The Methuselah Foundation and SENS Research Foundation are two of the more important organizations involved in changing the face of aging research from a field of investigation to a field of intervention, speeding progress towards the effective treatment of aging and production of actual, working rejuvenation therapies. Over the past year the staff at these two foundations have collaborated on a series of biotechnology-focused newsletters for supporters, each issue detailing recent research relevant to the goal of repairing and reversing the causes of degenerative aging. I tend to mention them when they turn up in my in-box for those not on the list, and here is the latest. This issue focuses on (a) heterochronic parabiosis, in which the circulatory systems of a young and old individual are linked in order to identify important changes in circulating signal proteins, and (b) indirect evidence for the benefits of targeted clearance of senescent cells from aging tissue, among other items:
We have been following GDF-11 research and are pleased to bring you these two new reports. In the first study, researchers showed that exposing older mice to GDF-11 either through parabiosis, or by administering injections of recombinant GDF-11, was able to induce remodeling of the blood vessels in their brains, inciting the growth of new neurons. Most excitingly, this had a functional impact on older mice. With advanced age, the mice had lost much of their sense of smell, but parabiosis completely restored it to youthful function. In the second study, the research group showed that, again, exposing older mice to GDF-11 - either through parabiosis or injection of recombinant GDF-11 - was able to reverse age-related impairments in the function of their skeletal muscles. The genomes of the muscle cells in aged mice treated with GDF-11 showed greater integrity, their muscle structure and function improved, and they could perform better in tests of strength and endurance.
At this point, GDF-11 appears to be able to exert "rejuvenative" effects on the heart muscle, skeletal muscle, and brains of old mice who have suffered declines in those areas. It is possible that it may have effects on other body systems as well; further research will be needed to test this. It seems unlikely that parabiosis itself could be brought into the clinic for human use, given all the youthful blood (and related ethical concerns that raises). There may also be significant potential roadblocks for recombinant GDF-11 for human clinical use. For example administration of GDF-11 itself would require unmanageably large quantities of the protein. However, it could be used as the basis of a modified version or a drug that targets the same metabolic processes as GDF-11 itself.
On the other hand, there do exist examples of protein drugs in clinical use in large quantities, such as recombinant insulin for diabetics. To illustrate the order of magnitude of recombinant protein production currently in clinical use, researchers estimate that by 2025, there could be a need of approximately 16,000 kg/year of recombinant insulin for diabetics. So it also seems possible that recombinant GDF-11 could be used clinically, but it might be very challenging and expensive. Interestingly, GDF-11 has no effect on young mice at the doses tested. In the skeletal muscle study, the researchers treated both young and old mice with an identical regimen of GDF-11 injections, and it did not change young mouse muscle stem cell number, DNA integrity, or function. In the older mice, the dose of GDF-11 given was meant to recreate the physiological levels of GDF-11 in young mice (which decline with age). So, while restoring GDF-11 to "youthful" levels in older animals appears to rejuvenate several of their tissues - for example, restoring their muscle strength and endurance to "youthful" levels - it does not, for instance, make young mice abnormally strong for their age. Whether GDF-11 at higher doses would have greater effects is not yet known.
A major concern among rejuvenation biotechnology researchers is the accumulation of "senescent" cells in the body with age. Senescent cells are cells that have accumulated DNA damage, lost the ability to divide, and may create areas prone to the development of cancer within tissues where they reside. These "tissue microenvironments" (the biochemical environment in an extremely small area of tissue) near senescent cells may become more prone to the development of cancers because of secretion of molecules such as growth and inflammatory factors and enzymes that break down the supporting tissue around the senescent cells. Senescent cells accumulate in all tissues with age. A reason for attempting to eliminate senescent cells is the possibility that this hormonal and biochemical milieu in aged tissue microenvironments, in addition to the cells themselves, may contribute to some of the problems in aging, such as the development of cancer.
In this study, researchers exposed rats to chemical toxins that induce liver cancer. They next transplanted the rats with healthy liver cells from other, younger rats; the donor rats were genetically matched to the recipients to avoid problems with immune rejection of the transplanted cells. They performed the transplant by simply infusing the cells into the portal veins of the recipient rats. The transplanted cells then took up residence in the recipient rats' livers. One year later, 50% of the control rats that had not received transplanted liver cells had developed liver cancer. However, there was zero liver cancer observed in the group of rats that had received the liver cell transplant. The researchers also observed that after one year, the control group of rats had lots of senescent liver cells (induced by the cancer-causing protocol), but the transplant recipients had fewer senescent liver cells.
Although it was a small sample size (8 rats in the treatment group), it was remarkable that the researchers were able to change the incidence of development of liver cancer from 50% in the control group to 0% in the treatment group. We cannot help but wonder: if more time had passed, would liver cancer have developed in the treatment group? On the other hand, a 1-year follow-up is a relatively long time for rats. Although it is an impressive result, some things about this study are still unclear. The authors claimed that senescent cells in the livers of transplant recipient rats were removed, but it's not clear whether this truly happened. Senescent cell numbers may simply have been "diluted" by the influx of donor liver cells. There is no clear mechanism by which the senescent cells could have been removed, since the transplanted cells were liver cells, not the "natural killer cells" that carry out the body's own, limited ability to clear senescent cells from tissues.
Although the senescent cells may not have been cleared as the authors claimed, this study still provides evidence that via a relatively simple protocol (infusing healthy liver cells), the tissue microenvironment can be changed and malignancies can be kept at bay. We may eventually be able to apply this strategy to human tissues to create tissue microenvironments where cancers do not thrive.
To add to the caveats above, as I said at the time, I'd like to see this cell transplant study repeated in old rats with natural levels of cellular senescence before giving it too much more attention. Based on another study of liver cell senescence and cell transplantation it is vaguely possible that these cell populations can to some degree reverse their senescent status given the right environmental cues. It is perhaps worthy of note that liver tissue is naturally more regenerative than other tissues in mammals, capable of regrowing lost portions of the organ if necessary. But this is all quite speculative, and while there is a lot more that might be done here to iron out uncertainties and fill in the gaps, none of that is terribly relevant to the more direct path of building targeted cell clearance mechanisms and trying them out. The results of that experiment would be far more useful.