Glucosamine Displays a Potent Caloric Restriction Mimetic Effect in Senescent Rats by Activating Mitohormosis.

Aging is strongly correlated with several noncommunicable disorders such as diabetes, obesity, cardiovascular disease, and neurodegenerative conditions. Glucosamine (2-amino-2-deoxy-d-glucose, GlcN) is a naturally occurring amino sugar and is reported to act as a caloric restriction mimetic (CRM). In young and d-galactose-induced accelerated rat aging models, we tested a persistent oral dietary dose of GlcN and evaluated various aging biomarkers in erythrocytes and plasma. A significant increase in the reactive oxygen species (ROS) was observed in GlcN-treated young and accelerated senescent rat model. Increased value of ferric reducing ability of plasma (FRAP), superoxide dismutase, catalase, and plasma membrane redox system (PMRS) was observed. We suggest that GlcN induces a mitohormetic impact by a transient increase in ROS. Our findings indicate that GlcN may be a successful CRM.

2 -Deoxy - d-glucose at chronic low dose acts as a caloric restriction mimetic through a mitohormetic induction of ROS in the brain of accelerated senescence model of rat.

INTRODUCTION: Aging induces significant molecular alteration in brain morphology. Glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) is considered to act as a caloric restriction mimetic (CRM) but it is correlated with elevated mortality risk in rats at persistent high dosage. MATERIALS AND METHODS: In young and d-galactose induced accelerated senescent rat aging models, we tested a persistent low-dose dietary 2-DG administration and evaluated various aging biomarkers in brain tissue. RESULTS: A significant increase in reactive oxygen species (ROS) was observed in 2-DG treated (both young and accelerated senescent rat model). Increased Ferric reducing antioxidant potential (FRAP) value, Superoxide Dismutase (SOD), Catalase (CAT), and activity of mitochondrial complexes I and IV was observed. There was also significant improvements in the autophagy expression of genes (Beclin-1 and Atg-3) after 2- DG treatment. CONCLUSION: We propose that 2-DG induces a mitohormetic effect through elevation of ROS which reinforces defensive mechanism(s) through increased FRAP, SOD, CAT and autophagy gene expression. Our observations indicate that a consistently low dose 2-DG could be a valuable CRM.

Glycolytic Inhibitor 2-Deoxy-D-Glucose at Chronic Low Dose Mimics Calorie Restriction in Rats Through Mitohormetic Induction of Reactive Oxygen Species.

Caloric restriction mimetics (CRMs) provide an exciting antiaging intervention strategy. 2-Deoxy-D-glucose (2-DG), a glycolytic inhibitor, is known to work as a CRM at high doses; however, at chronic high dose it has been linked to increased mortality in rats. We have investigated chronic low-dose dietary administration of 2-DG on age-related stress protection in young and old male Wistar rats by evaluating age-dependent biomarkers in plasma and erythrocytes. Significant increase was observed in reactive oxygen species levels in 2-DG-treated rats (both young and old), concomitant with increase in activities of erythrocyte plasma membrane redox system (PMRS), catalase (CAT), and superoxide dismutase (SOD). 2-DG treatment also decreased plasma sialic acid and advanced glycation end products. We propose that 2-DG induces a mitohormetic response resulting in augmentation of defense mechanism(s) manifested by higher activity of PMRS, CAT, and SOD. Our findings provide evidence that at chronic low dose 2-DG could be a potential CRM.

Novel strategies for anti-aging drug discovery.

INTRODUCTION: Scientific achievements in the last few decades, leading to effective therapeutic interventions, have dramatically improved human life expectancy. Consequently, aging has become a significant problem and represents the major risk factor for most human pathologies including diabetes, cardiovascular diseases, neurological disorders, and cancer. Scientific discoveries over the past two decades have been instrumental in dissecting molecular mechanism(s) which play important roles in determining longevity. The same understanding has also led to the acknowledgement of the plurality of 'causes' which act either alone or in combination to create the condition which can be defined as 'aging'. Areas covered: Over the years, several concepts have been put forward for the development of a viable anti-aging regimen. In this review, the authors extensively review anti aging interventions based on caloric restriction, activation of telomerase, autophagy inducers, senolytic therapeutics, plasma membrane redox system (PMRS) activators, epigenetic modulators, and stem cell therapies. Expert opinion: Based upon our current understanding, one of the most promising approaches for a successful anti-aging strategy includes the activation of adenosine monophosphate dependent protein kinase (AMPK). Another strategy may involve activation of PMRS. Future research efforts are likely to focus on nutrient and energy sensing molecular pathways which include mTOR, IGF-1, AMPK and the sirtuins.