Targeting the Mitochondria-Proteostasis Axis to Delay Aging

Abstract

Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence

“…Furthermore, ROS can damage the proteins involved in mitochondrial proteostasis, which play an important role in maintaining and regulating protein quality within mitochondria [ 47 ]. Defects in mitochondrial proteostasis impair protein folding and the processing of misfolded or aggregated proteins, leading to aging and age-related diseases through accelerated proteostatic collapse [ 47 , 48 ]. The causal relationship between senescence and dysfunctional mitochondria is supported by findings that the accumulation of dysfunctional mitochondria leads to detrimental effects, including altered cellular homeostasis and degenerative changes in tissues [ 49 , 50 , 51 , 52 ].…”

Sex‐ and strain‐specific effects of mitochondrial uncoupling on age‐related metabolic diseases in high‐fat diet‐fed mice

“…The quest to understand why we age has given rise to numerous lines of investigation that have gradually converged on the mitochondria as a major player in metabolic control (Lopez‐Otin et al, 2013 ; Mookerjee et al, 2010 ; Zimmermann et al, 2021 ). In particular, mitochondrial dysfunction, including reduced oxidative capacity and increased ROS production, has emerged as one of the main hallmarks of mammalian aging (Baker & Peleg, 2017 ; Bratic & Larsson, 2013 ; Chistiakov et al, 2014 ; Wang & Hekimi, 2015 ).…”

NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities

“… 62 Hence, future studies focusing on the mitochondrial axis are needed to elucidate the role of NAD + in decelerating the manifestation of age-related diseases. 63 …”