Tuesday, June 07, 2022
Every cell of your body has the ability to reset itself to a more youthful state, at any age.
This statement has recently been confirmed by 3 key scientific studies from Stanford University, Harvard University and the Salk Institute for Biological Studies. This groundbreaking study series, that we review in this article, show unequivocally that cells, organs, and the body know how to rejuvenate, that the information is already stored in the DNA. All we have to do is remove the obstacles and activate this inherent intelligence in us in order to reverse the signs of aging.
What is cellular rejuvenation?
If all human cells have an inherent capacity for youthfulness and health, at any age, then how can we activate this? The answers this question lie in biologics and cell rejuvenation science.
Cells and tissues accumulate damage over time. This is due to numerous physiological mechanisms responding to the daily wear and tear — the DNA damage, telomere attrition, senescence, protein folding mistakes, stem cell depletion and so on. At the DNA level, aging causes progressive accumulation of epigenetic errors that eventually lead to faulty gene regulation that cause all the trouble with our health.
If given the right building blocks, however, the scientists have shown that we can repair a lot of this accumulated damage and wipe the epigenetic slate clean. The result is a healthier epigenetic signature of the cell, of the tissue, of the organ, of the body.
What is an epigenetic signature?
One way to think about this is in terms of 'epigenetic state' or 'biochemical state' or 'phenotype' of the cell. You can think of aging and of youthfulness as physiological states that can be altered.
Aging Epigenetic Signature, Aging Phenotype: You age biologically if you are exposed to cellular aging factors (toxins, stress, senescence, DNA errors, all the damage of age-related diseases). The biochemical epigenetic state (or signature) of an aging cell is full of DNA damage, misfolded proteins, mitochondrial dysfunction, poor nutrient sensing, senescence and overall damaged cell function and homeostasis. The state of the cell is old, aging, and dying.
Youthful Epigenetic Signature, Young Phenotype: You can reverse aging biologically if you are exposed to cellular rejuvenation factors that can wipe the epigenetic slate clean at the chromatin level, the DNA level. Exposure to unique nuclear reprogramming factors are key for this process to take place. The biochemical epigenetic state (or signature) of a rejuvenated cell is DNA repaired, telomeres elongated, protein folding correctly, mitochondria aplenty pumping out ample ATP, and overall well regulated cellular homeostasis. The state of the cell is healthy. The molecular clock set to 'younger!'
How is biological age measured?
Scientists use DNA methylation epigenetic clocks to measure the biological age of a cell/tissue. These are molecular clocks that identify unique epigenetic marks on the DNA. With the passage of time, changes in DNA methylation and resulting epigenetic marks accumulate. Dr. David Sinclair PhD, Senior author of the Harvard study, refers to this as accumulation of noise that point to the biological age of cells. This epigenetic noise is picked up by the DNA methylation biological clock, pointing to cell/tissue and organisms age.
What is cellular reprogramming?
In scientific literature, cellular rejuvenation is referred to as 'cellular reprogramming' or 'epigenetic reprogramming' or 'nuclear reprogramming'. The reprogramming event occurs in the cell, alters epigenetic markers, in the nucleus, at the DNA level. Hence the different terms pointing at the very same process.
To be even more specific, the studies reviewed here in this article make a case for 'transient reprogramming' or 'partial reprogramming' or 'incomplete reprogramming'. The reprogramming event that rejuvenates a cell/tissue for healthier lives and longevity must preserve cellular identity. A skin cell must remain a skin cell. A liver must remain a liver cell. They must not convert all the way to pluripotent embryonic-like state. That is not what we want in clinical rejuvenation. We want to preserve somatic cell identity. We simply introduce nuclear reprogramming factors, in short bursts, in transient pulsing doses, and these partially, incompletely reprogram the cell back in epigenetic time to a more youthful state. We are after younger skin cells, liver cells, cardiac cells, and so on. Transient/partial/incomplete epigenetic landscape modification is the reprogramming-induced rejuvenation therapeutics we're after.
What does the science say? What are the most recent reprogramming studies?
THE ORIGINAL EPIGENETIC REPROGRAMMING STUDY
Shinya Yamanaka, 2006
The original groundbreaking study that pointed to the possibility of epigenetic reprogramming came from Japan. The reprogramming active agent, the Yamanaka transcription factors – Oct4, Sox2, Klf4 and cMyc, were originally pioneered by Nobel Prize-winning Japanese scientist, Dr. Shinya Yamanaka in a 2006 study. In this study, the team of researchers were able to demonstrate that somatic cell identity, ex: that of a skin cell in adult tissues, can be reverted back to pluripotent epigenetic state, essentially wiping clean the epigenetic errors, turning back the molecular clock (in mice, animals) and creating an iPSC induced (embryonic stem cell like) pluripotent stem cell.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663-76. doi: 10.1016/j.cell.2006.07.024. Epub 2006 Aug 10. PMID: 16904174.
3 MOST RECENT PARTIAL REPROGRAMMING STUDIES
Standford University School of Medicine
Senior Author: Vittorio Sebastiano, 2020
This study showed that transient expression of nuclear reprogramming factors, Yamanaka Factors (Oct4, Sox2, Klf4 and c-Myc), ameliorates cellular aging of adult cells in human tissue lines. It resets the epigenetic clock, reduces the inflammatory profile in cartilage cells, and restores a youthful regenerative response to aged human muscle stem cells (pointing to muscle regeneration and possible treatment for age-related weaker muscles). In all cases rejuvenation was achieved without abolishing cellular identity. The key groundbreaking piece of this study is the preservation of somatic cell identity while achieving cellular age reversal in different cell types in human tissue in vitro, when compared to untreated cells.
Sarkar TJ, Quarta M, Mukherjee S, Colville A, Paine P, Doan L, Tran CM, Chu CR, Horvath S, Qi LS, Bhutani N, Rando TA, Sebastiano V. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun. 2020 Mar 24;11(1):1545. doi: 10.1038/s41467-020-15174-3. PMID: 32210226; PMCID: PMC7093390.
Harvard Medical School
Senior Author: David Sinclair, 2020
Dr. David Sinclair is best known for his 'information theory of aging' in understanding why we age, and how to slow its effects. According to his theory, the accumulation of epigenetic noise that disrupts gene expression patterns leads to decrease in tissue function and regenerative capacity. If we can transiently restore the cells to a healthier and younger epigenetic state, we will see functional results.
In 2020, he and his scientific team were able to promote axon regeneration after optic nerve damage in glaucoma (in mice, animals). By inducing optic nerve injuries (injury to retinal ganglion cells) and exposing the tissue to transient nuclear reprogramming factors (Oct4, Sox2 and Klf4) they were able to revive the function of the optic nerve. This was a successful attempt at vision loss restoration, serving as a model for future for human glaucoma research and therapeutics (glaucoma-induced vision loss) and for age-related vision loss.
Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, Karg MM, Schultz MB, Kane AE, Davidsohn N, Korobkina E, Chwalek K, Rajman LA, Church GM, Hochedlinger K, Gladyshev VN, Horvath S, Levine ME, Gregory-Ksander MS, Ksander BR, He Z, Sinclair DA. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-129. doi: 10.1038/s41586-020-2975-4. Epub 2020 Dec 2. PMID: 33268865; PMCID: PMC7752134.
Salk Institute for Biological Studies
Senior Author: Juan Carlos Izpisua Belmonte, 2022
Scientists at the Salk Institute for Biological Studies published a paper showing that longer-term partial reprogramming regimens reverse the epigenetic age of various tissues in mice, leading to longer lifespans. Izpisua Belmonte and his Salk Institute scientific team showed that exposing mice to Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc) at different time intervals, for differing lengths of time, they were able to show that treatment period can be safely lengthened, reversal of biological age achieved without any occurrence of teratomas. They found no blood cell alterations, no cancers, the safety of partial-reprogramming with pluripotency established even further.
Izpisua Belmonte's international team tested treatment period variations, onset timings, and different age mouse model types, (healthy animals, aged mice, middle-aged and elderly mice) to find the sweet spot in reprogramming-induced rejuvenation. One group of mice received regular doses of the Yamanaka factors from the time they were 15 months old until 22 months, (age 50 through 70 in humans). Another group was treated from 12 through 22 months, (age 35 to 70 in humans). And a third group was treated for just one month at age 25 months, (age 80 in humans). They found that longer-term regimens were more effective in reversing aging than short-term reprogramming. They also found that the older mouse model showed the least reprogramming potential, theorizing that senescence or a refractory period may render reprogramming age reversal more challenging. The threshold needed to overcome senescence and the window of opportunity, the ideal time span, the sweet spot for cellular rejuvenation need to be further explored in future studies, the groundbreaking study authors conclude.
Browder, K.C., Reddy, P., Yamamoto, M. et al.In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice.Nat Aging, 2022
Pluripotent Stem Cell Treatment
At Stemaid Institute, we offer long-term pluripotent stem cell treatment programs. This approach to treatment has been developed by our scientific and clinical teams for over 15 years, with consistent beneficial effects seen in thousands of patients. We've treated a wide range of diseases in humans, including neurodegenerative diseases, traumatic brain injury, cardiovascular disease, viral infections, essentially the whole spectrum of disease situations we encounter as we get sick and as we age.
What we have found in all the years of therapeutics is that reprogramming-induced rejuvenation with pluripotency is effective and safe. When administered in pulsing doses daily for 2-5 weeks, we see gradual improvement in all parameters of health and metabolic profiles. We are conducting a current study to measure Telomere length, Predictive age assessed via Deep Learning Algorithms, and DNA methylation markers using epigenetic clocks pre- and post- Stemaid Program Therapeutics.
Are there any risks to Pluripotent stem cells?
Much like the studies reviewed above show, the safety profile of pluripotent stem cells and exosomes is strong. When it comes to assessment risk, blood tumor markers are the first line of testing. The tumor markers of all our patients are monitored pre-, during and post- treatment and the results are always pointing to the well-established anti-tumorigenic effect of pluripotency that we see in scientific literature.
We stand confidently by the scientific and clinical experience that pluripotent stem cells can be applied even in cancer treatments safely. Numerous studies have shown how pluripotent stem cells create an active anti-tumorigenic micro-environment, and can reverse and prevent tumor growth. We are in the midst of publishing a current study showcasing our 10+ years of safety with blood cancer markers.
Unwanted side effects and negative side effects usually occur with toxic agents. Pluripotent stem cells are biologically harmonious with human physiology and are a natural and gentle approach in regenerative medicine. They are non-toxic and highly bio-compatible, especially Stemaid's autologous pluripotent stem cells (APSC). In treating thousands of patients, we've clinically seen no negative effects.
The cellular rejuvenation approach we take at Stemaid Institute is innovative, effective and gentle, bio-compatible with the human physiology and what it needs to reprogram and rejuvenate.
The studies reviewed in this article and in our years of clinical experience show how potent and safe pluripotency is. We see clinical signs of rejuvenation in every patient that comes through, whether they come for biohacking and age reversal programs or whether they come with severe chronic conditions. The epigenetic reprogramming takes place in all patients, in all complex tissues, in every type of cell, even in aged cells.
Our future directions include clinical research, international clinical and laboratories expansion and scientific innovation that may include combining the partial reprogramming intelligence of pluripotency with cloning and gene therapy science.
1. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice - Nature Aging
2. Reprogramming to recover youthful epigenetic information and restore vision - PubMed
3. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming - PubMed
4. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock - PubMed
5. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells
7. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors - PubMed
8. Emerging rejuvenation strategies—Reducing the biological age