NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle

Abstract

Aging is characterized by loss of proteostasis and mitochondrial homeostasis. Here, we provide bioinformatic evidence of dysregulation of mitochondrial and proteostasis pathways in muscle aging and diseases. Moreover, we show accumulation of amyloid-like deposits and mitochondrial dysfunction during natural aging in the body wall muscle of C. elegans, in human primary myotubes, and in mouse skeletal muscle, partially phenocopying inclusion body myositis (IBM). Importantly, NAD + homeostasis is critical to control age-associated muscle amyloidosis. Treatment of either aged N2 worms, a nematode model of amyloid-beta muscle proteotoxicity, human aged myotubes, or old mice with the NAD + boosters nicotinamide riboside (NR) and olaparib (AZD) increases mitochondrial function and muscle homeostasis while attenuating amyloid accumulation. Hence, our data reveal that age-related amyloidosis is a contributing factor to mitochondrial dysfunction and that both are features of the aging muscle that can be ameliorated by NAD + metabolism-enhancing approaches, warranting further clinical studies.

From the Bench to the Bedside: Branched Amino Acid and Micronutrient Strategies to Improve Mitochondrial Dysfunction Leading to Sarcopenia

“…Abundant literature has described an age-dependent impairment of mitochondrial function, and an alteration of mitochondrial structure across species from yeast to humans, which in turn contributes to age-associated cellular quality control decline and tissue dysfunction [ 38 , 39 ]. Though dysregulation of mitochondrial homeostasis is a global hallmark of aging, there are tissues in which it is more prominently observed.…”

“…Though dysregulation of mitochondrial homeostasis is a global hallmark of aging, there are tissues in which it is more prominently observed. These typically include post-mitotic and highly metabolic tissues, such as skeletal muscle, which are therefore more sensitive to the dysregulation of mitochondrial-mediated processes [ 38 , 40 ]. Hence, it is not surprising that altered mitochondrial homeostasis has been long suggested as key player in the development of sarcopenia.…”

“…Conversely, interventions aiming at improving UPR mt and mitophagy mediate numerous anti-aging effects in different tissues from nematodes to mammals, including increased lifespan and fitness. Pharmacological-, genetic-, or exercise-induced mitochondrial quality control upregulation mediates a restoration of mitochondrial function and muscle homeostasis in aged flies, rodents, and patients [ 38 , 56 , 60 , 61 , 62 , 63 ]. The beneficial effects of mitochondrial quality control boosting in muscle tissue has encouraged the initiation of different clinical trials to assess the therapeutic potential of this strategy in muscle health and sarcopenic patients [ 64 , 65 , 66 , 67 ].…”

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

“…HRI adds a phosphate group to the protein eIF2α, and this phosphorylation slows the synthesis of most cellular proteins from messenger RNA, mediated by the ribosome complex, but promotes the production of the transcription factors ATF4, ATF5 and CHOP. Treatments that activate the UPR mt have been shown to ameliorate mitochondrial function in amyloid-β proteotoxic diseases, such as Alzheimer’s disease [ 44 ], age-associated amyloidosis [ 45 ], and kidney injury [ 46 ]. Conversely, tuning the chronic integrated stress response activation might potentially rescue synaptic plasticity loss [ 47 ], and reverse age-related cognitive decline [ 48 ], and sepsis-induced kidney injury [ 49 ].…”

Artificial‐intelligence‐driven discovery of prognostic biomarker for sarcopenia

“…Sarcopenia is often associated with physical frailty, 23 reduced muscle function, 27 and mitochondrial dysfunction. 14 In addition, recent studies revealed that amyloidosis in skeletal muscle is associated with mitochondrial dysfunction 28 , 29 and muscle diseases including inclusion body myositis, 30 , 31 indicating that both mitochondrial dysfunction and amyloidosis may trigger sarcopenia. In group γ, which generated a negative cluster against both groups α and β, most of the HPO terms were related to neoplasms.…”