Reversal of Markers of Aging in Cells Following Small Molecule Partial Reprogramming

Partial reprogramming by exposure to Yamanaka factors resets many of the epigenetic changes characteristic of cells in aged tissue. This is a potential approach to the production of future rejuvenation therapies. At present, some research groups are attempting to move away from genetic interventions to find small molecules that can provoke reprogramming. There are some avenues that seem promising. Here, researchers assess the effects of partial reprogramming by small molecules on a range of omics data and functional parameters for cells, finding that the outcomes are much as one would expect for a successful protocol.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear.

Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites.

Using both transcriptomic clock and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.


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