Research into reprogramming aims to induce some aspects of the dramatic change in gene expression and cell function that take place during early embryonic development, when adult germline cells shed the epigenetic changes characteristic of age to become young embryonic stem cells. Cell function becomes youthful, mitochondrial function is restored. Researchers can recapture the entire process, which is what happens when somatic cells are reprogrammed into induced pluripotent stem cells via exposure to the Yamanaka factors, but present efforts are turning to finding effective ways to induce only rejuvenation of function, without inducing pluripotency and loss of cell type.
Exploration of what has come to be called partial reprogramming, rejuvenation without pluripotency or other undesirable cell state changes, started with the use of genetic technologies to produce short-term expression of one or more Yamanaka factors. A few companies are slowly moving in the direction of clinical trials with initial gene therapies that focused on carefully narrow use cases, such as diseases of the eye or aspects of skin aging. Gene therapy vectors cannot at present effectively deliver their cargo to the whole body, and many organs remain impossible to target with vectors in any way other than direct injection. Thus there is interest in the alternative path of development of small molecules that can induce reprogramming, as small molecules are capable of reaching the entire body.
Much of the work on small molecule reprogramming is presently focused on a small number of compounds, those that go into the 7c and 2c combinations discussed in today's open access paper. 7c includes some undesirably toxic molecules, and researchers have thus focused more of their recent efforts on 2c, the combination of RepSox and tranylcypromine. This relatively narrow range of possibilities is characteristic of early stage research and development. Companies and research groups are undertaking the search for other starting points in the design of small molecule reprogramming agents, but one should expect progress on that front to emerge only slowly over a span of years.
Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan
During development, cellular reprogramming induces zygotic and primordial germ cell formation following a dramatic chromatin reorganization to create totipotent and pluripotent cells free of aged molecular defects, demonstrating that both cell identity and age are reversible. Importantly, this manipulation of cell identity has been recapitulated in vitro by several methods, including somatic cell nuclear transfer, forced expression of transcription factors, and most recently treatment with small molecules.
Although restoration of aged phenotypes such as telomere length, mitochondrial function, proliferation, and transcriptomic signature in vitro was demonstrated over a decade ago, application of cellular reprogramming in vivo was initially proven unsafe due to the loss of cellular identity leading to tumor and teratoma formation. To overcome this issue, in vivo partial reprogramming by short-term cyclic induction of Oct4, Sox2, Klf4, and c-Myc (OSKM) was a critical advance as it avoided the detrimental loss of cellular identity. Importantly, this limited cyclic expression of OSKM was sufficient to ameliorate multiple aging hallmarks and extend the lifespan of a progeroid mouse strain. Improved regenerative capacity and function has also been demonstrated following therapeutic application of cellular reprogramming in multiple tissues and organs including the intervertebral disc, heart, skin, skeletal muscle, liver, optic nerve, and dentate gyrus.
Here, we report that short-term treatment of human cells with seven small molecules (7c - CHIR99021, DZNep, Forskolin, TTNPB, Valproic acid, Repsox, and Tranylcypromine), previously identified for their capacity to induce pluripotent stem cells, leads to the improvement of molecular hallmarks of aging. In addition, we show that an optimized cocktail, containing only two of these small molecules (2c - Repsox and Tranylcypromine), is sufficient to restore multiple aging phenotypes, including genomic instability, epigenetic dysregulation, cellular senescence, and elevated reactive oxygen species. Finally, in vivo application of this 2c reprogramming cocktail extends both lifespan and healthspan in C. elegans.
View the full article at FightAging
