A group of US researchers have demonstrated the potential to induce greater regeneration in heart tissue through overexpression of PIM-1. This is one of many varied approaches to generating greater repair and maintenance of tissues presently under development or in the clinic, ranging from stem cell transplants to the search for signal molecules that spur old tissues into greater activity. The researchers working on PIM-1 have been involved in this program for a number of years now: if you look back in the Fight Aging! archives, you'll find a report from 2012, for example. Sadly, from an outsider's perspective there is little visible difference between the state of this project then and now. The high level outline is the much the same and the expected course ahead is much the same. Benefits have been demonstrated in laboratory animals and human tissues, and the researchers would like to move to clinical trials, but lack the funding needed to take that step.
This is the situation for a lot of medical research these days, stuck at the level of gathering more data and creating more variants on the basic technology demonstration, seeking sufficient funding to enter the path to clinical trials. Thanks to the modern regulatory straitjacket for medical technology it is the case that moving beyond the laboratory has become so enormously and unnecessarily expensive in comparison to building a proof of concept that potential therapies can languish indefinitely in this state of demonstrated promise but lack of meaningful progress. I think this will be a growing class of research program in the future, absent some sort of sweeping change, as the cost of early stage research is falling precipitously while the cost of regulatory compliance for clinical development is steadily rising. Something has to give eventually.
The heart in particular seems to be resistant to developing cancerous cells. "When's the last time you heard of anyone having heart cancer? It's almost unheard of." That's not surprising from an evolutionary standpoint. If heart cells make a grave transcription error during cell division and your ticker ticks its last tock, there's no fixing the problem. So it makes sense that heart cells are incredibly careful when it comes to proliferating. But it's this very meticulousness that makes heart disease such an intractable problem. Over time, the cells burn themselves out. Their ability to repair themselves and generate fresh replacements gets progressively worse. By the time you reach old age and start experiencing symptoms of age-related heart disease, your cardiac cells are running on fumes and aren't able to properly divide into new cells.
Researchers are exploring the results of taking an enzyme, Pim, known to be associated with growth and survival of certain types of cancer cells, and causing it to be overexpressed in cardiac progenitor cells in mice. In healthy cells, Pim helps facilitate chromosome splitting, a key part of the cellular division process. The gene that encodes the production of this enzyme, PIM1, is what's known as a proto-oncogene. That means that by itself, the gene doesn't cause cancer. But when it teams up with another gene, Myc, tumors are likely to form. Fortunately, the Pim/Myc combination isn't an issue in heart progenitor cells, meaning you could tweak those cells to overexpress the PIM1 gene without raising the risk of cancer.
Researchers modified mouse heart progenitor cells to overexpress PIM1 in specific locations within the cell, targeting specific locations with more of the critical Pim enzyme in hopes that it would protect against aging-related heart disease. And it worked. Compared to controls, the mice with overexpressed PIM1 lived longer and showed stronger cell proliferation. But interestingly, the way it worked was different depending on where in the cell the gene was overexpressed. If the researchers caused PIM1 to be overexpressed in the progenitor cell's nucleus, they saw increased proliferation into new cells. If they overexpressed the gene in a different region of the cell, the mitochondria, they found that the enzyme inhibited the cell's natural self-destruct signals, causing them to live longer.
Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence.