Connecting NANOG Expression with the Response to Methionine Restriction
Calorie restriction is known to slow aging, albeit to a much greater degree in short-lived species than in long-lived species. Finding important mechanisms involved in the beneficial response to calorie restriction continues to be a major focus on the research community, even though it is questionable as to whether this is a good approach to the treatment of aging. A sizable fraction of the response to calorie restriction appears to be mediated by methionine sensing, at least judging by the degree to which reducing methioninine intake can reproduce the benefits of full calorie restriction.
In today's open access paper, researchers connect NANOG expression to the methionine restriction response, certainly an interesting link. NANOG is a pluripotency factor expressed in embryonic stem cells, studied in the contexts of regeneration, cancer, and cell reprogramming. One might not expect it to employ methionine sensing mechanisms to achieve changes on cell metabolism, and yet it does. Everything connects to everything else when it comes to regulation of cell behavior, it seems.
More pertinently, senescent cells are metabolically active, with a high methionine metabolism driving their ability to generate harmful signaling. Expressing NANOG squashes that activity to restore better function. This is perhaps a good idea in severe conditions such as progeria in which a sizable fraction of cells become senescent, but less of a good idea in normal aging, even given a role of cellular senescence in the onset of age-related disease, given the balance between NANOG expression and risk of cancer.
A recent study demonstrated that a methionine-restricted (MR) diet improved mitochondrial function and upregulated autophagy-related genes, resulting in a 45% extension of rodent lifespan. Other studies also demonstrated that MR regulates energy expenditure in the aged musculoskeletal system, activated insulin signaling that improved type II diabetes, and decreased lipid peroxidation that reduced hyperlipidemia. Clearly, decreasing dietary methionine has beneficial physiologic effects. However, a pathway connecting methionine to these pathologies is yet to be elucidated. Methionine breakdown begins with MAT2A, which catalyzes the production of S-adenosyl methionine (SAMe) from methionine.
Previously, our laboratory reported similar pathologies affecting cells from progeria patients and cells undergone replicative senescence. Further, we demonstrated that with ectopic expression of the pluripotency factor, NANOG could effectively reverse aging hallmarks and reestablish young attributes in older cells to restore their myogenic differentiation capacity, decrease senescence-associated beta-galactosidase (SA-βgal), restore mitochondrial function, and repair DNA damage. NANOG also restored the ability of senescent myoblasts to differentiate into healthy skeletal myotubes and ameliorated the hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction in human skeletal myoblasts and restored the number of myogenic progenitors in a mouse model of premature aging.
However, the mechanism through which NANOG imparts its rejuvenating effects is not known. Using NANOG as an investigative tool, we examined whether metabolic impairments due to senescence or premature aging could be reversed, restoring muscle function. We discovered that senescent myoblasts used methionine to meet their metabolic demands and that increased use of methionine contributed to the loss of skeletal muscle function. Conversely, inhibition of MAT2A catabolism by NANOG expression or chemical inhibition restored glucose-based bioenergetics and the force-generating capacity of aged skeletal muscle in a mouse model of premature aging.