By Isabelle Hall
In 2016, Ambrosia was founded by Jesse Karmazin. The start-up sought to provide transfusions of blood plasma from people aged 16-25 to patients over 35, at a cost of $8000 per litre. Karmazin claimed that the transfusions had led to positive changes in his clients, appearing to reduce the burden of certain issues associated with ageing. However, Karmazin’s work drew criticism at the time due to the absence of control and placebo groups (Adee, 2017), and the company suspended operations in 2019 following a warning by the FDA against transfusions of young plasma, due to the lack of evidence showing clinical benefit. Ambrosia has since reopened (Corbyn, 2020).
It has been theorised in the past that blood may act as a fountain of youth or medical treatment; records indicate that Ancient Egyptian kings bathed in blood in search of rejuvenation, and the blood of fallen Roman gladiators was drunk for strength. The case of Pope Innocent VIII (also known as Cibo) may present one of the earliest instances of blood transfusion; in the 1490s, the Pope suffered from an illness which left him in a partially comatose state. He may have received treatment for his condition in the form of blood transfusions from three boys aged 10 (Learoyd, 2012).
Parabiosis is one experimental technique which has produced results lending support to the idea that young blood holds therapeutic potential for age-related illness and other conditions. This procedure involves the surgical joining of two organisms. It has previously been used to bind young and old mice (heterochronic parabiosis), enabling the sharing of physiological systems. Such work has demonstrated improved tissue function and extension of lifespan for the older parabiont (Conboy et al., 2013).
These effects may be the result of numerous factors, including dilution of older blood, and the presence of components more prevalent in younger blood. In analysing the outcome of parabiosis experiments, the contribution from the sharing of organ systems also ought to be considered (Rebo et al., 2016).
The age of blood appears to influence multiple processes within the body, including cognitive functioning. In older years, a decline in cognitive ability is observed, in part due to loss of synaptic connectivity and a general reduction in neuronal function. Certain manifestations of this age-related decline, including impaired learning and memory, can be reversed through transfusion of younger blood, as shown in mice. Subsequent research has examined the effect of blood serum from young mice on neurons in culture, demonstrating promotion of dendritic branching and synapse formation. An increase in the amplitude of excitatory postsynaptic currents was also observed for synaptic responses mediated by AMPA and NMDA receptors.
Further investigation into the potential factors responsible revealed that similar results could be obtained through application of THBS4 and SPARCL1 to the cultured neurons. In comparison to older serum, these proteins are present at greater concentrations in younger serum; THBS4 levels were approximately 400% higher, and SPARCL1 levels 200% higher (Gan & Südhof, 2019).
In connection to its apparent influence on general cognitive function, young blood has also been explored in the context of neurodegenerative diseases such as Alzheimer’s. In 3xTg-AD mice (a transgenic mouse model of Alzheimer’s disease, exhibiting Aβ and tau pathology), it has been demonstrated that treatment with young plasma inhibits brain inflammation, decreases tau pathology and Aβ plaque area, as well as reversing cognitive impairment (Zhao et al., 2020).
Young blood has also been shown to improve cardiovascular function. Use of heterochronic parabiosis has enabled regression of cardiac hypertrophy in old mice, occurring alongside molecular remodelling. Analysis of the blood serum and plasma collected from the test subjects led to identification of GDF11 as a key determinant here. This growth and differentiation factor was far less abundant in samples from the older mice. Recombinant GDF11 therapy produced antihypertrophic effects on cultured cardiomyocytes, and reversed cardiac hypertrophy in vivo (Loffredo et al., 2013). One way of adapting medical treatment to incorporate findings on the benefits of young blood may involve altering levels of specific factors in patients’ circulation, such as GDF11 for the aforementioned heart condition. In other cases, the apparent improvements offered by young blood may be mimicked to an extent through therapeutic plasma exchange (to remove plasma and replace it with a physiologic solution), in order to dilute age-elevated factors and other proteins which may be negatively impacting body function. Previous work utilising this approach has indicated that it is effective in achieving certain outcomes observed after heterochronic blood sharing, including enhanced muscle repair and decreased liver adiposity (Mehdipour et al., 2020).
While Ambrosia has inspired controversy, research has revealed that young blood influences essential processes such as cognition and cardiovascular function, demonstrating the need for further investigation into this field to assist development of therapies. Such work will require exploration of the beneficial factors present at higher concentrations in young blood, as well as harmful age-elevated factors which may be targeted.
References:
Adee, S. (2017). Human tests suggest young blood cuts cancer and Alzheimer’s risk. Available from: https://www.newscientist.com/article/2133311-human-tests-suggest-young-blood-cuts-cancer-and-alzheimers-risk/ [Accessed 2nd October 2021]
Conboy, M. J., Conboy, I. M., & Rando, T. A. (2013). Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell. 12 (3), 525–530. Available from: doi: 10.1111/acel.12065
Corbyn, Z. (2020). Could ‘young’ blood stop us getting old? Available from: https://www.theguardian.com/society/2020/feb/02/could-young-blood-stop-us-getting-old-transfusions-experiments-mice-plasma [Accessed 2nd October 2021]
Gan, K.J. and Südhof, T.C. (2019). Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proceedings of the National Academy of Sciences. 116 (25), 12524-12533. Available from: doi: 10.1073/pnas.1902672116
Learoyd, P. (2012). The history of blood transfusion prior to the 20th century – Part 1. Transfusion Medicine. 22 (5), 308-314. Available from: doi: 10.1111/j.1365-3148.2012.01180.x
Loffredo, F.S., Steinhauser, M.L., Jay, S.M., Gannon, J., Pancoast, J.R., Yalamanchi, P., et al. (2013). Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy. Cell. 153 (4), 828-839. Available from: doi: 10.1016/j.cell.2013.04.015
Mehdipour, M., Skinner, C., Wong, N., Lieb, M., Liu, C., Etienne, J., et al. (2020). Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin. Aging. 12 (10), 8790-8819. Available from: doi: 10.18632/aging.103418
Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M.J., et al. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature Communications. 7 (1), 1-11. Available from: doi: 10.1038/ncomms13363
Zhao, Y., Qian, R., Zhang, J., Liu, F., Iqbal, K., Dai, C.L., et al. (2020). Young blood plasma reduces Alzheimer’s disease-like brain pathologies and ameliorates cognitive impairment in 3× Tg-AD mice. Alzheimer’s Research & Therapy. 12:70, 1-13. Available from: doi: 10.1186/s13195-020-00639-w
Imperial Bioscience Review 