Changing Aging — 19

In aged mice, use of a drug for four days that helps reorganize blood stem cells (countering the process known as polarization) led to reversal of the epigenetic clock and expanded lifespan. The same pronounced antiaging effects were seen with the drug given to immunocompromised aged mice that received transplanted rejuvenated blood stem cells. These blood stem cell rejuvenation experiments shifted the balance of the immune system toward lymphocyte rather than white cell production and helped set the foundation for the next report, which was published in Nature.

That approach involved antiaging antibodies in old mice. Antibodies directed to deplete aberrant, aged stem cells (known as myeloid-based hematopoietic stem cells), considered to be drivers of inflammation (inflammaging), shifted the immune cell population, from the white blood cells of the innate system to production of T and B cells, rejuvenating adaptive immunity for several months after a single injection. The enhanced immune system showed its advantage in response to viral infection of the old mice as compared with controls. The lingering concern, as with so many antiaging interventions, is that this rebalance of the immune system may present a liability for cancer, such as T and B lymphocyte cancers.

Let’s return to my friend Juan Carlos Izpisua Belmonte and his seminal work in this area, which until now has been shown to rejuvenate mice genetically bred with the accelerated aging progeria gene mutation. When I visited with him recently, he told me about the dilemma for Altos Labs, which has attracted more than $3 billion of investments but has yet to initiate its first human clinical trial. Giving the Yamanaka factors systemically (throughout the body), even with a brief exposure, could promote cancer since two of the transcription factors can turn normal cells into cancer cells (c-Myc and OCT4). Teratoma tumors have formed in animals after exposure. Notably, Belmonte and his team have shown that short pulses of the four transcription factors, be they administered to the whole body or tissue targeted, avoided any cancer incidences in mouse models through twelve months. Perhaps instilling these factors into just one part of the body, such as a knee joint with severe degenerative osteoarthritis, might be a prudent initial step. In the eyes of old mice with glaucoma, giving three of the Yamanaka factors helped restore vision and reverse the epigenetic clock of retinal ganglion cells. Again, the concern is the trade-off between antiaging and the potential risk of cancer. By using short pulses of Yamanaka factors and a tissue-specific (and even damaged cell–specific rather than a whole-body) approach, the risk may be mitigated.