In vivo reprogramming has recently emerged as one of the most promising strategies for targeting aging, attracting great interest from both academic and private sectors. Nevertheless, despite its great potential, significant translational barriers such as safety and gene delivery will need to be overcome for the clinical application of reprogramming to humans. In this line, we have recently demonstrated that hepatic and intestinal failure lead to high mortality upon continuous induction of in vivo reprogramming. In addition, we have generated novel mouse strains that avoid the reprogramming of these organs allowing for more extensive in vivo reprogramming protocols. Lastly, we have shown that improvement of age-associate phenotypes and lifespan extension can be achieved by chemical induced partial reprogramming using small molecules, opening a path towards future clinical applications of cellular reprogramming.