This story on NANOG is part of an extended series on Regenerative Medicine. For other stories on this topic see and search for Regenerative Medicine. My definition of Regenerative Medicine is any medical modality that returns us to normal health when we are damaged by disease, injured by trauma, disadvantaged by birth, or worn by time. Modalities include chemicals, genes, proteins and cells used as drugs, gene editing, prosthetics, and mind-machine interfaces.

NANOG is a protein found in embryonic stem cells. As described in the previous article of this series, stem cells are pluripotent—they have the potential to develop into nearly any other cell type in the body. NANOG plays a key role in maintaining the pluripotency of stem cells by inhibiting chemical cues that can cause stem cells to mature, pointing to the role of NANOG in longevity and aging.

Although it is suspected that NANOG contains anti-aging properties, because of its ability to restore and repair cells, there are several new uses of NANOG that are currently being proposed. Here, we discuss NANOG and how it may support muscle growth and strength.

One of the potent effects of aging is muscle weakness. Skeletal muscle comprises nearly half of our body weight and is important for producing movements, maintaining posture, and regulating body temperature. When we are young, our bodies contain a host of stem cells called myogenic progenitors that allow us to regenerate skeletal muscle easily. As we age, our myogenic progenitors steadily decrease, impacting the ability of these stem cells to regenerate muscle tissue. This leads to muscle weakness and muscle loss that can severely impact movement and quality of life.

In a recent paper, Rajabian et al. investigate the ability of NANOG to restore supplies of myogenic progenitor cells. Shockingly, the researchers demonstrate how NANOG may even promote muscle growth and strength.

The first step was to determine how NANOG actually impacts muscle cells. By examining which genes were turned on or off over the course of myogenic progenitor cells’ lives, the team found that as myogenic progenitor cells age, two processes are heavily impacted: methionine metabolism and glycolysis.

What is methionine metabolism and glycolysis?

Methionine is an amino acid that is used to create proteins. Since it is heavily involved in the creation of proteins, methionine breakdown is an essential process in humans and plays a critical role in human health. Glycolysis is similarly important and describes how the body metabolizes sugar and creates ATP—a molecule that is used for energy.

Rajabian et al. found that genes related to glycolysis were less expressed or ’turned off’ as myogenic progenitors aged. This suggests that aged cells do not rely on glycolysis for energy.

So, if aged cells are not performing healthy metabolism through glycolysis, how are the cells surviving and producing ATP? Rajabian et al. speculated that aged cells may be relying more on amino acids and fatty acids as sources of ATP rather than glycolysis. To investigate their hypothesis, they used a molecule that prevents the cells from using amino acids for energy.

Rajabian et al. found that by inhibiting the use of amino acids for energy, ATP production was reduced in the aged cells. This supported their hypothesis that aged cells rely on amino acid breakdown like methionine as an energy source, contributing to the loss of muscle in aging.

The question that remained was whether NANOG could rescue the aged cells by restoring their glycolytic pathway. The researchers already determined that by exposing aged myogenic progenitor cells to NANOG, they could increase the levels of glycolysis in the cell.

To determine, if NANOG could promote muscle cell growth in animals, researchers used mice with a mutated lamin A gene. Mutations in the lamin A gene cause premature aging and skeletal muscle atrophy.

After crossbreeding the lamin A mice with mice containing the NANOG gene, Rajabian et al. activated NANOG gene expression in the mice to see if NANOG could increase levels of glycolysis in the mouse’s muscle cells. The researchers found that NANOG effectively restored glycolysis to levels that were comparable to younger cells, suggesting that the small protein somehow reverses aging in muscle cells and promotes healthy metabolism.

The researchers then inserted the NANOG gene into mice with progeria—a disease that causes rapid aging. In this experiment, Rajabian et al. only triggered NANOG expression in each mouse’s right leg. The left leg served as a control group and did not contain NANOG-expressing cells.

Rajabian et al. found that much like in the myogenic progenitor cells themselves, muscles with NANOG expression displayed a significant decrease in methionine metabolism and increased glycolysis.

If NANOG can reverse the effects of aging in cellular metabolism, could it regenerate skeletal muscle cells as well?

Rajabian et al. used a toxin to induce injury in the leg muscles of mice and decrease the number of healthy cells. When NANOG expression was turned on, surprisingly, the number of muscle cells increased suggesting that NANOG can actually regenerate muscles in injured tissues.

To test the strength of these new muscles, the researchers used an instrument called a force transducer to measure the force produced by the mice’s legs when their muscles twitched. Interestingly, muscles in the mice’s right legs, which were treated with NANOG, produced much greater force than the muscles in the mice’s left legs which were not treated with NANOG. This experiment shows that not only does NANOG promote muscle growth, but it increases overall strength in muscles.

Overall, this fascinating study demonstrates that NANOG is a powerful protein that not only restores muscle cells but might also increase strength. This study represents real progress in the search for anti-aging and regenerative proteins. While more research must be conducted to determine whether NANOG plays a similar role in the human body, this study provides hope for increased longevity and comfort as we age.

In the next part of this series, we will discuss the role of NANOG in longevity, particularly in the context of mitochondrial dysfunction.