Affiliations : The Douglas Institute, McGill, Canada
Journal reference: DOI: 10.1126/science.aaw2622
Summary: With the advance of technology, human activity levels have changed significantly. This fascinating article examines how transfusing healthy blood from an acitve lifestyle donor to elderly individuals can reverse age related memory deficits.
Ageing well is a growing preoccupation of our modern world. Why do some of us live long lives with good mental health, while others develop dementia and lose their autonomy?
In the past decades with the advent of technology, the human lifestyle has progressively shifted from a physically demanding life, as our grandparents may have known it, towards a more sedentary lifestyle. This transition is partly due to decreased daily physical activities impacting our long term health. We should however be able to preserve our physical and mental health across our lifespan in the current context.
One obvious way to do so is by rejuvenating the aged body, a good old trick to feed our fantasy of immortality. Based on recent studies, one promising approach entails the rejuvenation of tissues through blood transfusions.
Dr. Villeda’s laboratory at the University of San Diego California aims to understand the consequences of aging on brain functions by studying age-related changes of immune factors in the blood. In a first study published in 2011, the authors observed a deterioration of brain functions (decreased synaptic plasticity, and lower number of new neurons) in young mice following transfusion with the blood plasma from old donor mice. These dysfunctions can be explained by a change in cytokine CCL11, a small molecule implicated in allergic responses that was found to be abnormally elevated in the blood of old donor animals. This suggests that age-related changes that occur in the blood can be transferred from organism to organism, impacting brain structure and activity regardless of age.
Based on this observation, the authors further investigated whether the transfer of healthy blood could potentially be a therapeutic strategy to reverse the cognitive deficits that develop with ageing. In their new study published in the prestigious Science journal in July 2020, they demonstrated that the transfer of blood plasma from an active-lifestyle donor to an old sedentary receiver reverses age-related memory deficits.
Since exercise boosts memory performance and increases cognitive life expectancy healthy blood was taken from physically active rodents. Furthermore, exercise is a well-known non-pharmacological therapy that counteracts some aspects of the aging process – such as body mass changes, cardiovascular diseases, stroke, diabetes, cholesterol levels, inflammation, and blood pressure among others.
The experiment went as follows:
- Young and old mice had access to a running wheel for 6 weeks (this was called the exercised group), while control animals did not (the sedentary group). This period of training enhanced learning and memory performances, thereby confirming the positive effect of physical exercise on brain health.
- The authors then collected blood plasma from donor mice in four conditions: young sedentary, old sedentary, young exercised, and old exercised mice. Naïve old animals (receivers) received blood plasma injections from one of the 4 conditions. The brain and behavior improvements observed in old sedentary mice was independent of the age of the exercised donor suggesting that i) physical activity enhances cognitive functions at all ages and ii) physical activity-induced blood changes can be transferred to benefit a sedentary organism without requiring the receiver to actually exercise!
What was responsible for this cognitive improvement in sedentary mice you ask?
The liver. Proteins expressed by the liver were found in increased concentrations after exercise. While it is known that brain pathologies are often caused by serious liver damage, the extent to which liver detoxification shapes our cognitive performances under normal circumstances remains a hot topic. Among the candidate proteins identified in the liver, one is particularly interesting: GPDL1 (or glycerophosphodiester phosphodiesterase 1 for the curious among you). Increased levels of GPDL1 were not only found in exercized mice but also in healthy 60 to 80 year old humans.
Participants were monitored for their daily physical activity level during the period of the study. Compared to the less active participants, the more physically active participants had increased levels of GPLD1 circulating in their system. The researchers found further evidence in support of the central role that GPDL1 plays through virally engineering the overexpression of this protein in the liver of aged sedentary animals. This genetic manipulation was enough to mediate memory improvement.
Ultimately, this study is the first to link the GPDL1 protein to cognition, therefore identifying a new liver-to-brain axis through which beneficial effects of physical activity may act. This is a step forward to the goal of “breaking the blood code” to delay the effect of time and ageing. To date, blood-based therapy continues to be a relevant and strategic therapeutic candidate method to maintain, rescue or even prevent our brains from deteriorating.