• Hugo Creeth

Life's Elixir

Overview


Human lifespan is increasing day by day, the average life expectancy in the UK at the last check was 80.8 years old. With women living to 82.8 years and men living to 78.8 years. This is fantastic in many ways, however with age comes the inevitable effects of ageing. A study recently published in Nature Medicine has unearthed the potential role that young blood could play in helping reverse the age related degeneration of cognitive function and synaptic plasticity that is becoming more and more common as we as a race are living longer.





Reversing the Ageing Process


What causes ageing?


Ageing is a complex and intriguing field of research. Ageing in the broadest sense can encompass both physical, psychological and social changes. The area that this current research is concerned with is the physical effects of ageing, also known as biological ageing. There are many theories as to what causes animals (including humans) to age, including evolutionary, telomere and autoimmune theories that will be expanded upon in later issues of Compound Magazine.


Independent of the causes and reasons for the ageing process it is undeniable that it has detrimental effects on everything from the brain to the muscles of the body. This is what makes these latest findings by Villeda, Wyss-Coray and their team at Stanford University so exciting.


The Study

As animal rights activists call for animal research into cognitive brain disorders to be scrapped this study questions this view. In the study in question there were two distinct phases of research. Each of these phases and the key findings are described below.


Phase 1

The two cohorts of mice were previously characterised using genome wide microarray analysis of hippocampi from two parabiont models. A parabiont model is where two organisms are fused together artificially to form conjoined twins, sharing the same vascular system. This can be done in many ways, however the nature of this meant that these parabionts were made through the stitching of two laboratory mice together. The parabionts were divided into two groups:

  • Isochronic - Two 18 month mice joined together.

  • Heterochronic - An 18 month mouse joined to a 3 month mouse.

These mice spent five weeks sharing blood before the microarray analysis of specific genes in the hippocampus was performed. The cells of the hippocampus were targeted due to the fact that this brain region, named after the Sea Horse because of its appearance, is particularly vulnerable to the ageing process. The hippocampus exhibits a decrease in plasticity related genes, spine density and synaptic plasticity all contributing to deficits in cognitive function, specifically learning and memory.


The results of this first phase were fascinating. The gene analysis indicated distinct changes in gene activity associated with increased synaptic plasticity in the heterochronic cohort. In order to validate these findings the structural and functional changes of the hippocampus were mapped using two other analysis techniques: Golgi and LTP (long-term potentiation). Both dendritic spine number and electrophysical recordings were above normal in the heterochronic group.


Phase 2


The team used the findings from phase 1 to postulate the idea that it was the young blood that was contributing to enhanced structural and functional changes in the older mice in the heterochronic parabionts. Thus they hypothesised that by injecting older mice with this young blood cognitive performance would be improved, and so began phase 2...

This section of experiments didn't utilise parabionts, but instead two cohorts of either aged mice, or young donor mice. Both were baseline tested on specific behavioural assays in order to assess learning and memory. These tests were firstly a fear conditioning test in which mice were taught to link a mild electric foot shock to a light and sound cue with the consequential freezing behaviour being analysed. Secondly they were taught to navigate a radial arm water maze (RAWM) for 3 weeks.


Once the contextualised results were gathered the investigators proceeded to inject mice aged 18 months with the 100 µl blood plasma from the younger donor mice of the same strain, aged just 3 months, 3 times a week for the entire 3 week test period. In order to support any findings several controls were also set up, with other sets of 18 month old mice routinely injected with old plasma and also denatured plasma.


Plasma is the pale yellow liquid constituent of blood that doesn't contain red blood cells, but rather holds them in suspension. It usually makes up around 55% of the total blood volume and is jammed full of proteins, water (why staying hydrated is essential for a healthy vascular system) and hormones.


The outcomes of this fundamentally very simple idea are astonishing. The old mice with young blood plasma injected showed improved performance in the RAWM with a 25% drop in errors after 1 day of training compared to all control groups. They also demonstrated heightened freezing behaviour over the same period. Indicating that the impact of this young elixir is profound.


The Relevance


The two phases of research carried out by Villeda, Wyss-Coray and their team, when taken as a whole demonstrates young bloods ability to counteract the structural, functional and cognitive affects of ageing in the hippocampus in an old brain. The ramifications of these findings for the medical world are potentially huge. The exact factors in the plasma that act on the brain are not yet known but we have never been closer to finding the Holy Grail. The team at Stanford are already well on the way to isolating some of the candidates, and it is likely that there could well be more than one. Perhaps with multiple targets, not just in the brain, but also physical rejuvenation affects that could counteract various age related diseases, such as arthritis for example. In the clinical setting blood plasma transfusions are mainstream and could easily be adapted for use in wider far reaching ways. All of this points to an exciting future for this area of the clinical and research sciences. How ironic if life's elixir which we have been searching for so long has been coursing through the veins of the young all this time...


Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice S. A. Villeda and K. E. Plambeck and J. Middeldorp and J. M. Castellano and K. I. Mosher and J. Luo and L. K. Smith and G. Bieri and K. Lin and D. Berdnik and R. Wabl and J. Udeochu and E. G. Wheatley and B. Zou and D. A. Simmons and X. S. Xie and F. M. Longo and T. Wyss-Coray Nat Med   (2014)

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