How the ‘Everlasting Youth’ Protein NANOG Fights Aging in Muscle Cells
From fables about the fountain of youth to magical stories involving stones that bestow the owner with immortality, humans have been fascinated with preserving youth and preventing aging for millennia. One lesser-told tale is about the land of Tír Na nÓg, an ancient Irish myth involving a paradise-like supernatural realm of everlasting youth, beauty, and health.
With this youthful ideal in mind, researchers out of the University at Buffalo in New York centered on the anti-aging effects of the protein NANOG, named after this famed Celtic folklore, in aged skeletal muscle cells. Published in the journal Science Advances, Shahini and colleagues find that boosting NANOG activity reverses several signs of aging and promotes regeneration of muscle cells. Although it’s not quite providing everlasting youth and immortality, this research offers hope for the one-third of adults over age 60 affected by the often debilitating loss of muscle mass known as sarcopenia.
Senescence, Sarcopenia, and Skeletal Muscle
As early as age 30, our skeletal muscle mass and strength progressively decline, with 80-year-olds commonly losing 50% or more of the muscles they had when they were young. This drastic reduction in muscle amount and capacity in older adults leads to a decline in quality of life and independence with an increased risk of frailty, falls, fractures, and mortality.
Although many factors are at play in sarcopenic muscle loss, one theory involves accumulating senescent cells — dysfunctional zombie-like cells that stop growing and dividing but remain in the body, leaving a trail of inflammatory cellular debris behind. Researchers like Shahini and colleagues believe that increased senescence in muscle cells impedes the muscles’ ability to regenerate, causing sarcopenia and other age-related disorders.
The primary cells involved with muscle regeneration are myogenic progenitor cells — also known as myoblasts — which can grow and mature into muscle cells and regenerate damaged muscle fibers. However, both the quantity and regenerative quality of these cells decline with age, likely due in part to increased senescence.
As skeletal muscle regeneration depends on the activation of these myogenic progenitor cells, researchers are searching for simple ways to continue facilitating their activation as we grow older. Other research has looked into reprogramming senescent cells to become immature stem cells that can once again develop into mature cells; however, this process runs the risk of increasing tumor growth. Instead, this research team looked at increasing levels of NANOG, as previous studies found that boosting the activity of this “everlasting youth” protein restored several cellular functions that diminish with age, including reduced growth and maturation of cells.
Multiplying Mature Muscle Cells
In a series of experiments, Shahini and colleagues began by elevating NANOG levels in senescent human myoblasts — the precursor cells that mature into muscle cells called myocytes. They found that this abundance of NANOG increased total cell count and decreased the time it took to double the cells’ population. Notably, the cell growth plateaued after three weeks of boosting NANOG activity, suggesting that this method would not lead to the potential tumor growth that comes with indefinite cell proliferation. Overall, these results point to the ability of NANOG to reverse senescence — at least in this cell-based experiment.
This boost in NANOG activity also lowered levels of a common marker of cellular senescence. Plus, it restored several genes and pathways impaired by aging, including those related to DNA repair, cell growth and division, and protein stability. In addition, increasing NANOG levels also promoted autophagy — our body’s way of recycling and removing damaged or dysfunctional cells and cell parts — and improved the health and function of our cells’ energy powerhouses, the mitochondria.
From Men to Mice
Next, they studied the effects of elevating NANOG activity in the skeletal muscle of prematurely aged mice that showed signs of senescence and aging. Although these mice weren’t older, this mouse type is a well-accepted animal model for studying both aging and anti-aging therapies. After NANOG activity was boosted, the isolated myoblasts from these mice showed significantly reduced incidence of DNA damage, with restored mitochondrial function and elevated ATP (energy) inside cells. This suggests that increasing levels of NANOG in skeletal muscle cells of prematurely aged mice — and, likely, of typically aged mice, too — may be a beneficial way to fight back on the effects of cellular senescence.
Lastly, Shahini and colleagues looked at how locally activating NANOG in the mice’s lower limb muscles affected cell growth. They found that boosting NANOG significantly decreased the quantity of senescent myoblasts while increasing the number of regular, functional myoblasts. Notably, the NANOG-expressing muscle also had high levels of a specific type of fibrous protein involved in muscle contractions, suggesting signs of new muscle fiber formation.
A Future of Tír Na nÓg-Like Everlasting Youth?
With this work, Shahini and colleagues provide evidence of an alternative way for reversing senescence in myoblasts without having to reprogram the cells into immature versions first. As boosting the levels of NANOG in these human and mouse models diminished markers of age-related senescence and improved overall cell and mitochondrial health, this protein named after the mythical Land of Everlasting Youth lives up to its name — in skeletal muscle, at least.
A better understanding of NANOG and how it behaves in humans, both young and old, may be a crucial step in uncovering new ways to fight aging and its associated symptoms, like sarcopenia. As the study’s corresponding author, Stelios T. Andreadis, Ph.D., concludes, “Our work focuses on understanding the mechanisms of NANOG’s actions in hopes of discovering druggable targets in signaling or metabolic networks that mimic the anti-aging effects of NANOG. Ultimately, the work could help lead to new treatments or therapies that help reverse cellular senescence, and aid the many people suffering from age-related disorders.”
Mistriotis P, Bajpai VK, Wang X, et al. NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression. Stem Cells. 2017;35(1):207-221. doi:10.1002/stem.2452
Shahini A, Rajabian N, Choudhury D, et al. Ameliorating the hallmarks of cellular senescence in skeletal muscle myogenic progenitors in vitro and in vivo. Sci Adv. 2021;7(36):eabe5671. doi:10.1126/sciadv.abe5671