Chemicals Reversed Cellular Aging

Harvard’s David Sinclair and his research team have identified six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age.

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”.

Reversing Cellular Age Without Triggering Cancer

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.

Using Gene Therapies to Reverse Cellular Age

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.

Chemicals aka Drugs Can Be Cheaper and Faster to Develop

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 EPOCH method.

The effectiveness of the NCC system as an apparent surrogate biomarker for biological age reversal, with young, old, senescent, HGPS, and OSK-treated cell lines serving as controls, should set the stage for larger, more expansive screens for rejuvenation factors. Follow-up studies are underway to elucidate the cellular machinery that mediates these rejuvenative effects, with an emphasis on the mechanisms by which cells apparently write then later read a “backup copy” of earlier epigenetic information to reset chromatin structures and reestablish youthful gene expression patterns.

Future work will be directed to understanding how long the effects of these and other EPOCH treatments last in vivo and whether they reverse aspects of aging and extend lifespan in mice, paralleling treatment with AAV-OSK. The assays developed in this study, combined with robotics and the increasing power of artificial intelligence, will facilitate increasingly larger screens for genes, biologics, and small molecules that safely reverse mammalian aging, and, given that aging is the single greatest contributor to human disease and suffering, these advances cannot come soon enough.