In-vivo cell reprogramming for longer lives

This blog entry unifies three themes that have repeatedly been expressed in this blog: 1.  The possibility of extending lives via using “rebooted” cells, that is induced pluripotent stem cells (iPSCs), 2.  the key role of epigenetic factors in determining the health and longevity of cells, and 3. the health-producing and possibly life-extending properties of certain phytochemicals like curcumin and resveratrol.  Recent publications suggest that many of the same biological pathways involved in reprogramming cells to iPSCs are involved in aging, of course running in reverse.  Further, the publications suggest that substances like rapamycin and phytochemicals which generate health and possibly extend lives also drive the aging clocks in those pathways in reverse.

The October 2011 publication Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells reports that health and longevity promoting compounds increase the efficiency of IPSC creation.“ Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. This seminal work was followed by numerous studies reporting alternative (noninsertional) reprogramming methods and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency.  Here we report that inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition, the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. We further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin), and an activating adenosine monophosphate-activated protein kinase activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. Our results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity based on the regulation of cellular reprogramming.”

An earlier (August 2011) report by some of the same authors, Drs.  Zhao and Pei, is Why Cell Reprogramming is Functionally Linked to Aging? “Stem cell research meets aging research. Recent findings indicate that cell reprogramming share some regulatory mechanisms with aging. Modulation of epigenetic enzymes, blockage of TGF-β, MEK, and GSK3b cascades, as well as avoidance of oxidation can enhance the generation of iPSCs. Interestingly, dysfunction of these pathways has been considered as a cause of aging. Our latest study adds one more evidence that inhibition of IGF/PI-3K/mTOR pathway, activation of sirtuin, induction of autophagy, which all associate with increased longevity and the delayed onset of age-related disorders, promote somatic cell reprogramming. — These parallels could not be merely coincident. Organism aging involves decline of self-renew compartment function and somatic stem cell replication, which might be deteriorated by external aging-cues or aged stem cell niche [7]. Telomere dysfunction and/or DNA damage which are prevalent in aged cells correlates with a decreased reprogramming efficiency [8]. Dysregulation of signal pathways controlling cell proliferation potencies could decrease efficiency of cell reprogramming [9]. The initiation of cell reprogramming to pluripotency involves coordinated epigenetic changes that alter a genome-wide scale of chromatin structure and gene activity which is also critical for cell cycle transition. Thus reprogramming and aging also correlate well at levels of cellular function and cell signaling.”

Continuing, “To date, somatic cell reprogramming has been achieved in vitro. It would be of great importance to explore whether the anti-aging agents, e.g. rapamycin, could function to enhance stem cell function, protect stem cell prluripotency and even promote reprogramming in vivo. It is also very interesting to verify whether some or all adult organs/tissues do possess some significant regenerative capacity due to the suspected in vivo reprogramming. Furthermore, it has been reported that agents which effectively function for a common human disease by enhancing self-renewal could lose efficacy in older individuals due to the age-associated decline of replication [10]. Thus understanding and realization of in vivo cell reprogramming is not only a fundamental theoretical question but also a very promising strategy for anti-aging and regenerative medicine. — Reprogramming of somatic cells has been enthusiastically hoped to become an arsenal to against aging as it would leads to personalized stem-cell-based rejuvenation therapies. What we learn from research of stem cell and reprogramming could help us to develop two potential anti-aging approaches in adult and older: i) to protect, ameliorate or reverse the age-associated loss function of stem cell in vivo and ii) to replace the lost stem cells by reprogrammed pluripotent cells. Considering the shared mechanisms by anti-aging and reprogramming processes, we speculate that applying a cocktail of pharmacological agents (small or macro molecules), or even the herbal extracts (such as the traditional Chinese medicines) might achieve in vivo reprogramming and eventually lead to rejuvenation.”

To be clear, the fact that health and possibly life-extending substances also ease the creation of iPCs does not establish that in fact they also lead to creation of iPSCs in vivo.  Although that remains an attractive possibility, it is not yet established experimentally.  Yet, I believe there is significant hope that effective in-vivo reprogramming methods can be found as we learn more about cell reprogramming.  See the previous blog post  Progress update on induced pluripotent stem cells regarding pluripotency factors that facilitate iPSC reprogramming. 

It may be that there is an easier short term approach to renewing adult stem cells in older people than creating high-fidelity iPSCs and getting them to differentiate properly in the respective adult stem cell niches.  That approach could be finding ways to rejuvenate existing adult stems in aged individuals to younger epigenetic states.  In fact, significant progress is being made in identifying interventions that can potentially extend the vital lifespans of adult stem cells.    For example, the 2010 publication Systemic signals regulate ageing and rejuvenation of blood stem cell niches, though by completely different authors at Harvard instead of in China, articulates a similar theme as that in the above cited publications: “Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.”  That there is something in the blood serum of young animals that rejuvenates adult stem cells in older animals has been known for some time.  I reported this in the January 2010 blog entry What every vampire already knows – and something he doesn’t know.

The June 2011 report Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway reports “The results indicate that the senescence and dysfunction of MSCs (mesenchymal stem cells) in the medium containing ORS (old rat serum) is reversed by the Wnt/β-catenin signaling inhibitor DKK1 or by β-catenin siRNA. Moreover, the expression of γ-H2A.X, a molecular marker of DNA damage response, p16(INK4a), p53, and p21 is increased in senescent MSCs induced with ORS, and is also reversed by DKK1 or by β-catenin siRNA. In summary, our study indicates the Wnt/β-catenin signaling may play a critical role in MSC aging induced by the serum of aged animals and suggests that the DNA damage response and p53/p21 pathway may be the main mediators of MSC aging induced by excessive activation of Wnt/β-catenin signaling.”

There is ongoing research related to rejuvenating of aged cells of specialized types.  An example is described in an October 2011 report PDGF signalling controls age-dependent proliferation in pancreatic β-cells.  Speaking of the research covered in that publication, the October 2011 publication Research Rejuvenates Beta Cells relates “ As a person ages, the ability of their beta cells to divide and make new beta cells declines. By the time children reach the age of 10 to 12 years, the ability of their insulin-producing cells to replicate greatly diminishes. If these cells, called beta cells, are destroyed—as they are in type 1 diabetes—treatment with the hormone insulin becomes essential to regulate blood glucose levels and get energy from food. Now, longtime JDRF-funded researchers at Stanford University have identified a pathway responsible for this age-related decline, and have shown that they can tweak it to get older beta cells to act young again—and start dividing.  — In their work, the researchers, led by Seung Kim, M.D., Ph.D., of Stanford University, found that a protein called PDGF, or platelet derived growth factor, and its receptor send beta cells signals to start dividing via an intricate pathway that controls the levels of two proteins in the beta cell nucleus, where cell division occurs. Working with young mice, Dr. Kim and his team found that PDGF binds to its receptor on the beta cell’s surface and controls the level of these regulating proteins allowing cells to divide. However, in older mice, they discovered that beta cells lose PDGF receptors, and that this age-related change prevents beta cells from dividing. Dr. Kim and his colleagues further found that by artificially increasing the number of PDGF receptors, they can restore the ability of the beta cell to divide and generate new cells. — The researchers also show that this age-dependent beta cell proliferation pathway is also present in human beta cells. Similar to the findings with mice beta cells, the researchers found that juvenile human islet beta cells proliferate in response to PDGF, but adult human islet beta cells do not due to a reduced level of PDGF receptors.”

One way or the other, we are going to discover ways to create epigenetically younger adult stem cell populations in older people and that is likely to constitute a breakthrough in health and longevity.  If I had to bet, I would put more than even money on that happening through an in-vitro approach rather than through introducing rejuvenated stem cells into older bodies.  Besides, if Drs.  Zhao and Pei  are correct, that could possibly be happening in me right now to a limited extent as a result of my consuming the multiple phytosubstances I often write about.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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9 Responses to In-vivo cell reprogramming for longer lives

  1. Louis says:

    I’m becoming more and more convinced that the flavonoids in epimedium (horny goat weed), particularly icarriin, offer significant potential to renew adult stem cells in vivo. Epimedium seems to work in this regard in both the the bones, the brain, and the heart:

    Vince, this is a remarkable compound that is well-worth your time to investigate further, as related to your thesis in this article. I am also convinced that epimedium and icariin are operating through telomere mechanisms in these stem cells. The last link is particulary interesting: I believe however that their conclusion about telomerase activation is dead wrong (they have mismeasured, which is common in experiments that attempt to sense weak levels of telomerase activation).

  2. iraspastor says:

    Excellent distillation of the current state of reprogramming affairs

  3. Louis says:

    Epimedium promotes osteoblastogenesis in bone marrow stromal (stem) cells:

    Epimedium enhances osteogenic differentiation of bone marrow stromal (stem) cells:

    Epimedium promotes the proliferation and differentiation of neural stem cells:

    Epimedium activates endogenous stem cells:

    Epimedium (Icariin) stimulates adipose-derived stem cells to differentiate into cardiomyocytes:

    Epimedium (Icariin) induces embryonic stem cell differentiation into cardiomyocytes

  4. Louis says:

    Epimedium (horny goat weed) appears to enhance proliferation and differentiation of stem cells in 3 major organ systems: brain, heart, bone. Perhaps this compound should be considered as a candidate therapy for “in-vivo [stem] cell reprogramming” as you put it in this very nicely-written article? The research so far is tantalizing.

    Epimedium promotes osteoblastogenesis in bone marrow stromal (stem) cells:
    PMID: 19501202

    Epimedium enhances osteogenic differentiation of bone marrow stromal (stem) cells:
    PMID: 22009597
    PMID: 16398272

    Epimedium promotes the proliferation and differentiation of neural stem cells
    PMID: 19703337
    US Patent: US 2010/0317605 A1 (Dec 16, 2010)

    Epimedium activates endogenous stem cells:
    PMID: 19548445

    Epimedium (Icariin) stimulates adipose-derived stem cells to differentiate into cardiomyocytes:
    PMID: 20563742

    Epimedium (Icariin) induces embryonic stem cell differentiation into cardiomyocytes
    PMID: 21181238
    PMID: 18484897
    PMID: 15780198
    PMID: 17883938
    PMID: 17985362
    PMID: 18423597
    PMID: 18484897

    Epimedium (Icariin) enhances differentiation of bone marrow stromal (stem) cells
    PMID: 18236786
    PMID: 16398272
    PMID: 20669681

    Epimedium (Icariin) accelerates proliferation of bone marrow stromal (stem) cells
    PMID: 17326409

  5. Louis:
    Please forgive the long delay in responding to your cogent comments on Epidedium. I am finally turning my attention to the subject. I expect to be back again either with a much more comprehensive comment or a new post on Epidedium.

  6. Pingback: Focus on phytosubstances – amazing properties of epimedium and icariin | AGING SCIENCES – Anti-Aging Firewalls

  7. Louis:
    Please see my blog entry Focus on phytosubstances – amazing properties of epimedium and icariin at See my entry

  8. Pingback: New, emerging and potential treatments for cancers: Part 1 – focus on the mTOR pathway | AGING SCIENCES – Anti-Aging Firewalls

  9. Louis says:

    Hi Vince,

    See my comments to your excellent article — specifically on my own use of Epimedium and Ashwaganda as corner stones of my own personal program to improve the health of my stem cells.

    Best, Louis

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