, resveratrol's direct activation of SIRT1 has been refuted several times. In our study, we have provided a mechanistic explanation to this question, and have shown that resveratrol activates SIRT1 by increasing its binding with lamin A, thus aiding in the nuclear matrix (NM) localization of SIRT1. We have also shown that rescue of adult stem cell (ASC) decline in laminopathy-based premature aging mice by resveratrol is SIRT1-dependent. Further, resveratrol's ameliorating effects on progeria and its capacity to extend lifespan in progeria mice has been established. Here we have summarized these findings and their probable implications on other aspects, like chromatin remodeling, stem cell therapy, DNA damage responses, etc.

Keywords: Lamin A; SIRT1; Zmpste24; adult stem cells; nuclear matrix; progeria; resveratrol.

Figure 1. Schematic illustration showing (A) Lamin A interacts with SIRT1 to activate it causing further deacetylation of P53. (B) Resveratrol (RSV) in itself cannot activate SIRT1. (C) Resveratrol (RSV) further increases interaction between SIRT1 and Lamin A to enhance its deacetylation activity toward P53. (D) SIRT1’s interaction with prelamin A is compromised, but resveratrol (RSV) treatment enhances this binding, resulting in amelioration of progeroid features in Zmpste24^−/− bone marrow stromal cells (BMSCs).