Date Published: January 26, 2017
Publisher: Public Library of Science
Author(s): Cao Ma, Chenchen Pi, Yue Yang, Lin Lin, Yingai Shi, Yan Li, Yulin Li, Xu He, Antonio Paolo Beltrami.
Senescence restricts the development of applications involving mesenchymal stem cells (MSCs) in research fields, such as tissue engineering, and stem cell therapeutic strategies. Understanding the mechanisms underlying natural aging processes may contribute to the development of novel approaches to preventing age-related diseases or slowing individual aging processes. Nampt is a rate-limiting NAD biosynthetic enzyme that plays critical roles in energy metabolism, cell senescence and maintaining life spans. However, it remains unknown whether Nampt influences stem cell senescence. In this study, the function of Nampt was investigated using a rat model of natural aging. Our data show that Nampt expression was significantly lower in MSCs obtained from aged rats than in those obtained from young rats during physiological aging. Reducing the level of Nampt in aged MSCs resulted in lower intracellular concentrations of NAD+ and downregulated Sirt1 expression and activity. After the Nampt inhibitor FK866 was added, young MSCs were induced to become aged cells. The enhanced senescence was correlated with NAD+ depletion and Sirt1 activity attenuation. In addition, Nampt overexpression attenuated cell senescence in aged MSCs. Our findings provide a new explanation for the mechanisms underlying stem cell senescence and a novel target for delaying stem cell senescence and preventing and treating age-related diseases.
Cell senescence is a key characteristic of individual aging processes . The aging of stem cells has been shown to be the cellular basis underlying many age-related diseases , such as Alzheimer’s disease, osteoporosis, and atherosclerosis . However, age-related senescence limits the development of applications involving stem cells that can be used in tissue regenerative and cell therapeutic approaches. Based on our experience, the regenerative ability of mesenchymal stem cells (MSCs) that are obtained from aged individual is limited, and this severely restricts their therapeutic effects during autologous stem cell transplantation. Cell senescence is characterized by functional and morphological changes, such as irreversible growth cessation, metabolic abnormalities and fat brown pigment deposition [4,5]. In addition, aging cells display variations in senescence-associated-β-galactosidase (SA-β-gal) activity, oxidation levels, DNA damage, telomerase activity and the expression of senescence-associated factors [6–11]. In 2009, Imai proposed that “energy metabolism” might play a primary role in cell senescence. In mammalian cells, energy metabolism homeostasis is regulated by nicotinamide phosphoribosyl transferase (Nampt), nicotinamide adenine dinucleotide (NAD) and Sirt1 [12,13]. Nampt is the rate-limiting enzyme in the NAD re-salvaging pathway . Hence, by influencing the synthesis of NAD, Nampt indirectly regulates the expression of Sirt1 . Sirt1, a mammalian NAD-dependent protein deacetylase, subsequently deacetylates a large number of downstream signaling molecules that affect functional and morphological changes related to senescence .
With increasing age, the body inevitably experiences physiological or chronological aging, after which the organism is referred to as an aged or natural aging individual . Cells extracted from aging individuals can be used to simulate the process of physiological aging. To minimize the impact of the external environment on cell aging, cells that were directly extracted from aging individuals were used as the research objects. In the present study, MSCs derived from both 1- to 2-month-old rats and 15- to 18-month-old rats were used to investigate the effects of age on biological characteristics and cellular senescence.