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  • Biological Clock Of Laboratory Mice Reset First Reprogrammed Aged Laboratory Mice Returned To Youthful State

    December 16, 2016: by Bill Sardi

    The first images of laboratory mice reprogrammed to reverse aging are presented above. [Cell Dec 15, 2016] Laboratory mice genetically altered to age prematurely show signs of age reversal upon epigenetic reprogramming. The mouse on the right (-Dox) exhibits a curved spine characteristic of a premature aging syndrome called progeria in humans. The reprogrammed mouse on the left (+Dox) exhibits a more youthful thicker coat and absence of the abnormal spine curvature. Internal organs were also more youthful in reprogrammed mice. Animals were genetically altered to produce a premature aging syndrome akin to progeria, which results in shortened lifespan (~13 years in humans) with premature baldness, cataracts and skin wrinkling in youth. While progeria is caused by a mutation in a single gene (LMNA, pronounced lamin-A) researchers were able to reverse aging changes in these animals by alteration of protein-making (i.e. epigenetics) in just four genes (known as Yamanaka factors). Mice and humans house a similar library of genes (~25,000) in the nucleus of their cells. The age-reversal effects were accomplished by returning cells back to their original embryonic state in order to remove certain epigenetic marks that occur in aging without altering the abnormal sequence of DNA (gene mutations) responsible for premature aging itself. This suggests biological fate can be changed.

    Mouse comparison

    What Biologists Aren’t Telling You About The Laboratory Mice That Were Reprogrammed Back To A State Of Youthfulness

    By Bill Sardi

    Scientists at the Salk Institute in La Jolla, Calif. report they have reversed aging in old laboratory animals that were genetically altered to mimic a premature aging syndrome (Hutchinson-Gilford progeria). The effects were dramatic and visible, with correction of curved spines in the treated animals and were achieved by epigenetically reprogramming just four genes. The reprogrammed mice lived 30% longer (though not longer than healthy normal mice). [Cell Dec 15, 2016]

    In the words of the researchers: “these results demonstrate that short-term in vitro (lab dish) induction of four genes in cells derived from a premature aging mouse ameliorates multiple age-associated hallmarks observed during physiological aging, including the accumulation of DNA damage, cellular senescence and epigenetic dysregulation.”

    Normal healthy mice not carrying the premature aging genetic mutation did not experience any prolongation of life, so this particular experiment does not have immediate direct application to normally healthy humans today but the experiment did reverse cellular and tissue changes characteristic of normal aging in humans. However, there are other known properties of natural molecular medicines, namely the red wine molecule resveratrol, that may be able to mimic this experiment via activation of the same genetic pathway (PI3K/AKT).

    Epigenetics is the dynamic protein-making function of genes where genes are influenced by environmental factors (diet, temperature, radiation) whereas gene therapy consists of correction of inherited gene mutations (restoration of the proper sequence of nucleotides which are the steps on the DNA ladder). In this instance, epigenetics overcame genetic flaws. The astounding conclusion that can be drawn from this animal lab study is, what was once genetic fate can now be undone.

    While the effect was only demonstrated among genetically-modified animals (no effect on normal animals), youthful effects were also shown in human cells (lab dish).

    The Salk Institute scientists report they epigenetically reprogrammed cells back to embryonic-like state where they are capable of becoming any cell type in the body. They did this first in a lab dish and then demonstrated it in live animals.

    Here is how the researchers described it:

    “The results were striking: compared to untreated mice, the reprogrammed mice looked younger; their cardiovascular and other organ function improved and—most surprising of all—they lived 30 percent longer, yet did not develop cancer. On a cellular level, the animals showed the recovery of molecular aging hallmarks that are affected not only in progeria, but also in normal aging.”

    What did the biologists use to provoke prematurely aged cells back to a youthful state?

    Prior studies show doxycycline, an antibacterial agent, exerts “dramatic effects” on human cells, promoting their survival and self-renewal. Researchers employed doxycycline in this experiment. This youthful effect does not emanate from doxycycline’s antibiotic action but from its direct activation of a known genetic pathway called PI3K-AKT (Phosphatidylinositol-3 kinases). [Stem Cell Reports Aug 12, 2014]

    Why did researchers only give lab animals a short-term dose of doxycycline?

    Researchers aren’t letting on, but they apparently caught living cells in mid-transformation from healthy to cancer cells. Short-term administration of doxycycline to these lab animals in their drinking water for only 2 days a week averted their otherwise predicted demise that occurred in earlier experiments, which triggered the formation of extensive tumors. In this experiment, no tumors developed.

    How does doxycycline alter the protein-making (expression) of genes to reverse the biological clock in living cells back to their embryonic state?

    Doxycycline possesses iron/copper-chelating (iron/copper-binding) properties. [Antimicrobial Agents Chemotherapy March 2000]

    Iron chelators have been demonstrated to prolong the survival of patients undergoing stem cell transplantation. [Transfusion Apheresis Science Oct 2013] Copper, another metal, drives stem cells to morph from their embryonic state into cells with specific functions. [Journal Cellular Biochemistry 2002] Copper chelators do the opposite.

    Copper chelators (key-lay-tors) have also been demonstrated to promote the survival of stem cells in the skin. [Journal Peptide Science Nov 2012] Copper withdrawal delays stem-like (progenitor) cell differentiation. [British Journal Haematology 2002] It is no surprise that metal chelation is proposed as an anti-aging strategy. [Mechanisms Ageing Development March 2014]

    Stopping mid-way towards cellular conversion to cancer

    Salk Institute researchers achieved reversal of aging via activation of AKT, which is known as a pro-oncogene, that is, it paradoxically promotes cancer. [Oncogene 2005; Cell Signaling Technology] This is precisely why the researchers at the Salk Institute activated the PI3K-AKT pathway only for a short period of time, to drive living cells to be reprogrammed towards becoming cancer cells then halt that process at a point before tumor formation occurs.

    Thus what occurs during the early formation of a human embryo where cells are virgin and have not morphed into various shapes and function as muscle, brain, skin cells, is reset in aged cells back to their embryonic state to be reprogrammed sans the epigenetic marks or memory they acquired during aging.

    Resveratrol activates the same mechanisms at measured doses

    Resveratrol in a measured dose range can activate the same PI3-kinase/AKT gene signaling pathway that doxycycline activated in the Salk Institute experiment. A dose of resveratrol that exceeds dietary intake but is considered modestly low (100-350 mg in humans) activates AKT whereas a higher dose inhibits AKT (see chart below).

    It’s plausible that an intermittent measured daily dose of resveratrol drives senescent cells in the body back towards an embryological state like doxycycline did in the animal experiment, thus reprogramming aged cells back to youthful function. Resveratrol pills have been in use for over a decade without any report of associated cancer.

    Chart: activation of AKT
    Human Dose of Resveratrol (154-lb human); activation of AKT

    Arbitrary units of AKT protein expression by resveratrol at varying doses (2.5 mg, 5.0 mg and 25 mg per kilogram of body weight, or 175 mg, 350 mg and 1750 mg human equivalent dose). Calculated for a 70 kilogram (154-lb) human. Source: Dose Response 2010] AKT (protein kinase B) is an enzyme that plays a role in various cellular processes. High-dose resveratrol is known to inhibit AKT and thus prevent cancer. [Journal Experimental Therapeutics Oncology 2009] AKT is a pro-oncogene, that is, it promotes cancer. [Oncogene 2005; Cell Signaling Technology] This is precisely why the researchers at the Salk Institute activated the PI3K-AKT pathway only for a short period of time, to drive living cells to be reprogrammed to become cancer cells but halt that process at a point before tumor formation occurs. Thus what resulted were living cells that reverted back to their virgin embryonic state where they had not morphed into various shapes and functions as muscle, brain, skin cells. In this manner the biological clock is reset in aged cells back to their embryonic state to be reprogrammed sans the epigenetic marks or memory they acquired during aging.

    The importance of dose is borne out by available research studies. A modest dose concentration (10 micromole) of resveratrol activated the PI3K-AKT pathway to protect nerve cells from damage by high sugar (glucose) levels. [Cellular Molecular Neurobiology 2015]

    Similarly, when the 175 mg human equivalent dose (2.5 mg/kilogram body weight) was employed in laboratory animals, resveratrol activated the PI3K/AKT pathway and limited scarring (fibrosis) of heart muscle and reduced the occurrence of fluttering heart muscle in the top chambers of the heart (atrial fibrillation). [Heart Rhythm 2015]

    Resveratrol has also been demonstrated to inhibit senescence of stem cells. [European Review Medical Pharmacological Sciences 2016]

    Take-Away lessons

    The take-away lessons from this landmark study are as follows:

    1. Aging is largely epigenetic rather than genetic, that is, controllable and reversible.
    2. A single molecule produced the reversal (doxycycline)
    3. Only 4 genes were needed to produce effect (Yamanaka factors)
    4. Epigenetics trumped a genetic mutation
    5. Aging was reversed, not just slowed
    6. Apparently researchers advantageously drove aged cells towards being reprogrammed into cancer cells, then abruptly halted the reprogramming before tumors developed, thus removing epigenetic memory from the cells to achieve restoration of youthful effects.
    7. Stem cell injections were not required to produce this effect. Instead, aged cells were programmed backwards biologically, which removed certain epigenetic memory from aged cells.
    8. The effect was demonstrated in older animals. A person may never be too old to benefit from the lessons of this experiment.
    9. Lifespan was lengthened, not just cosmetic or tissue regeneration.
    10. Many age-reversal effects are likely achieved via mineral chelation (iron, copper). Hence, doxycycline, a metal chelator, produced the reported results. Resveratrol, as a copper chelator, theoretically has similar properties.
    11. Nature provides iron and copper chelators (resveratrol/copper; quercetin/iron, IP6 phytate/all metallic metals), which in measured doses activate the same epigenetic pathway (PI3K-AKT) as identified in this landmark experiment.
    12. The scientific community says it will be another decade before the lessons from this landmark experiment can be translated into applied science, i.e. commercialized. For those individuals who haven’t time to wait for slow moving science, a measured-dose resveratrol pill may be a plausible alternative.
    13. On the political front, the new administration in Washington DC is said to offer Jim O’Neill as a candidate for FDA commissioner. O’Neill is a promoter of anti-aging treatments and technology. [ Dec 7, 2016] Yes, the times are a-changin. [Bob Dylan]

    © Bill Sardi,

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