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Abstract Background Characterizing immune cells and conditions that govern their recruitment and function in autoimmune diseases of the nervous system or in neurodegenerative processes is an area of active investigation. We sought to analyze the origin of antigen presenting cells associated with the induction of retinal autoimmunity using a system that relies on spontaneous autoimmunity, thus avoiding uncertainties associated with immunization with adjuvants at remotes sites or adoptive transfer of in vitro activated T cells. Methods R161H mice (B10.RIII background), which spontaneously and rapidly develop severe spontaneous autoimmune uveoretinitis (SAU), were crossed to CD11cDTR/GFP mice (B6/J) allowing us to track the recruitment to and/or expansion within the retina of activated, antigen presenting cells (GFPhi cells) in R161H+/− × CD11cDTR/GFP F1 mice relative to the course of SAU. Parabiosis between R161H+/− × CD11cDTR/GFP F1 mice and B10.RIII × B6/J F1 (wild-type recipient) mice was done to explore the origin and phenotype of antigen presenting cells crucial for the induction of autoimmunity. Analysis was done by retinal imaging, flow cytometry, and histology. Results Onset of SAU in R161H+/− × CD11cDTR/GFP F1 mice was delayed relative to B10.RIII-R161H+/− mice revealing a disease prophase prior to frank autoimmunity that was characterized by expansion of GFPhi cells within the retina prior to any clinical or histological evidence of autoimmunity. Parabiosis between mice carrying the R161H and CD11cDTR/GFP transgenes and transgene negative recipients showed that recruitment of circulating GFPhi cells into retinas was highly correlative with the occurrence of SAU. Conclusions Our results here contrast with our previous findings showing that retinal antigen presenting cells expanding in response to either sterile mechanical injury or neurodegeneration were derived from myeloid cells within the retina or optic nerve, thus highlighting a unique facet of retinal autoimmunity.

In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis.

The strong interest shown in the study of the causes of aging in recent decades has uncovered many mechanisms that could contribute to the rate of aging. These include mitochondrial ROS production, DNA modification and repair, lipid peroxidation-induced membrane fatty acid unsaturation, autophagy, telomere shortening rate, apoptosis, proteostasis, senescent cells, and most likely there are many others waiting to be discovered. However, all these well-known mechanisms work only or mainly at the cellular level. Although it is known that organs within a single individual do not age at exactly the same rate, there is a well-defined species longevity. Therefore, loose coordination of aging rate among the different cells and tissues is needed to ensure species lifespan. In this article we focus on less known extracellular, systemic, and whole organism level mechanisms that could loosely coordinate aging of the whole individual to keep it within the margins of its species longevity. We discuss heterochronic parabiosis experiments, systemic factors distributed through the vascular system like DAMPs, mitochondrial DNA and its fragments, TF-like vascular proteins, and inflammaging, as well as epigenetic and proposed aging clocks situated at different levels of organization from individual cells to the brain. These interorgan systems can help to determine species longevity as a further adaptation to the ecosystem.

Abstract Studies analyzing heterochronic parabiosis mice models showed that molecules in the blood of young mice rejuvenate aged mice. Therefore, blood-based therapies have become one of the therapeutic approaches to be considered for age-related diseases. Blood includes numerous biologically active molecules such as proteins, metabolites, hormones, miRNAs, etc. and accumulating evidence indicates some of these change their concentration with chronological aging or age-related disorders. The level of some circulating molecules showed a negative or positive correlation with all-cause mortality, cardiovascular events, or metabolic disorders. Through analyses of clinical/translation/basic research, some molecules were focused on as therapeutic targets. One approach is the supplementation of circulating anti-aging molecules. Favorable results in preclinical studies let some molecules to be tested in humans. These showed beneficial or neutral results, and some were inconsistent. Studies with rodents and humans indicate circulating molecules can be recognized as biomarkers or therapeutic targets mediating their pro-aging or anti-aging effects. Characterization of these molecules with aging, testing their biological effects, and finding mimetics of young systemic milieu continue to be an interesting and important research topic to be explored.

The contribution of bone-marrow derived cells (BMCs) to a newly formed beta-cell population in adults is controversial. Previous studies have only used models of bone marrow transplantation from sex-mismatched donors (or other models of genetic labeling) into recipient animals that had undergone irradiation. This approach suffers from the significant shortcoming of the off-target effects of irradiation. Partial pancreatic duct ligation (PDL) is a mouse model of acute pancreatitis with a modest increase in beta-cell number. However, the possibility that recruited BMCs in the inflamed pancreas may convert into beta-cells has not been examined. Here, we used an irradiation-free model to track the fate of the BMCs from the donor mice. A ROSA-mTmG red fluorescent mouse was surgically joined to an INS1Cre knock-in mouse by parabiosis to establish a mixed circulation. PDL was then performed in the INS1Cre mice 2 weeks after parabiosis, which was one week after establishment of the stable blood chimera. The contribution of red cells from ROSA-mTmG mice to beta-cells in INS1Cre mouse was evaluated based on red fluorescence, while cell fusion was evaluated by the presence of green fluorescence in beta-cells. We did not detect any red or green insulin+ cells in the INS1Cre mice, suggesting that there was no contribution of BMCs to the newly formed beta-cells, either by direct differentiation, or by cell fusion. Thus, the contribution of BMCs to beta-cells in the inflamed pancreas should be minimal, if any.

Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood–nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand–receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.

Surgical parabiosis enables sharing of the circulating milieu between two organisms. This powerful model presents diverse complications based on age, strain, sex, and other experimental parameters. Here, we provide an optimized parabiosis protocol for the surgical union of two mice internally at the elbow and knee joints with continuous external joining of the skin. This protocol incorporates guidance and solutions to complications that can occur, particularly in aging studies, including non-cohesive pairing, variable anesthesia sensitivity, external and internal dehiscence, dehydration, and weight loss. We also offer a straightforward method for validating postoperative blood chimerism and confirming its time course using flow cytometry. Utilization of our optimized protocol can facilitate reproducible parabiosis experimentation to dynamically explore mechanisms of aging and rejuvenation.

Aging is inevitable in life. It is defined as impaired adaptive capacity to environmental or internal stresses with growing rates of disease and death. Aging is also an important risk factor for various kidney diseases such as acute kidney injury and chronic kidney disease. Patients older than 65 years have nearly 28% risk of failing recovery of kidney function when suffering from acute kidney injury. It is reported that more than a third of population aged 65 years and older have chronic kidney disease in Taiwan, and the occurrence of multiple age-related disorders is predicted to increase in parallel. Renal aging is a complex, multifactorial process characterized by many anatomical and functional changes. Several factors are involved in renal aging, such as loss of telomeres, cell cycle arrest, chronic inflammation, activation of renin-angiotensin system, decreased klotho expression, and development of tertiary lymphoid tissues. These changes can also be observed in many other different types of renal injury. Recent studies suggested that young blood may rejuvenate aged organs, including the kidneys. In order to develop new therapeutic strategies for renal aging, the mechanisms underlying renal aging and by which young blood can halt or reverse aging process warrants further study.

Eusociality represents an extreme form of social behavior characterized by a reproductive division of labor. Eusociality necessarily evolved through kin selection, which requires interactions among related individuals. However, many eusocial taxa also show cooperation between non-kin groups, challenging the idea that cooperative actions should only occur among relatives. This review explores the causes and consequences of non-kin cooperation in ants. Ants display a diversity of behaviors that lead to non-kin cooperation within and between species. These interactions occur among both reproductive and non-reproductive individuals. The proximate and ultimate mechanisms leading to non-kin cooperative interactions differ substantially depending on the biotic and abiotic environment. We end this review with directions for future research and suggest that the investigation of non-kin cooperative actions provides insight into processes leading to social evolution.

Background: Huntington's disease (HD) starts its pathology long before clinical manifestation, however, there is no therapy to cure it completely and only a few studies have been reported for delaying the progression of HD. Recently, it has been shown that heterochronic parabiosis can modulate the neurodegenerative diseases. Despite the importance of the transportation process of positive factors during heterochronic parabiosis, there were limited understandings because the transportation process is nanoscale, which makes it difficult to identify the messenger unit. We demonstrated that heterochronic parabiosis could modulate HD in R6/2 mice model, and identified the messenger unit for transferring positive factors in the young blood serum. Methods: R6/2 mice were surgically connected with young wild-type mice (n = 13), old wild-type mice (n = 8), or R6/2 mice (n = 6) to examine the effect of heterochronic parabiosis. Parabionts composed of 5- to 6-week-old transgenic and wild-type mice were observed for 6 weeks in a single cage. The in vitro cellular model of HD cells were treated by the blood serum of the young or old mice, and by the exosomes isolated from thereof. The in vitro cellular model of HD were developed by differentiating neural stem cells cultured from SVZ of the brain. Results: After the heterochronic parabiosis, the weight loss and survival of HD mice was improved. Also, mutant Huntingtin aggregation (EM48 p

Group 2 innate lymphoid cells (ILC2s) are tissue resident in the lung and activated by inhaled allergens via epithelial-derived alarmins including IL-33. Activated ILC2s proliferate, produce IL-5 and IL-13, and induce eosinophilic inflammation. Here, we report that intranasal IL-33 or the protease allergen papain administration resulted in increased numbers of ILC2s not only in the lung but also in peripheral blood and liver. Analyses of IL-33 treated parabiosis mice showed that the increase in lung ILC2s was due to proliferation of lung resident ILC2s, whereas the increase in liver ILC2s was due to the migration of activated lung ILC2s. Lung-derived ILC2s induced eosinophilic hepatitis and expression of fibrosis-related genes. Intranasal IL-33 pre-treatment also attenuated concanavalin A-induced acute hepatitis and cirrhosis. These results suggest that activated lung resident ILC2s emigrate from the lung, circulate, settle in the liver and promote type 2 inflammation and attenuate type 1 inflammation.

Immune cell infiltration plays a key role in acute kidney injury (AKI) to chronic kidney disease (CKD) progression. T lymphocytes, neutrophils, monocytes/macrophages and other immune cells regulate inflammation, tissue remodelling and repair. To determine the kinetics of accumulation of various immune cell populations, we established an animal model combining parabiosis and separation surgery to explore the fate and lifespan of peripheral leucocytes that migrate to the kidney. We found that peripheral T lymphocytes could survive for a long time (more than 14 days), whereas peripheral neutrophils survived for a short time in both healthy and ischaemia-induced damaged kidneys. Nearly half of the peripheral-derived macrophages disappeared after 14 days in normal kidneys, while their existing time in the inflammatory kidneys was prolonged. A fraction of F4/80high macrophages were renewed from the circulating monocyte pool. In addition, we found that after renal ischaemia reperfusion, neutrophils increased significantly in the early phase, and T lymphocytes mainly accumulated in the late stage, whereas macrophages infiltrated throughout AKI-CKD progression and were sustained longer in injured as opposed to normal kidneys. In conclusion, peripheral-derived macrophages, T lymphocytes and neutrophils exhibit different lifespans in the kidney, which may play different roles during AKI-CKD progression.

The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.

In Parkinson's disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the central nervous system. Recent evidences collected in non-human primates challenge however the hypothesis of a transmission of α-synuclein (α-syn) pathology through the vagus nerve. Would the hypothesis whereby the bloodstream acts as a route for long-distance transmission of pathological α-syn hold true, an inter-individual transmission of synucleinopathy could occur via blood contact. Here, we used a parabiosis approach to join the circulatory systems of wild type and GFP transgenic C57BL/6 J mice, for which one of the partners parabiont received a stereotaxic intranigral injection of patient-derived α-syn aggregates. While the Lewy Body-receiving mice exhibited a loss of dopamine neurons and an increase in nigral S129 phosphorylated α-syn immunoreactivity, their parabiotic bloodstream-sharing partners did not show any trend for a lesion or change in S129 phosphorylated-α-syn levels. Altogether, our study suggests that, in the patient-derived α-synuclein aggregates-injected mouse model and within the selected time frame, the disease is not “transmitted” through the bloodstream.

Summary: Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. However, some attempts have failed due to low replacement efficiency, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB), and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

As a pathological biomarker of Parkinson’s disease, α-synuclein is thought to be a prion-like protein, but evidence for the transmission of α-synuclein from blood to the brain is unclear. The goals of this study were to determine whether blood-derived α-synuclein could enter the brains of mice and whether α-synuclein in the brain could be cleared by parabiosis. Heterochronic parabiosis was performed on SNCAA53T transgenic mice (A53T mice) and wildtype mice. The levels of human α-synuclein in the blood and substantia nigra of wildtype mice were significantly increased after 4-month parabiosis with A53T mice. Moreover, the expression of α-synuclein filament, but not of total α-synuclein, was significantly increased in the substantia nigra of wildtype mice that were paired with A53T mice. However, the levels of human α-synuclein displayed no significant change in the serum, blood, or substantia nigra of A53T mice. These results provide direct evidence that pathological α-synuclein can be transmitted from blood to the brain in the heterochronic parabiosis system; however, it appears to be difficult to clear it from the brain in a short period of time.

Transfusion (or drinking) of blood or of its components has been thought as a rejuvenation method since ancient times. Parabiosis, the procedure of joining two animals so that they share each others blood circulation, has revitalized the concept of blood as a putative drug. Since 2005, a number of papers have reported the anti-ageing effect of heterochronic parabiosis, which is joining an aged mouse to a young partner. The hallmark of aging is the decline of regenerative properties in most tissues, partially attributed to impaired function of stem and progenitor cells. In the parabiosis experiments, it was elegantly shown that factors derived from the young systemic environment are able to activate molecular signaling pathways in hepatic, muscle or neural stem cells of the old parabiont leading to increased tissue regeneration. Eventually, further studies have brought to identify some soluble factors in part responsible for these rejuvenating effects, including the chemokine CCL11, the growth differentiation factor 11, a member of the TGF-β superfamily, and oxytocin. The question about giving whole blood or specific factors in helping rejuvenation is open, as well as the mechanisms of action of these factors, deserving further studies to be translated into the life of (old) human beings.

Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by a lack of dystrophin expression in the sarcolemma of muscle fibers. DMD patients acquire bone abnormalities including osteopenia, fragility fractures, and scoliosis indicating a deficiency in skeletal homeostasis. The dKO (dystrophin/Utrophin double knockout) is a more severe mouse model of DMD than the mdx mouse (dystrophin deficient), and display numerous clinically-relevant manifestations, including a spectrum of degenerative changes outside skeletal muscle including bone, articular cartilage, and intervertebral discs. To examine the influence of systemic factors on the bone abnormalities and healing in DMD, parabiotic pairing between dKO mice and mdx mice was established. Notably, heterochronic parabiosis with young mdx mice significantly increased bone mass and improved bone micro-structure in old dKO-hetero mice, which showed progressive bone deterioration. Furthermore, heterochronic parabiosis with WT C56/10J mice significantly improved tibia bone defect healing in dKO-homo mice. These results suggest that systemic blood-borne factor(s) and/or progenitors from WT and young mdx mice can influence the bone deficiencies in dKO mice. Understanding these circulating factors or progenitor cells that are responsible to alleviate the bone abnormalities in dKO mice after heterochronic parabiosis might be useful for the management of poor bone health in DMD.

Adiponectin is exclusively synthesized by adipocytes and exhibits anti-diabetic, anti-atherosclerotic and anti-inflammatory properties. Hypoadiponectinemia is associated in obese individuals with insulin resistance and atherosclerosis. However, the mechanisms responsible for hypoadiponectinemia remain unclear. Here, we investigated adiponectin movement using hetero parabiosis model of wild type (WT) and adiponectin-deficient (KO) mice. WT mice were parabiosed with WT mice (WT–WT) or KO mice (WT–KO) and adiponectin levels were measured serially up to 63 days after surgery. In the WT–KO parabiosis model, circulating adiponectin levels of the WT partners decreased rapidly, on the other hand, those of KO partners increased, and then these reached comparable levels each other at day 7. Circulating adiponectin levels decreased further to the detection limit of assay, and remained low up to day 63. However, adiponectin protein was detected in the adipose tissues of not only the WT partner but also WT–KO mice. In the diet-induced obesity model, high adiponectin protein levels were detected in adipose stromal vascular fraction of diet-induced obese KO partner, without changes in its binding proteins. The use of parabiosis experiments shed light on movement of native adiponectin among different tissues such as the state of hypoadiponectinemia in obesity.

Aging is a complicated pathophysiological process accompanied by a wide array of biological adaptations. The physiological deterioration correlates with the reduced regenerative capacity of tissues. The rejuvenation of tissue regeneration in aging organisms has also been observed after heterochronic parabiosis. With this model, it has been shown that exposure to young blood can rejuvenate the regenerative capacity of peripheral tissues and brain in aged animals. An endogenous compound called growth differentiation factor 11 (GDF11) is a circulating negative regulator of cardiac hypertrophy, suggesting that raising GDF11 levels could potentially treat or prevent cardiac diseases. The protein GDF11 is found in humans as well as animals. The existence of endogenous regulators of regenerative capacity, such as GDF11, in peripheral tissues and brain has now been demonstrated. It will be important to investigate the mechanisms with therapeutic promise that induce the regenerative effects of GDF11 for a variety of age-related diseases.

We determined whether host matrix metalloproteinase (MMP) 9 is essential to angiogenesis and to the growth of L3.6pl human pancreatic cancer cells implanted into the pancreas of wild-type (MMP−9+/+) and knockout (MMP−9−/−) nude mice. Four weeks after tumor cell injection, pancreatic tumors in MMP−9+/+ mice were large, had many blood vessels, and contained many macrophages expressing MMP−9. In contrast, pancreatic tumors in MMP−9−/− mice were significantly smaller, had few blood vessels, and had few macrophages. Next, we parabiosed MMP−9+/+ mice with MMP−9+/+ mice, MMP−9−/− mice with MMP−9−/− mice, and MMP−9+/+ mice with MMP−9−/− mice. Two weeks after parabiosis, we implanted L3.6pl cells into the pancreas of the recipient mouse in each pair. Four weeks later, the mice were necropsied. The parabiosis experiment revealed a direct correlation between intratumoral MMP−9+/+ expressing macrophages, angiogenesis, and progressive tumor growth. Because the expression of MMP−9 by L3.6pl tumor cells was similar in all parabionts, the data clearly demonstrate a major role for host-derived MMP−9 in angiogenesis and in the growth of human pancreatic cancer in the pancreas of nude mice.

Despite the numerous records of ant-mimicking arthropods, reports of ant species that are mimics among themselves are still rare. In the savannah of central Brazil we found two ant species that are remarkably similar in color pattern and body size, Pseudomyrmex termitarius and Camponotus blandus. Both species are widely distributed in the Neotropical Region, but the cases of mimicry between them are apparently restricted to populations inhabiting nests of the termite Cornitermes cumulans in the Brazilian Cerrado. Field observations and excavation of the termitaries revealed that Camponotus blandus shares nest chambers and foraging trials with P. termitarius, and workers of both species are mutually tolerant. Our observations suggest that the morphological and behavioral similarities between these species represent a Batesian mimicry relationship in which the relatively palatable Camponotus blandus mimics the unpalatable P. termitarius for predator avoidance. The pacific association between the termitophilous colonies of these species may also suggest some level of parabiotic interaction.

Modern medicine wields the power to treat large numbers of diseases and injuries most of us would have died from just a hundred years ago, yet many of the most devastating diseases of our time are still untreatable. Chronic conditions of age such as cardiovascular disease, diabetes, osteoarthritis or Alzheimer’s disease turn out to be of a complexity that may require transformative ideas and paradigms to understand and treat them. Parabiosis, which is characterised by a shared blood supply between two surgically connected animals, may just provide such a transformative experimental paradigm. Although forgotten and shunned now in many countries, it has contributed to major breakthroughs in tumour biology, endocrinology and transplantation research in the past century. Interestingly, recent studies from the United States and Britain are reporting stunning advances in stem cell biology and tissue regeneration using parabiosis between young and old mice, indicating a possible revival of this paradigm. We review here briefly the history of parabiosis and discuss its utility to study physiological and pathophysiological processes. We argue that parabiosis is a technique that should enjoy wider acceptance and application, and that policies should be revisited to allow its use in biomedical research.

Subcutaneous fat cells were isolated from genetically obese rats and from rats with obesity produced by hypothalamic lesions. Insulin did not augment the oxidation of fatty acids or their synthesis from glucose-1-14c or glucose-1-3H by fat cells from either group. Radioactivity from pyruvate-3-14C was incorporated into fatty acids to the same degree by fat cells from these two groups.The presence of 5 mm glucose in the incubation medium containing fat cells and pyruvate-3-14C or aspartate-3-14C stimulated the synthesis of fatty acids to a greater extent in cells of genetically obese rats. Fasting, in contrast, reduced the incorporation of radioactivity from pyruvate and glucose into fatty acids by fat cells from the genetically obese animals. In all experiments the fat cells from genetically obese rats converted more radioactivity into glyceride-glycerol relative to CO2 than did fat cells from hypothalamic obese rats.Parabiosis between one thin and one genetically obese litter mate was performed in three pairs of rats without influencing growth of either rat.Thus in the present studies fat cells from genetically obese rats showed two differences from normal fat cells: they channeled more radioactivity from pyruvate into fatty acids in the presence of glucose, and they uniformly converted more radioactivity into glyceride-glycerol.