Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures.

Giovanni Pagano,Maria Toscanesi,Luca Tiano,Marco Trifuoggi,Alex Lyakhovich,Maria Rosa Fittipaldi,Federico V Pallardó

doi:10.3390/ijms21197060

Abstract

A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential–and distinct—roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.

Highlights

The multiple phases of mitochondrial function and the combined relationships of mitochondrial machineries with oxidative stress (OS) have been established since early studies in the mid-20th century and the ensuing studies are still a major subject of up-to-date reports [1,2,3]
Beyond the above-cited experimental and clinical reports, the extensive literature discusses the potential benefits of treating aging-related disorders (ARD) and mitochondria-defective diseases using mitochondrial nutrients” (MNs) [14,25,134,135,136,137,138,139,140,141,142,143,144]
Consistent with the available database from pre-clinical and clinical investigations, the available mitochondrial dysfunction (MDF)-related reviews mainly focus on the potential advantages of using individual MNs in the treatment of mitochondria-defective disorders, with the exception of the “mitochondrial cocktail” perspective proposed by Tarnopolsky [136] and as discussed in our previous review [137]

Summary

Introduction

The multiple phases of mitochondrial function and the combined relationships of mitochondrial machineries with OS have been established since early studies in the mid-20th century and the ensuing studies are still a major subject of up-to-date reports [1,2,3]. Mitochondria are commonly recognized as the main cell’s powerplant and the first victims of their energy-producing and prooxidant functions These organelles display strong antioxidant properties, and this is the case for ALA, involved in the citric acid cycle, for CoQ10, involved in the electron transport chain (ETC), and for CARN, the main carrier of acyl groups across the mitochondrial membrane. This background knowledge has led to the awareness of the key roles of mitochondrial cofactors in aging and in ARD.

Basic Research Studies

The Case of Progerias

The Case of Optic Neuropathies

MNs in the Content of Microbiome and Aging

Findings

Concluding Remarks