Heterochronic parabiosis has become a growing line of research these past few years. It involves connecting the circulatory systems of two individuals, such as two laboratory mice, of different ages. Researchers have shown that the old mouse of the pair regains somewhat more youthful characteristics in stem cell activity, healing, neurogenesis, cardiac health and other aspects linked to tissue maintenance. It doesn't turn back the clock by more than a fraction, but the benefits are large enough in comparison to what can be achieved via other avenues in medical science for researchers to investigate further. An outcome of partial rejuvenation of function during parabiosis must be triggered by a different balance of factors that is present in youthful blood versus aged blood. Thus researchers conclude that some fraction of the decline in tissue maintenance and diminished stem cell activity that occurs in aging has signaling changes in the tissue environment as its proximate cause. The next logical path of action for the mainstream research community is to undertake a drug discovery program, aiming for treatments that can override age-related changes in signaling to at least some degree, and with minimal side-effects.
These age-related changes in the amount or type of proteins present in circulating blood are not a root cause. They are themselves most likely a reaction to the accumulating cellular and tissue damage that drives degenerative aging. So it is worth bearing in mind that any treatment focused on spurring greater stem cell activity by overriding the natural aged signaling balance is essentially a matter of pushing the accelerator on a damaged engine. These and other related studies in mice have not yet seen the potential threat of cancer that would be expected to arise from greater activity undertaken by damaged cells, but caution is still merited. It may well be the case that the evolved balance of stem cell decline is far from optimal, and researchers could turn the dial a way without producing a high risk of cancer or other issues as a result. The fastest way to find out is to try. Equally it would be nice to see more attention given to repairing the damage that causes aging rather than trying to compensate for the consequences one layer up while ignoring the damage entirely.
Researchers have recently reported another potential success for heterchronic parabiosis, claiming the identification of β-catenin signalling as important in age-related decline of bone regeneration. Note that while the popular press is focusing on the parabiosis portion of the research, the scientists involved also produced the same benefits with a more conventional transplant of young cells into an old individual. Given the recent news about GDF-11, however, it might be worth waiting a couple of years for firm confirmation and clarification of the mechanism involved before celebrating this advance.
Broken bones in older people are notoriously slow to heal. In studies using mice, researchers not only traced what signals go wrong when aged bones heal improperly, they also successfully manipulated the process by both circulating blood and transplanting bone marrow from a young mouse into an older mouse, prompting the bones to heal faster and better. The work builds on earlier research which identified an important role for a protein called beta-catenin in the healing process. The protein requires precise modulation for successful bone fracture repair. In older people, beta-catenin levels are elevated during the early phases of bone repair, leading to the production of tissue that is more like scar than bone, which is not good for bone healing.
Using mice as a surrogate for humans, the researchers found that they could manipulate beta-catenin levels by exposing older animals to the blood circulation of younger animals, essentially correcting the intricate formula necessary for healthy bone repair. "It's not that bone cells can't heal as efficiently as we age, but that they actually can heal if they are given the right cues from their environment. It's a matter of identifying the right pathway to target, and that's what's exciting about this work. The next steps are to figure out what's making beta-catenin go up in older adults, so that we can target that cause, and to explore drugs that can be used in patients to change beta-catenin levels safely and effectively."
The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals.
This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.