Boosting NAD+ Benefits Age-Related Muscle Loss By Blocking Buildups Of Bad Protein Bundles

Beginning as early as age 30, our muscle mass and strength decrease progressively year after year, with 80-year-olds experiencing a potential loss of 50% or more of the muscles they had when they were young. Also known as sarcopenia, this drastic reduction in muscle amount and ability in older adults leads to a decline in quality of life and independence with an increased risk of frailty, falls, fractures, and mortality. While sarcopenia was once thought to be a natural part of aging, many researchers now believe that this age-related muscle loss is not inevitable — and can even be reversed in later life.

Paralleling this decline in muscular health is a concurrent age-related drop in NAD+ (nicotinamide adenine dinucleotide) levels. Reductions in this vital coenzyme are implicated in premature aging, organ dysfunction, and many chronic diseases. Because of these coinciding reductions with age, Romani and colleagues looked at the effects of restoring NAD+ levels on age-related muscle deterioration. Published in Cell Reports, this collaborative research team from Switzerland and South Korea uncovered several new mechanisms behind why our muscles age — and what we can do about it.

Dictating the decline and deterioration of aging muscles

A myriad of complex reasons accelerate aging, but two known factors are mitochondrial dysfunction and a loss of proteostasis. The first involves a breakdown in the proper functioning of our cells’ energy powerhouses — the mitochondria. This leads to reduced ATP (energy) production and increased cellular damage from a buildup of inflammatory compounds called reactive oxygen species and free radicals. Second, aging can be characterized by a loss of proteostasis — the normal synthesis, folding, and functioning of proteins. With a loss of proteostasis comes an accumulation of misfolded proteins, which can aggregate, form toxic clumps, and trigger cell dysfunction and death. One well-known example of this involves Alzheimer’s disease, where proteins called tau and beta-amyloid pile up, causing brain cell loss and cognitive impairment. 

Researchers now believe that a loss of proteostasis is not only implicated in Alzheimer’s disease but also muscular diseases, like inclusion body myositis (IBM). Although relatively rare, IBM is a debilitating and degenerative muscular disorder that is most common in people over age 50. Despite Alzheimer’s disease affecting the brain and IBM involving the muscles, the two conditions have one surprising factor in common: amyloid protein aggregates. 

Throughout the natural aging process, people experience similar muscular declines as IBM patients, including a loss of skeletal muscle mass and function and reduced mitochondrial activity. While it’s been documented that amyloid protein accumulation causes muscle decline in IBM, it hadn’t been explored yet if naturally aged muscles also experience the same damaging protein aggregates — until now. 

From garnering genetic activity to assessing amyloid aggregates

Using IBM muscle cells as a comparative model, Romani and colleagues aimed to uncover if the sarcopenia that occurs in naturally aged muscles is also a result of amyloid protein buildup. The research team compared protein folding, amyloid buildup, and mitochondrial activity in aged mice, worms, and human muscle cells.

First, they looked at the activity of genes related to these aging factors, comparing the genes from aged human muscle cells to genes from people with IBM and other muscle-related disorders, like muscular dystrophy and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). They found that genes related to mitochondrial function were markedly reduced in both the aged and diseased muscles, while genes related to protein degradation and protein misfolding were increased. These differences in gene activity indicate high similarities between age-related sarcopenia and degenerative muscle diseases.

Next, Romani and colleagues compared amyloid protein levels in young and aged human muscle cells (myoblasts), in addition to IBM patients’ cells. Using a dye that reacts to amyloid protein aggregates in cells, the researchers identified substantial increases in the protein clumps in the muscle cells of aged donors and IBM patients and in the muscles of aged mice. In contrast, young myoblasts and young mice did not show any amyloid aggregates.  The research team also looked at amyloid aggregate activity in the roundworm Caenorhabditis elegans (C. elegans), finding that aged worms also had more amyloid accumulation, reduced mitochondrial function, and declines in muscle integrity. 

Restoring NAD+ reverses muscular maladies

After gaining this knowledge that amyloid protein accumulation is, in fact, related to muscle deterioration — in both aging and degenerative muscle disorders — Romani and colleagues next tried boosting NAD+ levels to reverse the muscular dysfunction. Supplying the aged roundworms with nicotinamide riboside (NR), a precursor to NAD+, mitigated the amyloid protein buildups, even when NR treatment began in later life. Olaparib, another compound that boosts NAD+, also significantly decreased amyloid deposits. This late-life treatment also restored mitochondrial function and improved the worms’ muscular fitness, as measured by their muscle integrity and spontaneous movement. 

The NR treatment produced similar results in the muscle cells of aged humans and IBM patients, as well as in aged mice. These groups experienced significant drops in the number and size of amyloid aggregates, which mirrored an improvement in mitochondrial function. Essentially, boosting NAD+ levels in worms, mice, and human cells repairs proteostasis, enabling proper protein folding and attenuating amyloid buildup. 

Next steps: solidifying the science on sarcopenia

The researchers suggest that increasing NAD+ stores may be effective in delaying the progression of muscle-related disorders. Given the similarities between amyloid protein aggregates in the aging muscles and brain, increasing NAD+ may also prove to be a valuable tool.

Despite this research spanning several species, we still don’t know if increasing NAD+ will prevent, slow, or reverse sarcopenia in aged humans. While it is likely, we don’t know for sure if other precursors to NAD+, like nicotinamide mononucleotide (NMN), would produce the same beneficial results as NR did in this study. For now, we’ll have to wait for the human clinical trials to know if boosting NAD+ will allow Grandma to switch from a walker to weightlifting.

References: 

Romani M, Sorrentino V, Oh CM, et al. NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle. Cell Rep. 2021;34(3):108660. doi:10.1016/j.celrep.2020.108660