Amyloids are misfolded proteins that can cause other molecules of the same protein to misfold in the same way, linking together into solid deposits that are disruptive to normal cell and tissue function. There are only a score or so of different types of amyloid in the human body, and most are conclusively linked to at least one age-related condition. In today's open access research materials, the scientists involved report on the involvement of amyloid-β (and potentially other amyloids) in muscle aging, connecting loss of mitochondrial function with the growing presence of amyloids.
In order to test the direction of causation in this relationship, the researchers first boosted mitochondrial function in old animals by increasing NAD+ levels. NAD+ is essential to mitochondrial function, but declines with age for a variety of reasons. The proximate causes are fairly well mapped, meaning a loss of efficiency in NAD synthesis and NAD recycling pathways, but connections to the underlying causes of aging remain to be discovered. In this study, improved mitochondrial function reduced the burden of amyloid in muscle tissue. Separately, the researchers also removed amyloid from tissues in a targeted way, and found that this improved mitochondrial function. Thus the relationship appears bidirectional. Amyloid degrades mitochondrial function, while forcing an improvement in mitochondrial function gives cells a greater ability to clear amyloid.
The older we grow, the weaker our muscles get, riddling old age with frailty and physical disability. Researchers have now looked at the issue through a different angle: the similarities between muscle aging and degenerative muscle diseases. In the study, the scientists identify amyloid-like protein aggregates in aged muscles from different species, from the nematode C. elegans all the way to humans. In addition, they also found that these aggregates also impair mitochondrial function. Although aggregated proteins have been suggested to contribute to brain aging, this is the first time that they have been shown to contribute to muscle aging and to directly damage mitochondria.
But can the formation of the protein aggregates be reversed? To answer this, the researchers fed worms the vitamin nicotinamide riboside and the antitumor agent Olaparib, both of which boost the levels of nicotinamide adenine dinucleotide (NAD+), a biomolecule that is essential for maintaining mitochondrial function, and whose levels decline during aging. In the worms, the two compounds turned on the defense systems of the mitochondria, even when provided at advanced age. Turning on the so-called "mitochondrial quality control system" of mitophagy reduced the age-related amyloid protein aggregates and improved the worms' fitness and lifespan.
The scientists then moved on to human muscle tissue taken from aged subjects. Turning on the same mitochondrial quality control systems produced similar improvements in protein and mitochondrial homeostasis. The encouraging results led the researchers to test nicotinamide riboside in aged mice. The treatment also activated the mitochondrial defense systems and reduced the number and size of amyloid aggregates in different skeletal muscle tissues.
Due to the fact that mitochondrial function and proteostasis are essential to ensure cellular homeostasis, are functionally interconnected, and decline in aging, it is not surprising that mitochondrial dysfunction and abnormal proteostasis are involved in chronic age-associated neuromuscular proteinopathies, such as Alzheimer's disease (AD), and inclusion body myositis (IBM), a debilitating age-associated muscle disease. Although affecting different organs, AD and IBM are both protein aggregation diseases characterized by the accumulation of amyloid protein deposits. IBM is the most common muscle proteinopathy affecting the elderly; however, it is generally considered a rare disorder, with its overall prevalence still under debate. Skeletal muscle decay instead is one of the most prominent features of aging, characterized by loss of muscle mass and function and by a decline in mitochondrial function. In addition, muscle aging is also typified by dysfunctional proteostasis pathways, including altered ubiquitin-proteasome system (UPS) activity and defective autophagy. Currently, the mechanism underlying the collapse of proteostasis in the aging muscle is not fully elucidated, and it is furthermore unclear whether amyloid deposition, a hallmark of IBM, is also at play in the aging muscle.
Here, we report that, during natural aging, muscle tissues accumulate amyloid-like deposits, a process which is evolutionary conserved in C. elegans, in mouse and human muscle cells and tissues, with molecular features recapitulating some aspects of IBM. Moreover, we also discovered the reversible nature of these deposits, which can be reduced by interventions aimed at restoring mitochondrial homeostasis, such as by enhancing nicotinamide adenine dinucleotide (NAD+) metabolism, even at the onset of aging. Importantly, we show that reduction of the accumulation of amyloid-like deposits in aging is sufficient to improve muscle mitochondrial homeostasis.