Mitochondrial and metabolic dysfunction in ageing and age-related diseases

Abstract

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.

Fig. 1 |. Longevity signalling pathways control mitochondrial health.

Caloric restriction reduces the concentrations of glucose, amino acids and lipids, while raising the concentrations of key metabolites, such as NAD⁺ and AMP. These metabolites modulate the activity of metabolic sensors, such as the sirtuins (SIRTs), AMP kinase (AMPK), the target of rapamycin (TOR) and insulin–IGF1 signalling (IIS). Downstream to metabolic sensors, transcription factors, such as forkhead box O (FOXO) and the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), orchestrate mitochondrial physiology and homeostasis. Dysregulation of this multilevel regulatory system reduces mitochondrial homeostasis, resulting in frailty and disease. Ac, acetyl group; ACC, acetyl-CoA carboxylase; LKB1, liver kinase B1; ULK1, UNC51-like kinase 1.

Fig. 2 |. Mitochondrial dysfunction in age-related metabolic diseases.

Mitochondrial dysfunction during ageing predisposes the elderly to age-related metabolic diseases. Diseases associated with metabolic deregulation can occur in various tissues, especially organs that have high energy demands. NAFLD, non-alcoholic fatty liver disease.