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Embryonic gene, Nanog, can reverse cell aging

The fountain of youth may reside in a gene in embryonic stem cells called Nanog. It's discovery may lead to treatments for age-related disorders such as atherosclerosis, osteoporosis, Alzheimer's and Progeria syndrome in children.


In a series of experiments at the University at Buffalo (UB), the Nanog gene woke up dormant cellular mechanics key to preventing weak bones, clogged arteries and other signs of growing old.




Published June 29 in the journal Stem Cells,the findings show promise in counteracting premature aging in children as found in Progeria, or Hutchinson-Gilford progeria syndrome (HGPS). An extremely rare genetic disorder affecting 1 in 8 million.

Hutchinson-Gilford progeria syndrome

"Our research into Nanog is helping us to better understand the process of aging and ultimately how to reverse it."

Stelios T. Andreadis PhD, Professor and Chair, Department of Chemical and Biological Engineering, University at Buffalo, School of Engineering and Applied Sciences, and lead author of the study.


To battle aging, the human body holds a reservoir of unspecialized cells, called adult stem cells, that can regenerate organs. These cells are located in every tissue of the body and respond rapidly when needed for repairs.

But as people age, fewer adult stem cells perform well, a scenario leading to age-related disorders. Reversing the effects of aging on adult stem cells, essentially reboots them, helping to overcome the aging process.

In previous research, Andreadis had shown how adult stem cells have the capacity to form muscle. But over time, this ability declines. Specifically, he examined smooth muscle cells located in the pili muscles of skin (these erector muscles adjust the angle of each hair shaft), the ciliary muscle in the eye that adjust for distance and change the shape of the lens, the iris of the eye that resizes the pupil, arteries, veins, bladder, reproductive tracts, intestines and other tissues.


"Not only does Nanog have the capacity to delay aging, it has the potential in some cases to reverse it,"

Stelios T. Andreadis PhD

In this new study, Panagiotis Mistriotis, a graduate student in Andreadis' lab and first author, introduced Nanog into aging stem cells and found Nanog opens two key cell pathways: Rho-associated protein kinase (ROCK) and Transforming growth factor beta (TGF-β).

Rock and TGF-β jumpstart proteins — such as actin — that lie dormant in adult stem cells. These proteins are needed to build cytoskeletal cells that contract muscles. Contracting muscles ultimately generate the force needed for adult stem cells to regenerate.

Andreadis points out that embryonic stem cell genes have an affect on three different models of aging: (1) cells isolated from aged donors, (2) cells aged in culture, and (3) cells isolated from patients with Hutchinson-Gilford progeria syndrome.


Researchers also found Nanog activates serum response factor (SRF), the central regulator of muscle formation.This suggests the same results that apply for skeletal cells, may also apply for cardiac cells, and other muscle types.


Andreadis' team is now identifying drugs that can replace or mimic the effects of NANOG. This will allow them to study whether aspects of aging inside the body can be reversed. This could have implications in an array of illnesses, everything from atherosclerosis and osteoporosis to Alzheimer's disease.

Abstract
Cellular senescence as a result of organismal aging or progeroid diseases leads to stem cell pool exhaustion hindering tissue regeneration and contributing to the progression of age related disorders. Here we discovered that ectopic expression of the pluripotent factor NANOG in senescent or progeroid myogenic progenitors reversed cellular aging and restored completely the ability to generate contractile force. To elicit its effects, NANOG enabled reactivation of the ROCK and Transforming Growth Factor (TGF)-β pathways—both of which were impaired in senescent cells—leading to ACTIN polymerization, MRTF-A translocation into the nucleus and serum response factor (SRF)-dependent myogenic gene expression. Collectively our data reveal that cellular senescence can be reversed and provide a novel strategy to regain the lost function of aged stem cells without reprogramming to the pluripotent state. Stem Cells 2016

Additional authors come from UB's Department of Biomedical Engineering, a joint program between UB's engineering school and the Jacobs School of Medicine and Biomedical Sciences at UB, and the Department of Biostatistics and Bioinformatics at Roswell Park Cancer Institute in Buffalo.

The work was supported by a National Institutes of Health grant.
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The Fountain of Youth

The Fountain of Youth
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