Re: [GRG] Kidney donor ages…

Hi Harold,

You raise a number of good points, and I think some of the answers, in general terms at least, may be inferable from the existing literature.

I think that cellular “rejuvenation” is likely dependent upon both molecular signaling from young cells and on the environmental/cellular milieu. Another of the huge failures in translational research has been comparative lack of efficacy of stem cell treatments in humans. The bulk of these experiments were done in adult, but not old mice, and it is increasingly well established that the condition of the stem cell niches is critical for successful engraftment, proliferation and resumption of normal, youthful, stem cell function. 

Conversely, administration of mesenchymal stem cells into older mice with experimentally induced osteoporosis not only effectively treats their osteoporosis, but pretty dramatically extends their mean and maximum lifespan:  http://ift.tt/18XnGhE

Effect of BMSCs transplantation on the life span of Balb/c mice.

(A) The lifespan of mice without (control, n = 10) and with BMSCs transplants from either young (n = 14) or old mice (n = 10). (B) The mean survival time of control animals vs. BMSCs transplanted mice. Kaplan-Meier Log Rank pairwise comparison statistics revealed significant differences of lifespan between the control and young BMSCs transplantation groups (p = 0.009), and between young BMSC transplantation and old BMSCs transplantation groups (p = 0.002). There was no significant difference between the control and old BMSCs transplantation groups (p = 0.846). **: p<0.01.

The data above are pretty dramatic and, given that the administration of stem cells was not undertaken until the animals were over 600 days old, this indicates that aged niches are not an absolute contraindication to stem cell engraftment, survival or the ability of the transplanted cells to effect not only rejuvenation (reversal of osteoporosis) but also to dramatically extend both mean and maximum lifespan. When looking at the data above, it's important to keep in mind that these were old mice when the Tx was given! 

However, the reverse also seems true, in that short lived, non-dividing cells, in this case cerebellar neuron's, placed in the brains of longer lived animals take on the aging rate of the longer lived host, as has been shown by the work of Magrassi, et.,al. They transplanted fetal mouse neuron's into the brains of adult rats. The rats used for this study live twice as long the mice whose neuron's were engraft into the brains of the adult rats. The mouse neurons survived in situ in the rats for twice as long as the mean lifespan of the animals from which they were taken, which is also, of course, well over the maximum lifespan for this strain of mouse: http://ift.tt/1MeYRfc, clearly the cellular milieu has a large potential impact on the aging and survival of the cells that inhabit it. Thus, aging appears to be a two way street in this regard, with both the cellular milieu and the cells themselves contributing importantly to cell lifespan and to cellular rejuvenation potential.

The critically important things about fetal-maternal chimerization that I feel have been consistently overlooked by the anti-aging community are theses:

1) Fetal cells routine chimerize pregnant females and remain present, presumably mostly in the quiescent state, throughout the remainder of the mother's lifespan.

2) Fetal stem cells can and do act to repair damage, minor or serious, to injured maternal organs during pregnancy, and perhaps beyond.

3) Fetal stem cells, even those from embryos unrelated to the mother, engraft, survive and function without inducing an adverse immune reaction from the mother, or graft vs. host disease in the mother.

So, to directly answer your question about how mothers handle colonization by fetal stem cells, the answer is that, with one possible caveat, they tolerate them just fine. There is even speculation that some of the increased longevity of females seen across multiple species may be due to what is effectively "fetal stem cell therapy" given during the reproductive period. 

The caveat is that it has long been known that women suffer a disproportionately higher incidence of some kinds of auto-immune diseases during their childbearing years and afterwards, and there is emerging evidence that some or all of this may be due to fetal-maternal chimerism. Very interestingly, the amount of fetal-maternal chimerism is greatly increased if the fetus is not carried to term, as is the case with abortion. Since the legalization of abortion roughly 40 years ago, there has been a steadily rising incidence of these autoimmune disorders in women of childbearing age. Miech, has proposed that this phenomenon is due to maternal colonization by immature fetal progenitor T-cells:  http://ift.tt/18XnHSH this hypothesis is the fact that male fetal cells have been found in the synovial fluid of women with Rheumatoid arthritis. 

Still, this occurs in a tiny minority of women who undergo abortions and it should be fairly easy to remove fetal progenitor T and B stem cells, or otherwise exclude them from the population of stem cells that is to be subjected to expansion post retrieval, in vivo, before they are administered to the recipient. And, even if this were not the case, the projected lifespan of an elderly human, particularly an individual who is not aging well and who is suffering from age associated degenerative disease(s) is so short, and the quality of life so compromised, it is hard to see how treatment with allogenic fetal stem cells would differ from bone marrow transplant, which is used a the raft of terminal and debilitating diseases and for which it is currently accepted therapy, despite the considerable risk of graft vs. host disease. Given that there are 219 abortions per 1,000 live births in the U.S. alone (almost all first trimester), there is no shortage of fetal stem material of diverse tissue types: 

http://ift.tt/1MeYRfg the Russian Federation there are currently about 42 abortions per 100 live births: http://ift.tt/18XnHSJ

Roy and I have tried repeatedly to interest investigators who have the facilities to rapidly evaluate the efficacy of this approach to near term rejuvenation in relevant animal models, such as rats and dogs, with no success. No specific objections have been raised, which leads me to believe that the problem is simply a lack of perception of the likely workability and enormous potential of this approach. Another likely "cognitive blocking" factor is the confusion of fetal stem cells with embryonic stem cells. They could not be more different! Embryonic stem cell transplants result in multiple adverse complications, most notable and intractably, teratoma formation. This does NOT happen when fetal cells are transplanted, probably as a result of their greater degree of differentiation. 

I would further note that HLA and D-locus matching of fetal stem cells to the recipient should further reduce the risk of graft vs. host like autoimmune diseases. It's also worth noting that RA and related T-cell (and even B-cell) mediated disease are increasingly yielding to therapeutic interventions with advent of a range of MAB drugs, combined with traditional cytotoxic and steroid chemotherapy at much reduced doses. Treatment for these disorders is now much more successful than is treatment for graft vs. host disease in marrow, or solid organ transplant recipients. Considering the terrible morbidity and completely lethality of old age, fetal stem cell Tx would seem less risky, and would certainly seem as justified (on the basis of both prognosis and morbidity burden), as does bone marrow transplantation for hematologic and genetic diseases.

Mike Darwin

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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