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

    Bitto A, Kaeberlein M. Rejuvenation: It’s in Our Blood. Cell Metabolism 2014;20(1):2-4. http://www.cell.com/cell-metabolism/abstract/S1550-4131(14)00272-1

    It has been known for some time that blood from young mice can positively impact aged animals, while blood from old mice has the opposite effect. Recent studies report that rejuvenating effects of young blood extend to multiple tissues and have identified GDF11 and CCL11 as factors mediating these effects.

    GDF11, a member of the TGF-beta superfamily, declines in blood with age and restoration of youthful levels of GDF11 are sufficient to enhance stem cell and tissue function in heart.

    In contrast, blood levels of CCL11 increase with age, and this increase appears to contribute to the decline in neurogenesis and function of neural stem cells in the hippocampus.

    Now, two new studies have found that GDF11 also has beneficial effects on skeletal muscle, the subventricular nuclei, and the hippocampus. Supplementation with GDF11 alone restored skeletal muscle strength, physical endurance, and regeneration following injury in aged mice. Similarly, old mice treated with GDF11 had improved olfactory perception, brain vascularization, and neural stem cell function, which could translate into increased protection of the nervous system against age-related challenges.

    Conversely, injecting CCL11 impaired learning and memory in young mice, likely by reducing neurogenesis in the hippocampus. A CCL11-neutralizing antibody abrogated the negative effects of CCL11 treatment in young mice, although it was not reported whether the CCL11-neutralizing antibody alone could improve function in aged mice.

    These discoveries set the stage for interesting times, as many remaining questions begin to be answered and the translational potential is explored. It seems likely that GDF11 and CCL11 are only the first two in a series of circulating molecules that will be found to influence aging of different tissues. Whether these are the most important or most potent molecules remains to be seen. Future studies in this area will likely bring forth new and exciting knowledge about the dynamics of aging and novel approaches to regenerative medicine.
     
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  2. So if I do blood transfusions with my 2 year old nephew will I start to get younger ? Lol . Wishful thinking . ~Ogh
     
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  3. BIGMESC

    BIGMESC Member

    MiMi !!! Papa is taking our blood again.
     
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Laviano A. Young blood. N Engl J Med. 2014;371(6):573-5. http://www.nejm.org/doi/full/10.1056/NEJMcibr1407158

    Morphologic and Functional Changes Associated with “Young” Extrinsic Factors. The administration of young extrinsic factors to old animals — by means of parabiosis, plasma transfusion, or direct administration of growth differentiation factor 11 (GDF11) — results in the rejuvenation of aged organs and tissues, as revealed by the restoration of more youthful macroscopic and microscopic patterns.

    Morphologic changes translate into relevant functional improvement, including increased cognitive function and muscular performance.

    If confirmed in clinical trials, these results may substantially contribute to the treatment of many age-related diseases, including Alzheimer's disease and frailty, as well as clinically relevant syndromes, including disease-associated cachexia and muscle loss after prolonged bed rest.

    “Young” Extrinsic Factors.jpg
     
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  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Andersen RE, Lim DA. An ingredient for the elixir of youth. Cell Res. http://www.nature.com/cr/journal/vaop/ncurrent/full/cr2014107a.html

    Emerging evidence indicates that there are factors within the blood of young animals that have the ability to restore youthful characteristics to a number of organ systems in older animals.

    Growth/differentiation factor 11 (GDF11) is the first of such factors to be identified, and two new studies demonstrate that this “factor of youth” rejuvenates stem cells found in the skeletal muscle and brain of aged mice.

    GDF11 Rejuvenates Aged Skeletal Muscle and Brain

    (A) Heterochronic parabiosis, which couples the circulatory systems of a young and old mouse, can restore youthful properties to many aged organs.

    (B)Treatment with rGDF11 alone revitalizes the skeletal muscle and brain of aged mice, resulting in functional improvements in strength and odorant detection.

    GDF11 rejuvenates.jpg
     
    Millard Baker likes this.
  6. Good read Doc ... Very informative. Those poor mice continue to take one for the team. Successful clinical trials would definitely be ground breaking!
     
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Grifols to make a major equity investment in Alkahest
    http://www.prnewswire.com/news-rele...-equity-investment-in-alkahest-300045224.html

    -- Alkahest is a company founded in 2014 by leading scientists who demonstrated at Stanford University (US) that factors in the blood of young animals were able to restore mental capabilities in old animals

    -- Grifols acquires 45% of the equity of Alkahest for $37.5 million

    -- Alkahest and Grifols to work together to develop plasma-based products for the treatment of cognitive decline in aging and other central nervous system (CNS) disorders[1], including Alzheimer's

    -- Grifols to have commercialization rights to collaboration products

    About Alkahest

    Alkahest was established in 2014 by Drs. Tony Wyss-Coray and Karoly Nikolich to further develop and commercialize the pioneering work of Dr. Wyss-Coray, and other leading scientists at Stanford University who demonstrated that factors in the blood of young animals were able to restore mental capabilities in old animals. In their study published online May 4, 2014 in Nature Medicine the scientists characterized important molecular, neuroanatomical and neurophysiological changes in the brains of old mice that shared the blood of young mice. Alkahest is now conducting clinical studies to determine if this promising data in animals can be translated to humans. In addition to Grifols, Alkahest's investors include Bioville Investment Limited, Full House Investment Limited and Stanford University.
     
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  8. BBC3

    BBC3 Member

    Well when you consider real past practices in some cultures (at least I saw it in the movies).. Sacrifices, drinking blood, etc... For youth... DON'T LET SOME OF THESE WOMEN AT THESE PLASTIC SURGEONS OFFICES GET THIS NOTION....! They might skip the botox and EAT YOUR CHILD...

    But more seriously. Now WHAT does a unit of blood from a healthy 15 year old go for anyway? And how many to swap it ALL OUT?? 11,, 13..? I wonder. So then what is that market price if I was a 15 year old today...? The sick old fucker with the vampire fantasy advertising up on the corner... $500.00 bucks? I'd have done it for that back then if was guaranteed safe. One unit and out at the local blood bank supervising. Or at least a docs office where I knew others knew what was going on to protect me...

    I know blood can't just be siphoned and slammed. It has to be prepped in some way right? Checked for the details in compatibility.? I wonder the risk if all was right and tried to completely swap it out. What's the safe max amount you can transfuse in one sitting? LOL

    Makes you wonder WHO has connections at the Red Cross. And just WHAT the true perks are? Perhaps I am missing my calling....:confused::confused::confused::D
     
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  9. Millard Baker

    Millard Baker Member

    Amazing stuff. Thanks @Michael Scally MD for always sharing fascinating new research and keeping us abreast of developments.

    I feel fortunate to live in a time with science/technology advancing so rapidly.
     
  10. greenddog1

    greenddog1 Member

    Now I need to convince my grandkids blood transfusions are cool and fun to do.
     
  11. Nick9

    Nick9 Member

    Wow. That is a good read. I'm interested to see how far this is going to go, and when human trials will start.
     
  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration

    Highlights
    · GDF11 inhibits rather than helps muscle regeneration
    · A GDF11-specific immunoassay shows a trend to GDF11 levels increasing in human and rat sera
    · GDF11 blockade may be an appropriate treatment for muscle disease

    Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, et al. GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration. Cell Metabolism. http://www.sciencedirect.com/science/article/pii/S1550413115002223

    Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-β molecules myostatin and GDF11 in regeneration is unclear.

    Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies.

    We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific.

    We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age.

    Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice.

    Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.

    1-s2.0-S1550413115002223-fx1.jpg
     
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  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    BBC3 likes this.
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Sinha I, Sinha-Hikim AP, Wagers AJ, Sinha-Hikim I. testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 2014;357(3):815-21. http://link.springer.com/article/10.1007/s00441-014-1900-2

    As humans age, they lose both muscle mass and strength (sarcopenia). Testosterone, a circulating hormone, progressively declines in aging and is associated with loss of muscle mass and strength.

    The surgical joining of a young and old mouse (heterochronic parabiosis) activates Notch signaling and restores muscle regenerative potential in aged mice. We hypothesize that testosterone is at least one of the factors required for the improvement seen in muscles in old mice in heterochronic parabiosis with young mice.

    To test this hypothesis, we established the following heterochronic parabioses between young (Y; 5 months old) and old (O; 22-23 months old) C57BL6 male mice: (1) Y:O; (2) castrated Y:O (OY:O); (3) castrated + testosterone-treated Y:O (OY + T:O).

    A group of normal young mice received empty implants, and old mice were used as controls. Parabiotic pairings were maintained for 4 weeks prior to analysis. Serum testosterone levels were three-fold higher in young than in old mice.

    The OY + T:O pairing demonstrated significantly elevated levels of serum testosterone and an improvement in gastrocnemius muscle weight, muscle ultrastructure, muscle fiber cross-sectional area, and Notch-1 expression in old mice. These changes were not present in aged mice in the OY:O pairing.

    These data indicate that testosterone has a critical role in mediating the improved muscle mass and ultrastructure seen in an experimental model of heterochronic parabiosis.
     
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Castellano JM, Kirby ED, Wyss-Coray T. Blood-Borne Revitalization of the Aged Brain. JAMA Neurol. http://archneur.jamanetwork.com/article.aspx?articleid=2398915

    In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy.

    With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy.

    Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain.

    Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment.

    Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs.

    Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors.

    The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice.

    However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic.

    Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research.

    We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies.
     
  16. BBC3

    BBC3 Member

  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

     
  18. Isaac

    Isaac Member

    Hard to take the findings seriously when some of the research contradicts itself.
    Exciting regardless, I'm sure it has sufficient funding from just about any pharmaceutical company with half a brain for investment.
     
    Last edited: Aug 31, 2015
  19. glycomann

    glycomann Member

    I wonder what happens to GDF11 levels when on TRT and replacement GH?
     
  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Reduced Circulating GDF11 Is Unlikely Responsible for Age-dependent Changes in Mouse Heart, Muscle, and Brain

    Rodgers BD, Eldridge JA. Reduced Circulating GDF11 Is Unlikely Responsible for Age-dependent Changes in Mouse Heart, Muscle, and Brain. Endocrinology. http://press.endocrine.org/doi/abs/10.1210/en.2015-1628

    Recent high-profile studies report conflicting data on the age-related change in circulating growth/differentiation factor 11 (GDF11) and myostatin as well as the former's influence on muscle regeneration.

    Both ligands bind and activate ActRIIB receptors with similar affinities and should therefore have similar actions, yet these studies suggest that GDF11 activates muscle regeneration whereas myostatin is well known to inhibit it. They also suggest that circulating GDF11 levels, but not those of myostatin, decline with age.

    We performed a careful assessment of the ELISA used to quantify circulating myostatin in these studies and determined that assay reagents significantly cross react with each protein, each of which is highly homologous.

    Circulating myostatin levels decreased with age and estimates of GDF11 levels using myostatin null mice indicate that they were almost 500 times lower than those for myostatin.

    This suggests that circulating GDF11 has little physiological relevance as it could not outcompete myostatin for ActRIIB binding sites.

    Together, these results further suggest that the previously reported aging muscle, heart, and brain phenotypes attributed to reduced circulating GDF11 should be reconsidered.