Reversing Cellular Age Without Triggering Cancer by Chemical Means

Thursday - July 20 2023, 19:55 UTC - 1 year ago

This study demonstrates that cellular aging can be reversed and injury recovery can be accelerated by chemicals rather than genetic means. Small molecules can reverse the transcriptomic age of cells safely without erasing cell identity or inducing iPSC-like states, making this approach more accessible, less costly, and more widely applicable.

Rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means. Molecules that reverse cellular aging and rejuvenate human cells without altering the genome. Sinclair and his team developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. In 2006, Takahashi and Yamanaka demonstrated that the expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as "OSKM"), reprograms the developmental potential of adult cells, enabling them to be converted into various cell types. These findings initiated the field of cell reprogramming, with a string of publications in the 2000s showing that the identity of many different types of adult cells from different species could be erased to become induced pluripotent stem cells, commonly known as "iPSCs".

The ability of the Yamanaka factors to erase cellular identity raised a key question: is it possible to reverse cellular aging in vivo without causing uncontrolled cell growth and tumorigenesis? Initially, it didn’t seem so, as mice died within two days of expressing OSKM. But work by the Belmonte lab, our lab, and others have confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression or by continuously expressing only OSK, leaving out the oncogene c-MYC.

Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues. This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body.

Developing a chemical alternative to mimic OSK’s rejuvenating effects could lower costs and shorten timelines in regenerative medicine development. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation. In this study, they developed and utilized novel screening methods including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells. They identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.

In this study, the provide evidence, based on protein compartmentalization and gene expression patterns in young and senescent cells, that small molecules can reverse the transcriptomic age of cells without erasing cell identity or inducing iPSC-like states. They refer to this approach as the induction of cellular rejuvenation and use it to demonstrate that aging can be reversed and injury recovery can be accelerated without generating iPSC-like cells or adding genetic material to the cell. This could make this approach more accessible, less costly, and therefore more widely applicable.