stem cells in their environment
It's all in the blood: Can we turn back the ageing clock?
26 February 2015
By Christine Weber
Paul BertWhen Paul Bert, a French physiologist, first described experiments involving shared circulation between mice in 1864 he probably wasn't thinking about the fountain of youth. His main interest was tissue transplantation(1). Bert's successful attempts in parabiosis established that tissue grafts from one animal could also be used on the joined animal and clarified a few important immunological questions.
About 150 years later, these experiments were once again picked up by scientists; but this time they inspired a whole new scientific discipline: the understanding of ageing.
Rejuvenating blood donations
Professor Amy WagersProfessor Amy Wagers learned the technique of creating parabiotic mice during her time as a post-doc in Irving Weissman's lab in Stanford. Her work and that of Stanford colleagues, working in Thomas Rando's lab at the time, indicated intriguing effects that parabiotic mice could have on each other.
When old mice were joined to young mice, sustained muscle injuries healed much faster than in old mice alone. This effect was not caused by muscle stem cells from young mice entering tissue from old mice through the shared bloodstream. Instead, early muscle cells, so-called satellite cells (progenitor cells), within the old mice were directly activated and encouraged to divide and heal the damaged tissue, much like they would do in young mice.
These experiments showed that ageing satellite cells still had the ability to divide and regenerate the tissue, but "old" blood alone could not stimulate them sufficiently enough to do this. The ageing satellite cells needed the rejuvenating influence from young blood to kick-start their molecular pathways back into youthful capacity.
To scientists, influence usually means factors. Is there a combination of factors – proteins, molecules, hormones... – in a young mouse's blood that could be used as a power cocktail for old mice and heal them from diseases? And, more importantly, would it work in humans?
What are the secret ingredients that rejuvenate our stem cells?
Water from the fountain of youth is currently being analysed – and publications are piling up at a rapid pace with several highly interesting findings just from last year.
Following the initial report in 2004, many factors in young blood have been identified that can, also in vitro, boost the regenerative capacity of aged tissue and reverse symptoms of ageing.
An influence of Wnt and TGFβ signalling pathways has been confirmed in muscle ageing and regeneration. Cytokines and chemokines have been found to have an impact on neurogenesis and ageing brain function.
It has been suggested that oxytocin, a hormone well known for its role in lactation and social behaviour (also frequently hyped as the 'love hormone'), plays a role in age-dependent muscle degradation.
And most recently, another factor, GDF11 – initially reported to improve performance and size of failing hearts – was found to recover cerebral vasculature and enhance neurogenesis; both aspects are highly affected by age-dependent deterioration.
Considering this wealth of findings within just a few years, humankind certainly owes the parabiotic mice a few favours (and by that I don't mean the alleviation of their old age-symptoms). Older reports from the 1970s also hint at a longer lifespan achieved by old mice that were attached to young mice. However, a concluding remark on this is still outstanding.
Where are we now?
Together with Lee Rubin, Wagers is currently working on getting the rejuvenating factors into human clinical trials. Another trial using human blood plasma, donated by people under the age of 30, to treat patients with mild to moderate Alzheimer's disease, has already been initiated by a different group of researchers and results are eagerly awaited.
Professor Wagers clarifies that her experiments are not aimed at "de-ageing" animals. They are just designed to restore function to tissues and repair damage.
Whether this can be reliably sustained over a long period is unknown. To push ageing stem cells beyond their performance limit might damage them additionally with drastic consequences later on. Besides, the oldest and best-known associate of the fountain of youth is also still looming. The only kind of cell that has actually achieved true immortality and boundless replicative power: the cancer cell. Anyone attempting to force cells into improved regeneration and growth will undoubtedly have to consider the possibility of tumour development.
Professor Wagers will be presenting a seminar here at King's College London in April – more details can be found on the King's website.
Interested in the subject of ageing? The next Wattlab blog will aim to answer the question: "what is ageing, how does it affect our stem cells and can it be reversed?”
• (1)'A History of Organ Transplantation: Ancient Legends to Modern Practice' by David Hamilton.