In vivo chemical reprogramming is associated with a toxic accumulation of lipid droplets hindering rejuvenation

Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested.

Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes.