No Benefit to Survival from Injections of Young Blood Plasma Provided to Old Mice
The practice of heterochronic parabiosis, linking the circulatory systems of old and young mice and observing the results, produces measurable beneficial changes in the tissues of the old mice. Researchers have identified a few proteins such as GDF-11 where changes in the circulating levels occur with age, and artificially resetting these levels - such as via parabiosis - can alter the behavior of stem cells to make them more active in tissue maintenance. A range of other experiments are currently ongoing to try to better understand and catalog these results first identified via parabiosis studies. Some of these experiments are going to produce null or ambigious results, as is the case here, because nothing in biology is simple or straightforward. You'll probably want to skip ahead to the discussion section at the end of this open access paper, as that is where the interesting information can be found:
Aging is for now an irreversible process that affects multiple organs and is the leading cause of age-associated mortality and morbidity. The search for an efficient way to counter age-related changes in an organism is a task of high importance. Recently, scientific evidence of a rejuvenating effect of young blood on different tissue and organ functions was published. Among these studies, heterochronic parabiosis was particularly interesting: the model demonstrates the possibility of constant exchanges of cellular and humoral factors through the blood between animals of different ages.Still, after such mostly positive reports, the question of the overall beneficial effect becomes extremely intriguing: Instead of looking at a specific parameter or a short period of time, is maintaining a young milieu globally beneficial over time? This can be asked through a simple measure: Does it increase lifespan? In previous experiments, we looked at the survival of mice following temporary isochronic and heterochronic parabiosis (unpublished data). It was found that aged mice tended to live longer after a period of heterochronic parabiosis than isochronic parabiosis, suggesting a globally beneficial effect of the young milieu. However, the difference was not statistically significant, and lifespans were not in the range of those of untreated animals, possibly due to the traumatic condition of parabiosis. Therefore, general conclusions were very uncertain regarding "anti-aging" effects, and another model for long-term effects was sought, namely, plasma injections.
To assess the anti-aging effect of young blood we tested the influence of repeated injections of plasma from young mice on the lifespan of aged mice. One group of 36 CBA/Ca female mice aged 10-12 months was treated by repeated injections of plasma from 2- to 4-month-old females. Their lifespan was compared to a control group that received saline injections. The median lifespan of mice from the control group was 27 months versus 26.4 months in plasma-treated group; the repeated injections of young plasma did not significantly impact either median or maximal lifespan.
Probably not all that surprising, since young blood is only really going to mitigate some of the symptoms of damage; get cells to behave as if there's less damage around them and perhaps provide some blood components older blood isn't as good at generating. The damage is going to keep accumulating at its own merry pace regardless.
The injections in this study were done only once a week. How would we know, based on this study, that a constant and dynamic maintenance of plasma factor/hormone concentration would not have a beneficial effect on life and health span?
The difference between this and parabiosis is in this sense quite marked. The picture would be quite clearer if we had a machine that could maintain blood concentrations of components at the same level as the typical youthful mouse at all times.
Arcanyn has a good point, of course - eventually there is damage that will need repair regardless of what signals the body receives, but I don't find the methodology of this study convincing to say that such signals wouldn't be helpful.
A once a week plasma injection seems inadequate to me also if their intent was to simulate prior parabiosis work. To me the most interesting result described in the Discussion was that the young mice lived shorter lives when administered the old mouse plasma. (lol at the image of a mouse hooked up to a tiny plasmapheresis machine. I did an image search for such an image but came up empty). It seems equally probable to me that the benefit of parabiosis is the removal of something undesirable from older blood (I would guess cross and misfolded proteins), as it is the addition of something missing in older blood.
Isn't parabiosis just doubling the immunological space and unburdening the overcrowding of said space with the added benefit of new naive T cell production from the younger mouse's fully functioning thymus gland?
Damn. I was hopeful about this. I assume this means the human version of this experiment involving Alzheimer's patients in California will have the same result.
I guess they'll have to keep tinkering to find ways to better mimic heterochronic parabiosis. As others suggested, a logical next step would be more frequent transfusions. (and/or removal of the older organism's blood)
Incidentally, I wonder if a novel approach might be to attempt to change the procedure of heterochronic parabiosis itself to make it less traumatic. (There's got to be a better way than sewing mice together for goodness sake) The authors of the study did say the traumatic procedure itself may have been the reason mice saw no statistically significant increase in lifespan in the unpublished data.
I dont see why this is surprising. The effect of GDF-11 was always only for a few aspects of aging (muscles, brain, heart), not the whole organism. Obviously GDF-11, by itself, was never going to extend life very much, if at all. Anti-aging, life-extension, and so on are going to involve a multitude of treatments and approaches, I'm betting.
"Analysis of pathologies occurring in experimental animals upon aging shows a double effect. On the one hand, a slightly higher, but nonsignificant prevalence of cancer pathology was identified in the plasma-treated mice, which suggests the possibility that youth factors may perturb the aged host. The development of malignancies due to the uncontrolled influence of some enrichment in “youth stimuli” in an aged systemic environment have been previously suggested."
Interesting; maybe this bears on the research on telomerase?
The study to follow from California (Stanford Medical), mentioned previously, is this:
http://clinicaltrials.gov/ct2/show/NCT02256306?term=alkahest&rank=1
Eugene
The amount of plasma used was not sufficient. If enough youthful factors were introduced tissue would potentially revert to a more youthful state and become more efficient at damage control.
There are some forms of damage that it likely would not repair of course but past experiments have shown youthful blood can and does rejuvenate tissue. Sufficient amounts and time could potentially reset the body to a certain extent.