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Discussions of Stem Cell Rejuvenation


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#1 reason

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Posted 17 February 2017 - 10:06 PM


Earlier this week I noticed a couple of very readable open access papers in which the authors discuss the potential for rejuvenation of stem cells as a means to address some aspects of aging. Reversing age-related stem cell decline has long been a topic of considerable interest in the broader longevity science and advocacy communities, ever since the stem cell medicine industry started up in earnest. Indeed, back in the early days of SENS rejuvenation research advocacy, when stem cells were in the news every other week, it was frequently necessary to emphasize that stem cell repair and replacement was just one of a range of necessary approaches to the treatment of aging. Even if an individual's stem cells were somehow perpetually kept in pristine condition, the other forms of cell and tissue damage that lie at the root of aging would still result in degeneration and death. The degree of benefit achieved from fixing just one type of damage is an open question - we will most likely only find out some years after the relevant therapies become widely available, as is about to happen for senescent cell clearance.

Stem cells and their supporting structures are, of course, important in the aging process. Stem cells are responsible for generating replacement somatic cells needed to keep tissues functioning, but with advancing age the supply of new cells dwindles. This decline is one of the causes of frailty and organ failure. At present it looks likely that the changes in stem cell activity are as much a matter of altered cell signaling as of damage to the stem cells themselves. Temporarily restored signaling may be one of the means by which cell therapies produce benefits, by putting native cells back to work. Why does signaling change with aging, however? From an evolutionary perspective this reaction to rising levels of damage may exist because it serves to reduce cancer risk and thereby lengthen life, at the cost of a slower demise through organ failure, though programmed aging advocates would argue that stem cell decline is selected to promote aging as a fitness strategy. From a purely mechanical perspective, it is still up for debate as to the degree to which stem cell declines are secondary to the other forms of molecular damage and waste accumulation outlined in the SENS view of aging. It isn't unreasonable to think that comprehensive repair elsewhere would lead to some degree of renewed stem cell activity as the signaling environment becomes more youthful.

Rejuvenating stem cells to restore muscle regeneration in aging

Adult muscle stem cells, originally called satellite cells (SCs), are essential for muscle repair and regeneration throughout life. Besides a gradual loss of mass and function, muscle aging is characterized by a decline in the repair capacity, which blunts muscle recovery after injury in elderly individuals. A major effort has been dedicated in recent years to deciphering the causes of SC dysfunction in aging animals, with the ultimate goal of rejuvenating old SCs and improving muscle function in elderly people. The emerging evidence indicates that the functional and numerical loss of SCs is a progressive process occurring throughout the lifetime of the organism. The long-lived quiescent SC accumulates many lesions caused by loss of homeostasis, metabolic alterations, and the aging environment. Although this process is gradual, it is accelerated in advanced old age to the extent that SCs become practically non-functional owing to senescence or apoptosis. In this context, disputes about which factors, intrinsic or extrinsic, are more dominant in dictating the fate of old SCs seem misplaced, and it is likely that both make important contributions to SC functional decline with aging.

A degree of success has been obtained in restoring the regenerative capacity of old muscle with both parabiosis experiments (extrinsic effect) and transplantation of ex vivo-rejuvenated SCs into old animals (intrinsic effect). The simplest explanation for these effects is the heterogeneous nature of SCs. Even in old age, the SC population includes a small percentage of functional SCs, with only limited accumulated damage that can be reversed still by extrinsic signaling factors or by ex vivo pharmacological inhibition of stress pathways such as p38 MAPK or JAK/STAT3. It is thus likely that the success of biochemical or genetic strategies applied to old SCs in transplantation experiments results from the proliferative amplification of a subset of highly regenerative cells. Alternatively, the health and fitness of old SCs could be increased by refueling "clean up" activities such as autophagy (which declines with aging) to eliminate damage, thus improving SC regenerative capacity after muscle injury and in transplantation procedures. Future interventions that could also be considered for combating age-related muscle regenerative decline may utilize the restoration of SC-niche interactions via the delivery of bioengineered molecules.

The key finding that the SC pool enters a state of irreversible senescence at a geriatric age implies that any treatment to rejuvenate endogenous stem cells should be implemented before this point of no return. It is also important to consider the link between SC regenerative potential and quiescence. It is generally well accepted that the more quiescent a stem cell is, the more regenerative capacity it has. It has also become clear that somatic stem cell populations are heterogeneous, with cells showing differing levels of quiescence. Highly quiescent subpopulations probably change with aging to become less quiescent and therefore of reduced regenerative capacity. SC heterogeneity should therefore be further investigated, with the aim of deciphering the molecular basis of quiescence. Understanding the quiescent state will allow early intervention aimed at preserving the highly regenerative quiescent subpopulations throughout life.

Likewise, strategies directed towards the expansion of relevant subpopulations of resident progenitor cells in the SC niche may be envisioned for reversing the age-associated muscle regenerative loss. Another unresolved issue is the interaction among the various events contributing to the loss of SC regenerative potential with aging. Research needs to focus on determining which events are causative and which are consequential. For example, DNA damage may induce the loss of baseline autophagy flux in old SCs, or alternatively DNA damage may be the consequence of oxidative stress resulting from the loss of autophagy flux. Defining the hierarchy of events leading to SC deterioration will enable the targeting of upstream events in order to achieve more efficient rejuvenation of SCs. Last but not least, in a low-turnover tissue like muscle, much of the damage to the quiescent SC is the result of the gradual decline (aging) of the niche composition and the systemic system. Future efforts to rejuvenate the regenerative potential of SCs should thus adopt a holistic view of the SC and its supportive environment.

Preventing aging with stem cell rejuvenation: Feasible or infeasible?

Preventing pathological conditions caused by aging, including cancer, osteoporosis, sarcopenia, and cognitive disorders, is one of the most important issues for human health, especially in societies with large aging populations. Although aging, defined by functional decline of cells/organs or accumulation of cell/organ damage, is one of the most recognizable biological characteristics in all creatures, our understanding of mechanisms underlying the aging process remains incomplete. The primary cause of functional declines occurring along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Stem cell exhaustion is induced by several mechanisms, including accumulation of DNA damage and increased expression of cell cycle inhibitory factors, such as p16 and p21.

Meanwhile, aging at cellular, tissue, organ and organismic levels has been reversed by exposing tissues from old animals to a young environment. Recent studies have suggested that stem cell rejuvenation could reverse organismal aging phenotypes, and that this could be achieved by inhibiting fibroblast growth factor 2, mammalian target of rapamycin (mTOR) complex 1, guanosine triphosphatase and cell division control protein 42. Several additional experiments, such as cross-age transplantation and heterochronic parabiosis, have revealed that some factors in the young systemic milieu can rejuvenate declined thymus gland function, as well as neural and muscle stem cell functions, in samples derived from elderly donors. Furthermore, heterochronic parabiosis experiments have also shown strong inhibition of young tissue stem cells by the aged systemic milieu or old serum.

Although cumulative cellular "intrinsic changes", such as DNA damage, oxidative damage, increased expression of cell cycle inhibitors and mitochondria dysfunction, have been considered likely culprits for the tissue decline observed with aging, cellular rejuvenation induced by young systemic milieu would have been impossible if "intrinsic changes" were the only cause of cellular aging. Therefore, these so-called "causes of aging" should be more properly regarded as effects of aging (i.e., these processes are not causes, but rather consequences of aging), the result of cellular decisions often defined by responses to "extrinsic stimuli". Here some questions arise: If aging at the cellular level were reversed, would it lead to the rejuvenation of the animal at an organismic level? Would it result in prevention of aging and, eventually, life extension?


View the full article at FightAging
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#2 VanWinkle

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Posted 30 June 2017 - 11:11 PM

Here is a first hand report on my husband Doug's expanded autologous (your own cells) mesenchymal stem cell therapy at Celltex.

 

He had painful distorted finger joints, possibly rheumatoid arthritis, and an old hip injury. All of these problems resolved, and he experienced many rejuvenating effects he wasn't even anticipating.

 

 
Doug's health improvements from this therapy
In 2010 he saw an orthopedist for left hip pain, as he could barely raise his leg w/o sharp pain. The doctor advised to start cortisone injections, but that Doug would likely need a hip replacement in a few years. Doug didn't want to take the risk of cortisone, and kept dealing w/ the pain.
 
We heard about Celltex in Houston 2012 and started talking with some of the first patients, as well as Dr. Stanley Jones. The expanded dose method sounded like what the institutional trials were doing, like Mayo Clinic, Cleveland Clinic, Univ. Miami and others, rather than the lower dose that could be obtained at clinics in the U.S. 
 
Age 58, 1st Celltex treatment Aug. 2012, 2 IV infusions, 1 week apart, each IV 200 million autologous mesenchymal stem cells (MSC). He also had a direct hip injection of 50 million MSCs.

 

Results were not immediate, but started to show up after about 5 months.
*At 5 months Rheumatoid arthritis hand/finger pain gone, strength and dexterity back
*Painful hip better, more flex, can squat down to floor and stand up.
 
He wasn't expecting any of the improvements in these other conditions:
*Lower back pain gone (from herniated disk 2008) 
*Severe gout of 40 years resolved, big toes no loner swollen and painful
*Sleep through the night, don't get up to urinate 
*Increase in libido, back to his 20's
*Energy high, rarely take naps anymore 
*Skin smoother, fewer wrinkles 
*Fewer migraines for 3 years
*Claustrophobia and fear of heights gone (which came on suddenly in 2002 after he took Celexa for 4 months and quit without tapering off).
*After a few months could swing leg up over the back of a high back chair, about 4 feet.
  *Now at age 62, can do high martial arts kicks again, like in his 20's
Here is Doug showing the good results, this was 2015, 3 years after treatment Stem Cells for Orthopedic Conditions
There are many clinics in the U.S. that do "same-day" stem cells, they take 8 oz of fat via liposuction, centrifuge the cells, then give them back via IV. But you only get about 10 million MSCs  this way. Patients get some relief for a few months, but it doesn't last because the dose is too low. And if you need another dose, they have to repeat the 8 oz liposuction. Same for orthopedics, you have to get get repeat treatments in a year or so, with stem cell extraction each time. 
 
With Celltex, they bank your cells for life, after a mini-liposuction of 2 oz of fat. Then when you need a dose, they expanded the stem cells in the lab, so you get an IV of 200 million MSC, compared to the same day clinics that charge $16,000 for the 10 million MSCs per IV. 
Celltex uses adipose derived cells for orthopedic treatments like Doug had and it turns into new cartilage too. It doesn't have to be homologous between cell source and treated area. Our friend Cassi's knees were bone-ob-bone, after injection the pain stopped immediately, and w/i 7 months an xray showed 5mm new cartilage. This has lasted since 2012 too. Much nicer than a knee replacement surgery, and less expensive.
They also treat various neurodegnerative, autoimmune and other conditions with IV treatments.
 
This truly is the medicine of the future. 

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#3 SearchHorizon

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Posted 02 July 2017 - 05:53 AM

As I noted in another thread (maximizing stem cell proliferation), stem cells can be partly rejuvenated by NAD+ replenishment, using NAD+ precursors.

 

I don't think rejuvenating stem cells is enough, to see stronger anti aging effect. One has to drive the rejuvenated stem cells to divide. We can provide the proper stimulation (though intermittent fasting or exercise) for the stem cells to divide, but with aging, the mechanism for TRANSLATING the stimuli into a rejuvenating response breaks down. As far as we know, NAD+ replenishment is the only thing that improves this situation.

 

 

 



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#4 Evan Yang

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Posted 14 August 2017 - 12:13 PM

NAD+ will rejuvenate stem cells and reduce senescence of stem cells. It is better to supplement NAD+ precursors early in life from 35 before most of the stem cells already died. The purpose is to keep a majority of the stem cells to replace senescent cells. 

 

 


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