What will happen if young bone marrow is transplanted into aging animals?

Bone marrow is responsible for producing a variety of immune cells, including T and B cells, NK cells, and dendritic cells. These cells originate from bone marrow and migrate to the blood circulatory system. With this in mind, what will be the physical effects of transplanting young bone marrow into aging animals? To answer this question, a research team at Sechenov First Moscow State Medical University in Russia conducted a monumental animal study in 2019.

The research team selected 76 mice with the same age and genetic lineage. These mice were divided into two groups, 20 mice for the control group and 56 mice for the experimental group. The experiment was performed on old mice aged 15 months, equivalent to 75 years old in human age – an age when approximately 50% of all the subject mice had already died. The mice of the experimental group received intravenous tail injections of 100 million bone marrow cells collected from young syngeneic donors. As a result, the lifespan of the mice in the experimental group increased up to 28±5% compared to the mice in the control group, and the duration of survival after bone marrow transplantation also increased by 2.8±0.3 times.

Figure 1. Effect of nonablative transplantation of syngeneic bone marrow of young donors on the population dynamics of aging recipients. Open circles, experimental group; black squares, control group; gray curve, Gompertz–Makeham curve of control group; black stepped curve, experimental group corrected for embolism (embolic animals excluded).

The mice in the experimental group not only showed lifespan extension but also a large difference in activity, as shown in the videos below. Video 1 shows a day before the death of the 19.3-month-old mouse who did not receive bone marrow transplantation. Video 2 shows an active appearance of 19.3-month-old mice that received young bone marrow. Both videos were recorded on the same day.

  Video 1. A day before the death of the mouse that did not receive bone marrow transplantation.

  Video 2. The appearance of the mice that had received young bone marrow transplantation.

Meanwhile, another study showed that the memory and learning abilities of old mice that had received young bone marrow transplants were significantly improved. Professor Helen S. Goodridge’s research team from Cedars-Sinai Medical Center in the United States divided old (18-month-old) mice into two groups and transplanted into each group the bone marrow of young (4-month-old) mice and old (18-month-old) mice. Six months later, both transplanted groups underwent standard laboratory tests of spatial and working memory, learning, and activity level. As a result, the performance of the old mice that had received bone marrow transplants from young donor mice was much better than the performance of other old mice that had received bone marrow transplants from old donor mice. Their performance also exceeded that of the old mice not transplanted with bone marrow.

The research team dissected these old mice and assessed their hippocampus, which is the memory center of the brain. The result showed that the number of synaptic networks connecting different neurons was significantly higher in the old mice that had received bone marrow transplants from young donor mice than in the old mice that had received bone marrow transplants from old donor mice. The neuron numbers were not significantly different between the two groups, but synaptic density was much higher in the old mice that had received bone marrow transplants from young donor mice. Synapses are signal transduction pathways that branch off from neurons and connect with the synapses of other neurons. The strength and number of synapses directly affect cognitive function.

The research team also evaluated microglia, which affect synapses. The activity and number of microglia were reduced in the old mice that had received bone marrow transplants from young donor mice. Microglia that account for 10-15 % of all cells in the brain are called the immune cells of the brain and central nervous system, as they engulf damaged neurons, foreign materials, and infectious agents while monitoring the environment. However, the excessive activity of microglia causes the adverse effect of pruning neurons’ synapses. The research team explained that neurons are healthier, and the number of synapses is better maintained with fewer hyperactive microglia.

Figure 2. Microglia in brains of old mice have larger cell bodies with fewer and shorter branches than those in young mice. But microglia of old mice who received bone marrow transplants (BMT) from young mice resembled those of young mice; transplants from older mice didn’t have that effect. Microglia play an important role in brain health. Illustration by Cedars-Sinai and Communications Biology.

What will happen if young heart cells are transplanted into aging animals?

If young bone marrow transplantation extended lifespan and significantly improved memory and learning, will aging animals’ hearts restore their youth when young heart cells are transplanted into their hearts?

The research team led by Dr. Eduardo Marbán of the Cedars-Sinai Heart Institute in the United States reported that heart function in old (22-month-old) rats became as young as heart function in young (4-month-old) rats when cardiosphere-derived cells, harvested from newborn rats, were transplanted into the hearts of the old rats.

The research team first measured basic heart function in 4-month-old and 22-month-old rats through echocardiograms, treadmill stress tests, and blood analysis. Then, they transplanted the cardiosphere-derived cells, harvested from the cardiac muscular tissues of newborn rats, into the hearts of the old (22-month-old) rats. A month later, they measured heart function in the rats with the same methods. As a result, heart function in all the old rats improved significantly and their exercise performance increased by an average of 20%. The old rats also grew hairs faster than other old rats not transplanted with the cells.

“The way the cells work to reverse aging is fascinating,” Dr. Marbán said. “They secrete tiny vesicles that are chock-full of signaling molecules such as RNA and proteins. The vesicles from young cells appear to contain all the needed instructions to turn back the clock.”

Figure 3. Schematic depiction of heart aging and proposed mechanisms whereby young CDCs exert anti-senescent effects. The process of aging is depicted in the upper row. Transplanted CDCs secrete exosomes (CDC-XO) which lead to cellular rejuvenation. In the heart, left ventricular hypertrophy (LVH) is attenuated and fibrosis is decreased, leading to improved diastolic function. Systemically, a reduction of the senescence-associated secretory phenotype (SASP) contributes to systemic benefits. Although not shown here, we cannot rule out remote effects of CDCs or CDC-secreted exosomes on target tissues, independent of SASP.

At Embryll, our purpose is to restore youth in aging pets by transplanting young cells into them.

All diseases are derived from cell senescence and depletion when viewed from the cellular level. For example, diabetes is caused by senescence or depletion of insulin secreting cells, and Parkinson’s disease is caused by senescence or depletion of dopamine secreting cells. Could diseases be naturally cured and aging pets become young again if we can repopulate aged tissues with young cells?

At Embryll, our purpose is to restore youth in aging pets by transplanting young cells into them. Young cells with the same DNA as aging pet’s DNA are what makes this possible. At Embryll, we manufacture these young cells using oocyte-based reprogramming and animal cloning technology.

First, oocytes are retrieved from young and healthy animals that are the same species as an aging pet. DNA in the retrieved oocyte is removed and replaced by the aging pet’s DNA. This cloned embryo is transferred into the uterus of an ovulating surrogate mother, and the embryo is developed to the stage of organ formation. The cloned embryo is retrieved from the surrogate mother, and various types of primary cells that will be used for transplantation are manufactured from this embryo.

These cloned embryonic primary cells manufactured using the above-mentioned methods do not elicit immune responses in recipients during cell transplantation because the DNA of the cells matches with the recipient’s DNA 100%. Additionally, the processes of manufacturing these cells do not involve artificial modification, unlike stem cell engineering, so they do not cause tumors or other side effects after cell transplantation. Most importantly, these cells are very young, given they originate from embryos, the early stage of life. Aging pets who receive these cloned embryonic primary cells will naturally regain youth.

Here is a detailed explanation of how these cloned embryonic primary cells that aid in reclaiming youth are manufactured and transplanted.

References

[1] Puspa Thapa, Rebecca S. Guyer, Alexander Y. Yang, Christopher A. Parks, Todd M. Brusko, Maigan Brusko, Thomas J. Connors, Donna L. Farber. Infant T cells are developmentally adapted for robust lung immune responses through enhanced T cell receptor signaling. Science Immunology, 2021; 6 (66) https://doi.org/10.1126/sciimmunol.abj0789

[2] Columbia University Irving Medical Center. Infant immune systems are stronger than you think, research shows: New study may help explain why infants are less affected by COVID than adults. ScienceDaily. ScienceDaily, 10 December 2021. https://www.sciencedaily.com/releases/2021/12/211210140720.htm

[3] Kovina MV, Karnaukhov AV, Krasheninnikov ME, Kovin AL, Gazheev ST, Sergievich LA, Karnaukhova EV, Bogdanenko EV, Balyasin MV, Khodarovich YM, Dyuzheva TG and Lyundup AV (2019) Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice. Front. Genet. 10:310. https://doi.org/10.3389/fgene.2019.00310

[4] Melanie M. Das, Marlesa Godoy, Shuang Chen, V. Alexandra Moser, Pablo Avalos, Kristina M. Roxas, Ivy Dang, Alberto Yáñez, Wenxuan Zhang, Catherine Bresee, Moshe Arditi, George Y. Liu, Clive N. Svendsen, Helen S. Goodridge. Young bone marrow transplantation preserves learning and memory in old mice. Communications Biology, 2019; 2 (1) https://doi.org/10.1038/s42003-019-0298-5

[5] Cedars-Sinai Medical Center. “Young bone marrow rejuvenates aging mouse brains: Transplanting marrow from young lab mice to old mice preserves memory and learning skills.” ScienceDaily. ScienceDaily, 20 February 2019. https://www.sciencedaily.com/releases/2019/02/190220103341.htm

[6] Lilian Grigorian-Shamagian, Weixin Liu, Soraya Fereydooni, Ryan C. Middleton, Jackelyn Valle, Jae Hyung Cho, Eduardo Marbán, Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats, European Heart Journal, Volume 38, Issue 39, 14 October 2017, Pages 2957–2967, https://doi.org/10.1093/eurheartj/ehx454

[7] Cedars-Sinai Medical Center. “Cardiac stem cells from young hearts could rejuvenate old hearts: Animal study reveals that cardiosphere-derived cells secrete tiny vesicles that could ‘turn back the clock’ for age-related heart conditions.” ScienceDaily. ScienceDaily, 14 August 2017. https://www.sciencedaily.com/releases/2017/08/170814104402.htm