Rejuvenation: It’s in Our Blood

Discussion in 'Men's Health Forum' started by Michael Scally MD, Jul 4, 2014.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [Mice] GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy

    RATIONALE: GDF11 (Growth Differentiation Factor 11) is a member of the transforming growth factor beta (TGFbeta) super family of secreted factors. A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH), and restoring GDF11 to normal levels in old mice rescued PCH.

    OBJECTIVE: To determine if and by what mechanism GDF11 rescues aging dependent PCH.

    METHODS AND RESULTS: 24-month-old C57BL/6 mice were given a daily injection of either recombinant (r) GDF11 at 0.1mg/kg or vehicle for 28 days. rGDF11 bioactivity was confirmed in-vitro.

    After treatment, rGDF11 levels were significantly increased but there was no significant effect on either heart weight (HW) or body weight (BW). HW/BW ratios of old mice were not different from 8 or 12 week-old animals, and the PCH marker ANP was not different in young versus old mice.

    Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle treated animals at baseline and remained unchanged at 1, 2 and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals.

    In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes (NRVM), to explore the putative anti-hypertrophic effects of GDF11, showed that GDF11 did not reduce NRVM hypertrophy, but instead induced hypertrophy.

    CONCLUSIONS: Our studies show that there is no age-related PCH in disease free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.

    Smith SC, Zhang X, Zhang X, Gross P, Starosta T, et al. GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy. Circ Res. http://circres.ahajournals.org/content/early/2015/09/17/CIRCRESAHA.115.307527.abstract
     
  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Antiaging Protein Is The Real Deal, Harvard Team Claims
    http://news.sciencemag.org/biology/2015/10/antiaging-protein-real-deal-harvard-team-claims

    One has to love the concluding comment:

    Houser says he agrees that one of the Novartis team’s assays for GDF11 was probably detecting immunoglobulin. David Glass makes the same point. Sorting out what role GDF11 may play in aging is important, HOUSER adds. “I'm going to be 65 in a couple months. I'd love to have something that improves my heart, brain, and muscle function,” Houser says. “I think the field is going to figure this out and this is another piece of the puzzle.”
     
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  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Rochette L, Zeller M, Cottin Y, Vergely C. Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacol Ther. http://www.sciencedirect.com/science/article/pii/S0163725815001989

    Members of the TGF-beta superfamily transduce their signals through type I and II receptor serine/threonine kinases.

    The regulation of members of the TGF-beta family is known to be complex, because many proteins able to bind the ligands and inhibit their activities have been identified.

    Growth and differentiation factor 11 (Gdf11) as activins belong to the TGF-beta family. GDF11, like other members of the TGF-beta superfamily, is produced from precursor proteins by proteolytic processing.

    The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins.

    GDF11 signal through the ActRIIB pathway.

    Recent studies have reported that GDF11-ActRIIB-Smad2/3-dependent signaling is a key regulatory mechanism in proliferating erythroid precursors as it controls their late-stage maturation.

    The administration of GDF11 is effective in experimental cardiac hypertrophy, and the identification of GDF11 as a "rejuvenating factor" opens up perspectives for the treatment of age-related cardiac dysfunction.

    Recent studies of the heart indicate that exposure to young blood reverses age-related impairments. GDF11 could be one of the circulating molecules that influence the aging of different tissues.

    Is GDF11 an "elixir of youth"?
     
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  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Sun H, Wang Y. The Elusive Philosopher's Stone in Young Blood. Circ Res 2015;117(11):906-8. http://circres.ahajournals.org/content/117/11/906.full


    Smith SC, Zhang X, Zhang X, et al. GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy. Circulation Research 2015;117(11):926-32. http://circres.ahajournals.org/content/117/11/926.full

    Rationale: Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family of secreted factors. A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH) and restoring GDF11 to normal levels in old mice rescued PCH.

    Objective: To determine whether and by what mechanism GDF11 rescues aging dependent PCH.

    Methods and Results: Twenty-four–month-old C57BL/6 mice were given a daily injection of either recombinant (r) GDF11 at 0.1 mg/kg or vehicle for 28 days. rGDF11 bioactivity was confirmed in vitro. After treatment, rGDF11 levels were significantly increased, but there was no significant effect on either heart weight or body weight. Heart weight/body weight ratios of old mice were not different from 8- or 12-week-old animals, and the PCH marker atrial natriuretic peptide was not different in young versus old mice. Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle-treated animals at baseline and remained unchanged at 1, 2, and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals. In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes, to explore the putative antihypertrophic effects of GDF11, showed that GDF11 did not reduce neonatal rat ventricular myocytes hypertrophy, but instead induced hypertrophy.

    Conclusions: Our studies show that there is no age-related PCH in disease-free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.
     
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [Open Access] Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation

    Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor beta superfamily and are often perceived to serve similar or overlapping roles.

    Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations.

    GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes.

    In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain.

    We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease.

    Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.

    Walker RG, Poggioli T, Katsimpardi L, et al. Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation. Circ Res 2016;118(7):1125-42. http://circres.ahajournals.org/content/118/7/1125.full
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [Open Access] Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

    This “Controversies in Cardiovascular Research” article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction.

    Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups.

    These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals.

    One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known.

    The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies.

    There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals.

    There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies.

    Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect.

    Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.

    Harper SC, Brack A, MacDonnell S, et al. Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Circulation Research 2016;118(7):1143-50. Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?
     
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Rodgers BD. The Immateriality of Circulating GDF11. Circ Res 2016;118(10):1472-4. The Immateriality of Circulating GDF11

    Recent portrayals of growth differentiation factor (GDF)-11 as an endocrine fountain of youth fail to consider the competitive influences of myostatin, a homologous protein with true endocrine action that binds the identical receptor, activin receptor IIb (ActRIIb).

    Subsequent studies have disproven the original premise that circulating levels of GDF11, but not those of myostatin, decline with age as the exact opposite seems to be true.

    These latter studies also seriously question the validity of data presented in the previous reports and indicate that myostatin circulates at levels 500× greater than those of GDF11; yet, both ligands share nearly identical affinities for ActRIIb.

    The compromised striated muscle function, neurogenesis, and vascular remodeling that occur with advanced age are, therefore, not caused by reduced circulating GDF11 as it could never outcompete myostatin for shared receptor-binding sites.


     
  8. antipcman

    antipcman Member AnabolicLab.com Supporter

  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Schafer MJ, Atkinson EJ, Vanderboom PM, et al. Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease. Cell Metab 2016;23(6):1207-15. http://www.sciencedirect.com/science/article/pii/S1550413116302455

    Growth and differentiation factor 11 (GDF11) is a transforming growth factor beta superfamily member with a controversial role in aging processes.

    We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homolog, myostatin (MSTN), based on unique amino acid sequence features.

    Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging. Neither GDF11 nor MSTN levels differ as a function of age in healthy women.

    In an independent cohort of older adults with severe aortic stenosis, we show that individuals with higher GDF11 were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, higher GDF11 at surgical baseline was associated with rehospitalization and multiple adverse events.

    Cumulatively, our results show that GDF11 levels do not decline throughout aging but are associated with comorbidity, frailty, and greater operative risk in older adults with cardiovascular disease.
     
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  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Glass DJ. Elevated GDF11 Is a Risk Factor for Age-Related Frailty and Disease in Humans. Cell Metab 2016;24(1):7-8. http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30303-5

    GDF11 was reported to decline with age and to have muscle and heart rejuvenating effects. These reports were disputed. A Cell Metabolism paper now shows that in human beings, GDF11 does not decline with age and is actually a risk factor for frailty and other morbidities (Schafer et al., 2016).

    GDF11 Total Protein Levels and Mechanism

    Myostatin, GDF11, and activin signal through the ActRII/Alk4,5 complex, inducing SMAD2 and SMAD3 phosphorylation. This results in a decrease in skeletal muscle growth. Schafer et al. (2016)) find high levels of GDF11 to be associated with frailty and other co-morbidities of the aged. In human beings, GDF11 is not regulated by age, whereas myostatin decreases in males.

    GDF11 Total Protein Levels and Mechanism.jpg
     
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  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Highlights
    • Immunoplexed liquid chromatography mass spectrometric assessment of GDF11 and MSTN
    • Circulating GDF11 levels do not change in healthy adults throughout the lifespan
    • Previous reports of declining GDF11 levels may correspond to changes in MSTN
    • In CVD, GDF11 is associated with comorbidity, frailty, and post-operative outcomes
    Schafer MJ, Atkinson EJ, Vanderboom PM, et al. Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease. Cell Metabolism 2016;23(6):1207-15. http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30245-5

    Growth and differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in aging processes.

    We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homolog, myostatin (MSTN), based on unique amino acid sequence features.

    Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging. Neither GDF11 nor MSTN levels differ as a function of age in healthy women.

    In an independent cohort of older adults with severe aortic stenosis, we show that individuals with higher GDF11 were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, higher GDF11 at surgical baseline was associated with rehospitalization and multiple adverse events.

    Cumulatively, our results show that GDF11 levels do not decline throughout aging but are associated with comorbidity, frailty, and greater operative risk in older adults with cardiovascular disease.
     
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  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Peter Thiel Is Very, Very Interested in Young People's Blood
    The contrarian venture capitalist believes transfusions may hold the key to his dream of living forever.
    Peter Thiel Is Very, Very Interested in Young People's Blood

    More than anything, Peter Thiel, the billionaire technology investor and Donald Trump supporter, wants to find a way to escape death. He's channeled millions of dollars into startups working on anti-aging medicine, spends considerable time and money researching therapies for his personal use, and believes society ought to open its mind to life-extension methods that sound weird or unsavory.

    Speaking of weird and unsavory, if there's one thing that really excites Thiel, it's the prospect of having younger people's blood transfused into his own veins.

    That practice is known as parabiosis, and, according to Thiel, it's a potential biological Fountain of Youth--the closest thing science has discovered to an anti-aging panacea. Research into parabiosis began in the 1950s with crude experiments that involved cutting rats open and stitching their circulatory systems together. After decades languishing on the fringes, it's recently started getting attention from mainstream researchers, with multiple clinical trials underway in humans in the U.S. and even more advanced studies in China and Korea.

    Considering the science-fiction promise of parabiosis, the studies have received notably little fanfare. But Thiel has been watching closely.

    Thiel and Ambrosia.

    In Monterey, California, about 120 miles from San Francisco, a company called Ambrosia recently commenced one of the trials. Titled "Young Donor Plasma Transfusion and Age-Related Biomarkers," it has a simple protocol: Healthy participants aged 35 and older get a transfusion of blood plasma from donors under 25, and researchers monitor their blood over the next two years for molecular indicators of health and aging. The study is patient-funded; participants, who range in age from late 30s through 80s, must pay $8,000 to take part, and live in or travel to Monterey for treatments and follow-up assessments.

    Ambrosia's founder, the Stanford-trained physician Jesse Karmazin, has been studying aging for more than a decade. He became interested in launching a company around parabiosis after seeing impressive data from animals and studies conducted abroad in humans: In one trial after another, subjects experience a reversal of aging symptoms across every major organ system. While the mechanisms at play aren't totally understood, he said, young organisms' blood not only contains all sorts of proteins that improve cell function; somehow it also prompts the recipients' body to increase its production of those proteins.

    "The effects seem to be almost permanent," he says. "It's almost like there's a resetting of gene expression."

     
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  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Young Blood Antiaging Trial Raises Questions
    http://www.sciencemag.org/news/2016/08/young-blood-antiaging-trial-raises-questions

    It was one of most mind-bending scientific reports in 2014: Injecting old mice with the plasma portion of blood from young mice seemed to improve the elderly rodents’ memory and ability to learn. Inspired by such findings, a startup company has now launched the first clinical trial in the United States to test the antiaging benefits of young blood in relatively healthy people. But there's a big caveat: It's a pay-to-participate trial, a type that has raised ethical concerns before, most recently in the stem cell field.

    The firm’s co-founder and trial principal investigator is a 31-year-old physician named Jesse Karmazin. The company, Ambrosia in Monterey, California, plans to charge participants $8000 for lab tests and a one-time treatment with young plasma.

    The volunteers don’t have to be sick or even particularly aged—the trial is open to anyone 35 and older. Karmazin notes that the study passed ethical review and argues that it’s not that unusual to charge people to participate in clinical trials.

    To some ethicists and researchers, however, the trial raises red flags, both for its cost to participants and for a design that they say is unlikely to deliver much science. “There's just no clinical evidence [that the treatment will be beneficial], and you're basically abusing people's trust and the public excitement around this,” says neuroscientist Tony Wyss-Coray of Stanford University in Palo Alto, California, who led the 2014 young plasma study in mice.

     
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  14. Kakarot

    Kakarot Member AnabolicLab.com Supporter

  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Rebo J, Mehdipour M, Gathwala R, et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature Communications 2016;7:13363. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood : Nature Communications

    Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear.

    Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis.

    Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects.

    We also explore mechanistic explanations, including the role of B2M and TGF-beta.

    We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.

     
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  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Questionable “Young Blood” Transfusions Offered in U.S. as Anti-Aging Remedy
    This startup takes cash from aging adults in exchange for young people’s blood

    A startup called Ambrosia will fill your veins with the blood of young people and empty your pockets of $8,000.



    Jesse Karmazin is the entrepreneur who made the practice possible, by launching a clinical trial on the potential of “young blood” through his startup Ambrosia. Ambrosia Clinical Trial

    He says that within a month, most participants “see improvements” from the one-time infusion of a two-liter bagful of plasma, which is blood with the blood cells removed.

    Several scientists and clinicians say Karmazin’s trial is so poorly designed it cannot hope to provide evidence about the effects of the transfusions. And some say the pay-to-participate study, with the potential to collect up to $4.8 million from as many as 600 participants, amounts to a scam.

    What's certain is that it’s based on some intriguing if inconclusive science. Karmazin, a 32-year-old Princeton graduate and competitive rower, says he was inspired by studies on mice that researchers had sewn together, with their veins conjoined, in a procedure called parabiosis.

     
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation

    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-beta 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.

    Conese M, Carbone A, Beccia E, Angiolillo A. The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation. Open Med (Wars) 2017;12:376-83. The Fountain of Youth: A tale of parabiosis, stem cells, and rejuvenation : Open Medicine
     
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  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Role of Growth Differentiation Factor 11 In Development, Physiology and Disease

    Growth differentiation factor (GDF11) is a member of TGF-beta/BMP superfamily that activates Smad and non-Smad signaling pathways and regulates expression of its target nuclear genes.

    Since its discovery in 1999, studies have shown the involvement of GDF11 in normal physiological processes, such as embryonic development and erythropoiesis, as well as in the pathophysiology of aging, cardiovascular disease, diabetes mellitus, and cancer.

    In addition, there are contradictory reports regarding the role of GDF11 in aging, cardiovascular disease, diabetes mellitus, osteogenesis, skeletal muscle development, and neurogenesis.

    In this review, we describe the GDF11 signaling pathway and its potential role in development, physiology and disease.

    Zhang Y, Wei Y, Liu D, et al. Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget 2017;8(46):81604-16. http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=20258&path[]=64598
     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Young blood as anti-aging fountain of youth: hype or hope?
    Young blood as anti-aging fountain of youth: hype or hope? - The Niche



    The idea behind young blood helping the old fight aging has been around for a long time, recently mostly supported by studies in mice including parabiosis work (where a young and old mouse are literally sewn together so as to share a circulatory system) that reported some anti-aging effects. What about humans? Who knows? I’ve include reference to key papers at the bottom of this post. Overall, I just don’t think the data is there.



    Overall, there may be some real potential here conceptually with young blood or ‘young cells’ or specific compounds from them having anti-aging properties. The data so far are promising in animals, but this is one of those cases where hype is at risk of taking over an area of translational research and many people getting hurt. Yes, let’s study this concept carefully, but in my view you shouldn’t charge for it nor expose hundreds of people to risks in a single trial with little if any human data to support it.
     
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  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [OA] Aging, Disease, and Therapeutic Apheresis

    The greatest risk factor for nearly every major cause of mortality in developing nations is aging. In studies on aging, the primary objective is to improve the quality of life, not necessarily with the goal of extending life for a much longer period, but by combating disease.

    Some notable ways for doing such are discussed in a recent article and include:
    · reversing genome damage caused by aging, diet, and environmental factors;
    · researching new tissue and blood;
    · restricting caloric intake; and
    · reprogramming senescent cells.

    Rapamycin, an immunosuppressive drug, has been shown to extend life in mice. Studies on resveratrol in cell cultures and in animals have shown that it protects against inflammation, oxidative stress, and cancer and it seemingly extended the life span of worms.

    Senescent cells are cells that are programmed to stop dividing if they are in danger of becoming cancerous but are active to stimulate regeneration and repair. While they no longer divide, they continue to secrete signaling molecules as inflammation causing factors.

    Groups of senescent cells can produce such high levels of these chemicals that other normal cells turn senescent. This secreted cocktail can activate a variety of age‐related pathologies including heart disease and some types of cancer.

    A common feature of senescent cells is the accumulation of abnormal or damaged proteins in their cytosol that impairs cellular function. Protein accumulation results in part from impaired protein degradation with age. Most of the proteins that are responsible for different diseases and ageing need to be identified. Therapeutic approaches are developed to target and reprogram these cells and to deactivate them.

    · IS THERE A ROLE FOR THERAPEUTIC APHERESIS IN THE REMOVAL OF SUCH ABNORMAL OR DAMAGED PROTEINS?

    · REMOVE THE “BAD” AND/OR REPLACE WITH THE “GOOD”?

    · WHILE MORE RESULTS MAY BE FORTHCOMING FROM THESE TRIALS IN ALZHEIMER’S DISEASE PATIENTS, A MAJOR QUESTION STILL EXISTS: IS IT MORE IMPORTANT TO REMOVE THE “BAD” MOLECULES OR REPLACE WITH THE “GOOD”? ARE CRYOGLOBULINS ONE OF THE “BAD” MOLECULES?

    · CAN THERAPEUTIC APHERESIS SUPPORT OUR BIOLOGY TO IMPROVE LONGEVITY OR DECREASE MORBIDITY AND MORTALITY?

    · CAN THERAPEUTIC APHERESIS PLAY A ROLE IN EXTENDING LIFE AS WELL AS THE TREATMENT OF DISEASES? CAN THE REMOVAL OF PATHOGENIC MACROMOLECULES SERVE AS “ARTIFICIAL SENESCENT CELLS” TO RESTORE NORMAL DETOXIFICATION FUNCTIONS THAT DUE TO AGING AND DISEASE HAVE BECOME DEFICIENT AND INEFFECTIVE AND DISEASE CAUSING?

    Malchesky PS. Aging, Disease, and Therapeutic Apheresis. Therapeutic Apheresis and Dialysis 2018;22:312-6. https://onlinelibrary.wiley.com/doi/10.1111/1744-9987.12706