"PARABIOSIS AND GDF-11 HISTORY OF PARABIOSISParabiosis is a Greek word where ‘Para’ means next to and ‘bios’ means life (1). It refers tothe condition where two living animals are surgically joined thus sharing a commoncirculatory system. The earliest publication about parabiotic pairing was by Bert in the year1864, published in French titled as ‘‘Experiences et Considerations Sur la Greffe Animale’.In his experiments he showed that the fluid injected into the vein of one animal passed to thevein of the other animal when connected through parabiosis (2). Vascular channels were alsodeveloped between the two animals connected by parabiosis. Bert was awarded a prize inExperimental Physiology by the French Academy of Science in 1866 for this work. In theyear 1908 German surgeons Sauerbruch and Heyde coined the term ‘parabiosis’ (3).Experiments performed by Carrel to understand organ ageing and prolonged life lead to thedevelopment of a lifesaving procedure, organ transplantation (He invented the first perfusionpump) and is now influencing the studies of heterochronic parabiosis (4). Carrel received aNobel prize in Physiology or Medicine for developing a method for vascular suturingtechnique and he wrote, ‘Since the survival of entire organs outside of the body wouldundoubtedly have important physiological uses, I began in June, 1912, to develop a techniqueby means of which a system of organs could be made to live and functionate when separatedfrom the other organs’ (5). In 1972, Ludwig and Elashoff experiments provided the firstevidence that the older organism in heterochronic parabiotic pair live longer in response tothe young environment created by the pairing (6). In parabiosis, two mice are surgicallyjoined, such that they develop a shared blood circulation with rapid and continuous exchangeof cells and soluble factors at physiological levels through their common circulatory system(7). The reported rate of blood exchange between the parabiotic partners in mice is 2.0±0.2%per min (range, 0.71-3.1%) (8). If the pair of animals joined are of same age then it isisochronic parabiosis and if the animals are ofdifferent ages then it is called heterochronic parabiosis. The natural form of parabiosis is the abnormal development of embryos inmonozygotic twins or Siamese twins in humans. Heterochronic parabiosis is one of thephysiological approaches used to rejuvenate muscle regeneration and the molecularapproaches of this are exposure of aged muscle cells to the soluble proteins, including thosesecreted by embryonic stem cells. Fig 1: SA Villedaa & T Wyss-Coraya, The circulatory systemic environment as a modulatorof neurogenesis and brain aging. Autoimmunity Reviews, 2013; 12 (6): 674–677 PARABIOSIS AND GDF-11One of the disorders associated with age is heart failure due to loss of normal cardiacfunction. In parabiosis as two animals are connected, this experimental model is used to studywhether circulating factors can alter tissue function.Studies by I. M. Conboy et al. showedthat blood circulation of the young mice reverts ageing in old mice on exposure to a youngenvironment by heterochronic parabiosis (9). In old mice and in long-lived humans, heartfailure is one of the most frequent direct cause of death, thus treatment with a potential torejuvenate heart function may prove helpful in extending the longevity.In parabiosis experiments four weeks of parabiosis was sufficient to reduce cardiachypertrophy in old mice. This indicates that some factor in the young mice which was linkedto the old mice was responsible for reducing the effect of hypertrophy.Metabolomicprofiling and lipidomic profiling did not reveal any differences in young and old micewhereas the proteomic analysis identified growth differentiation factor 11(GDF 11) as ananti-hypertrophic factor (10). The levels of GDF 11 were more in young mice in comparisonwith the paired old mice. So GDF11 may be a candidate to reverse cardiac aging leading toincreased longevity (10). GDF 11 has shown to play some role in rejuvenation. Growthdifferentiation factor 11 is also known as bone morphogenetic protein 11(BMP-11), a proteinthat in humans is encoded by the GDF 11 gene. This is shown to suppress the neurogenesisthrough a pathway similar to that of myostatin including stopping the progenitor cell cycleduring G-phase. It belongs to the transforming growth factor beta super family. Theexpression and protein abundance of GDF 11 decreases with age (11).The process of ageing is due to loss of tissue function which is due to the exposure of cells todifferent changes leading to disruption of homeostasis and regenerative mechanisms. Stemcell demise which is partially regulated by the blood borne factors in the systemic environment might be a reason for the decline in regeneration. So, parabiosis is used as aprocedure to look for the different factors in these cellular processes (11). The effect of parabiosis in case of reversal of cardiac hypertrophy can be checked by thetranscriptional expression of the molecular markers of cardiac hypertrophy, the AtrialNatriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) (11). ANP is powerfulvasodilator, a polypeptide hormone secreted by the heart muscle cells involved inhomeostatic control of body water, sodium, potassium and fat. On the other hand BNP issecreted by the ventricles of the heart on excessive stretching of heart muscle cells. So boththese peptides act by decreasing the blood volume thereby lowering the systemic bloodpressure and increasing the cardiac output. Transcript level of ANP and BNP were reduced inthe heart of old mice exposed to young circulation by heterochronic parabiosis (11). Theother factor is the Sarcoplasmic reticulum calcium ATPase (SERCA-2) which is importantfor the normal diastolic relaxation. This expression was significantly higher in heart of agedmice exposed to young circulation (11). This provides in vivo evidence that some circulatingfactors in the blood of young mice might help in the reversal of age related cardiachypertrophy. This effect is not gender specific and is not due to the parabiosis procedure, orchanges in the blood pressure. A randomised blinded, vehicle-controlled study showed thatintraperitonial injection of recombinant GDF11 (rGDF11) to an old mice resulted in thesmaller cardiomyocytes compares to the saline injected controls. A significant reduction inthe molecular markers ANP and BNP was also seen in the rGDH11 treated mice (12).Although complete reversal is not observed by the use of Anti-hypertrophic factors such asGDF-11 but it may be candidates for therapeutics to prevent or reverse cardiac ageing. Thismay prove of significant benefit in elderly population. However, replication in other animalmodels is to be carried out and, if positive results are obtained then a subsequent humanclinical trials will highlight the preliminary status of GDF11 as a reguvenating agent (12). PARABIOIS IN OTHER CASES? Parabiosis has provided an excellent model for studying the non-resident progenitor stemand hematopoietic cells migrating from the circulating blood to the site of injury (13). ? Parabiosis is used to study tumour metastasis or to study the role of the circulatoryinflammatory cells or stem cells involved in the tumour formation. It has been shown thatBone marrow-derived circulating endothelial precursors do not contribute to vascularendothelium and are not needed for tumour growth (14, 15, and 16).? The obese mice (ob/ob) lost weight when parabioised to a wild type mice or db/db animal.This resulted in the identification of a protein leptin inhibits the growth of the adiposetissue by the release of one or more circulating factors (17, 18, 19).PARABIOSIS AND ITS USE IN STUDYING THE IMPAIREDSTEM CELL FUNCTIONTissues and organs regeneration capacity is dependent on the proliferative activity ofprogenitors derived from stem cells. Molecular signalling pathways in hepatic and musclecells are activated by the factors from the young systemic environment and thus increasingcell proliferation and tissue regeneration (20). The age associated changes in stem cell nicheare regulated systemically and it can be reversed by exposure to a young circulation by theheterochronic parabiosis (21). This indicates that the surrounding niche plays an importantrole in the maintaining the stem cell function with age.Heterochronic parabiosis has provided major information about the contribution of theintrinsic and extrinsic determinants of stem cell function in aged brain. On exposure to agedmice the young mice showed impaired neurogenesis, learning and memory (22).This was due to elevation of a chemokine eotaxin (CCL11) in young mice. The administration of thisto young mice resulted in the inhibitory effect of ageing on hippocampal neurogenesis (22). CONCLUSIONParabiosis can be considered as a viable procedure to study the different molecules involvedin causing different diseases that effect mankind. "