Age-related loss in muscle mass, sarcopenia, is a major medical problem facing the elderly and correlates with loss of metabolic function, disabilities, morbidity, and mortality. In addition, prolonged culture times are required to obtain the large numbers of cells necessary for regenerative medicine. As a result, the quality of the cells that are used to engineer tissues for cell therapies may be compromised by replicative senescence. In the past few years, our laboratory discovered that expression of a pluripotency-associated embryonic transcription factor, NANOG, could reverse senescence and completely restore the differentiation potential of senescent mesenchymal stem cells (MSC) and cells from progeria (accelerated aging disease) patients into functional smooth muscle cells. We also discovered that NANOG could reverse the impaired ability of senescent stem cells to produce collagen type III and elastin, which are severely affected by aging and affect the mechanical properties of tissues such as skin, arteries and skeletal muscle. Most recently we discovered that NANOG reversed the hallmarks of cellular senescence and restored the metabolic program of senescent skeletal myoblasts, ultimately restoring their ability form contractile myotubes and regenerate in response to injury. In this proposal we seek to better understand the mechanisms that mediate the effect of NANOG in vitro and in vivo through the following aims.
In Aim 1, we will examine the effects of NANOG on myoblast senescence in traditional cultures as well as using bioengineered 3D skeletal muscle tissues. NANOG is expressed after cells reach senescence, thereby enabling us to measure the reversal of the aging phenotype using a plethora of cellular, molecular and functional assays.
In Aim 2, we will study the effects of NANOG on restoring the metabolic function of aged myoblasts. We propose to study in detail the NANOG-induced metabolic reprogramming of aged cells and investigate potential signaling pathways that may mediate these effects. Finally, in Aim 3 we will develop a very innovative mouse model to investigate the effects of NANOG on animal physiology, skeletal muscle metabolism and regeneration. Impact: This is a very innovative proposal that seeks to investigate the potential of an embryonic transcription factor to ameliorate the effects of aging and enhance the regenerative ability of aged skeletal muscle (SkM). Understanding the mechanism(s) that mediate the effects of NANOG on metabolic reprogramming of aged SkM may enable identification of novel druggable targets and design of innovative strategies to restore the function of aged tissues. Given the surge in the aging population in the US and the world, the debilitating effects of aging on skeletal muscle and the resulting frailty condition affecting the elderly, successful attainment of this work may have significant impact in regenerative medicine and the quality of life of elderly patients.
We propose a highly innovative research plan to ameliorate the effects of aging and enhance the therapeutic potential of senescent cells and the regenerative capacity of aged skeletal muscle tissue. The proposed research is important and timely, given the surge in the aging population in the US and the world and the severe effects of aging on skeletal muscle and related frailty affecting the elderly. Successful attainment of this work will have significant impact in understanding cellular senescence as well as the development of treatments to restore tissue/organ function and ameliorate the negative effects of aging.
