Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches. 

Mitochondrial and metabolic dysfunction in ageing and age-related diseases

New insights into activation and function of the AMPK

Treatment of type 2 diabetes: challenges, hopes, and anticipated successes.

Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD+ ) via the 'salvage pathway'. In addition to playing a key role as a mitochondrial co-factor, NAD+ metabolites may contribute to the increase in GSIS (via enhanced Ca++ mobilization). Imeglimin has also been shown to preserve β-cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon-like peptide-1 receptor agonists.

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes.

Diabetes is considered a new pandemic of the modern world, and the number of sufferers is steadily increasing. Sustained hyperglycemia promotes the production of free radicals and leads to persistent, low-grade inflammation. Oxidative stress causes mitochondrial destruction, which along with activation of the hexosamine pathway, nuclear factor-κB (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), c-jun NH2 terminal kinase/stress-activated protein kinase (JNK/SAPK) or toll-like receptors (TLRs), leads to pancreatic β-cell dysfunction. However, there is also the protective mechanism that counteracts oxidative stress and inflammation in diabetes, mitophagy, which is a mitochondrial autophagy. An important part of the strategy to control diabetes is to lead a healthy lifestyle based on, among other things, regular physical activity, giving up smoking, eating a balanced diet containing ingredients with antioxidant potential, including vegetables and fruits, and using hypoglycemic pharmacotherapy. Tobacco smoke is a recognized modifiable risk factor for many diseases including diabetes, and it has been shown that the risk of the disease increases in proportion to the intensity of smoking. Physical activity as another component of therapy can effectively reduce glucose fluctuations, and high intensity interval exercise appears to have the most beneficial effect. A proper diet not only increases cellular sensitivity to insulin, but is also able to reduce inflammation and oxidative stress. Pharmacotherapy for diabetes can also affect oxidative stress and inflammation. Some oral drugs, such as metformin, pioglitazone, vildagliptin, liraglutide, and exenatide, cause a reduction in markers of oxidative stress and/or inflammation, while the new drug Imeglimin reverses pancreatic β-cell dysfunction. In studies of sitagliptin, vildagliptin and exenatide, beneficial effects on oxidative stress and inflammation were achieved by, among other things, reducing glycemic excursions. For insulin therapy, no corresponding correlation was observed. Insulin did not reduce oxidative stress parameters. There was no correlation between glucose variability and oxidative stress in patients on insulin therapy. The data used in this study were obtained by searching PubMed online databases, taking into account recent studies.

/pdf/the-influence-of-lifestyle-and-treatment-on-oxidative-stress-2q7gb0iv.pdf

The Influence of Lifestyle and Treatment on Oxidative Stress and Inflammation in Diabetes

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

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Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.