Metformin alleviates ageing cellular phenotypes in Hutchinson–Gilford progeria syndrome dermal fibroblasts

Abstract

Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and ageing prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature ageing and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients. Metformin treatment partially restored normal nuclear phenotypes, delayed senescence, activated the phosphorylation of AMP-activated protein kinase and decreased reactive oxygen species formation in HGPS dermal fibroblasts. Interestingly, metformin reduced the number of phosphorylated histone variant H2AX-positive DNA damage foci and suppressed progerin protein expression, compared to the control. Furthermore, metformin-supplemented aged mice showed higher splenocyte proliferation and mRNA expression of the antioxidant enzyme, superoxide dismutase 2 than the control mice. Collectively, our results show that metformin treatment alleviates the nuclear defects and premature ageing phenotypes in HGPS fibroblasts. Thus, metformin can be considered a promising therapeutic approach for life extension in HGPS.

Farnesyltransferase inhibitor and rapamycin correct aberrant genome organisation and decrease DNA damage respectively, in Hutchinson–Gilford progeria syndrome fibroblasts

“…The anti-diabetic drug metformin is also hailed as a treatment for HGPS as well as an anti-ageing treatment—given that diabetic patients on metformin live longer than the control group (Bannister et al 2014 ). Metformin treatment of HGPS cells results in the down-regulation of progerin expression (Egesipe et al 2016 ; Park and Shin 2017 ). Methylene blue is another anti-oxidant and potential anti-ageing product that seems to have great potential in treating HGPS (Xiong et al 2017 ).…”

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

“…With this in mind, it seems natural that metformin might benefit HGPS patients, where patients are known to have hyperinsulinemia, increased ROS, and increased DNA damage. Interestingly, when HGPS dermal fibroblasts were treated with metformin, there was partial restoration of normal nuclear phenotypes, delayed senescence, decreased DNA damage, activation of AMPK phosphorylation, and decreased ROS formation, all while also suppressing progerin expression [92]. Another group also showed the benefit of metformin, though suggested this might be through decreased SRSF1 expression, which has been shown to affect alternative splicing of LMNA in humans and mice [93].…”

Lysophosphatidic acid receptor LPA3 prevents oxidative stress and cellular senescence in Hutchinson–Gilford progeria syndrome

“…As a result, HGPS is studied as a model for understanding the fundamental biological processes of aging diseases. Given that increased levels of reactive oxygen species (ROS) play an important role in the developing symptoms of HGPS and normal aging (Viteri, Chung, & Stadtman, ), many current studies are focusing on ameliorating oxidative stress in HGPS cells (Park & Shin, ). Indeed, oxidative stress affects a wide range of physiological and pathological functions, and excess ROS will damage various cellular components, leading to aging‐related diseases and cancers (Cui, Kong, & Zhang, ).…”