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  • NEW ERA OF SENOLYTIC DRUGS WILL BLAST AWAY AGING

    December 10, 2018: by Bill Sardi

    In the anti-aging pill arena 2018 has been the year of senolytic drugs – the prospect that synthetic molecules could soon erase the ravages of aging produced by a progressive aging process called cell senescence.

    Four major milestones have been achieved in rapid fashion.These four developments started in 2011 with an animal study where the destruction of “senescent” cells improved the lifespan and health span of laboratory mice.That was followed by (2) the identification of small natural molecules that are capable of clearing the body of “senescent” cells; then (3) these molecules were then shown to improve the lifespan and function of aged mice; and (4) pre-clinical studies show these molecules are successful in quelling a wide range of maladies.

    The news media gush over the prospect of a new class of “senolytic” drugs that “are ready for human testing,” that may “transform medicine” say news reports, and they would likely be prescribed for all humans over age 40.Primary candidates for anti-senescence therapy would be 85+ year-olds, 45% of whom suffer from frailty and diminished mobility.

    Senolytic drugs selectively produce a natural die off (apoptosis) of senescent cells.These drugs hold promise to restore youthful function to senescent cells, cells that have retired and no longer replicate themselves.

    While biologically young non-senescent cells die off in what is called programmed cell death (apoptosis), senescent cells sneakily avoid this fate. They are slow to die.So senescent cells, even though they no longer replicate themselves, persist and cannot easily be killed.

    Only a small portion of these senescent orbs, all 37 trillion of them, become senescent, but they are roaming assassins, spreading inflammation, gene mutations and idiopathic (unexplainable) disease and frailty to even remote areas of the body.

    Transplantation of a very small number of senescent cells in animals representing just 1 in 10,000 live cells, had a profound effect on laboratory animals.Their risk of death increased 5.2-fold.The lab animals were of advanced age, roughly equivalent to a 75-year old human.A few senescent cells in the human body can wreak havoc to the point of death.These so-called senescent cells make up about 1/100th to 3/100ths of the population of all cells in the human body.

    Billionaire Silicon Valley oligarchs are pouring hundreds of millions of dollars into this class of drugs that will demand a handsome return on investment.Such senolytic drugs are likely to be affordable only to the top 10% of income earners unless aging can be declared a disease and insurance will pay for these youth pills.

    The news media appears to be pawn for these start-up drug companies.Senolytic natural molecules already exist, have been in widespread use for a number of years, are affordable, and pose little or no side effects.Botanical molecules called polyphenols like resveratrol, quercetin and catechin, derived from grapes/wine, red apple peel or tea leaves respectively, are at the top of the list.One report says, since senescent cells spread inflammation, “foods rich in polyphenols… have the potential to (act as) anti-senescent foods.”

    Here is what is being learned about cell senescence and senolytic drugs.

    The instillation of senescent cells into the knee joint of laboratory mice results in leg pain, impaired mobility and changes in tissues evidence by x-ray.Injection of non-senescent cells produced far fewer symptoms.

    In the study of cell senescence pharmacologists concede cancer chemotherapy drugs and radiation actually induce a state of cell senescence.So patients are biologically older after treatment.Removal of senescent cells immediately following chemotherapy makes cancer less likely to spread.

    Results of an experiment published in 2016 reveals a “fast food diet” comprised of high fructose corn syrup and milk fat hastened cellular senility.Physical exercise slowed this process.So did intermittent fasting.

    A small (20 subjects) human trial of a senolytic drug combo was launched in 2016 and will be completed in 2021.The human trial tests dasatinib, a monoclonal antibody enzyme inhibitor, and quercetin, a natural polyphenol found in red apples and onions.The study tests for frailty and stem cell function among subjects with chronic kidney disease.

    On July 9, 2018 Mayo Clinic researchers injected quercetin and dasatinib into 4-month old mice with senescent cells.Just two weeks after transplantation the mice exhibited impaired physical function (a decline in walking speed, muscle strength, physical endurance, daily activity, food intake and body weight.There were more senescent cells than were injected, suggesting senescent cells begat more senescent cells.Then these artificially senescent mice were injected with dasatinib and quercetin for just three days.This molecular combination selectively killed senescent cells and slowed the functional deterioration induced by the prior injection of senescent cells.

    Then in a stunning co-experiment, researchers injected dasatinib and quercetin into 20-month old mice (equivalent to a 75-year old human) and these aged mice regained physical function (walking speed, treadmill endurance, grip strength).Treating very old mice (24-27 months of age) biweekly with D & Q biweekly led to a 36-percent high average post-treatment life span and lower mortality, which suggests no one would be too old to benefit from senolytic drugs.

    Looking forward, a problem for dasatinib is that over the long term, like all “inib” kinase inhibitor drugs, it is subject to development of tissue and organ resistance.“Inib” drugs, even expired patent versions, are still very expensive.

    Both resveratrol and quercetin block the growth of tumor cells, induce programmed cell death (apoptosis) and slow down the cell renewal cycle, thus giving more time for gene mutations to undergo repair.

    Given that chemotherapy drugs induce cellular senescence, therapy like this may be restorative for cancer patients.

    There is a natural way senescent cells are eradicated in the human body.The immune system utilizes a class of white blood cells known as macrophages to engulf these zombie senescent cells and eliminate them.However, older mice with senescent cells have weak immune systems.

    Senescent cells are also characterized as producing misfolded proteins that are processed in the cell. That occurs in a cellular compartment called the endoplasmic reticulum.

    The question is, what is the initial and primary mechanism that induces cellular senescence.This is explained and better understood as part of the overmineralization theory of aging that this author penned a few years ago.

    The initial step towards cell senescence is explained in a recently published report that shows old cells are not able to efficiently mop up cellular debris.Cellular housecleaning is performed enzymatically in compartments within cells called lysosomes. Iron storage proteins called ferritin are not disposed of efficiently.Senescent cells accumulate up to 30-fold more iron than young cells.They begin to become inflamed, which describes the low-grade inflammation that characterizes aging.

    A universal feature of cellular senescence is the accumulation of metallic minerals, chiefly iron.The first report that cellular senescence is iron related was published in 2003.

    In a protective response, ferritin binds up this iron so it does not create iron-induced oxidation and in so doing produces intracellular anemia.Even though senescent cells are overloaded with iron, it is not available, it is bound to ferritin.Without iron the cell cannot divide and grow (mitosis).There is ten times more ferritin in senescent cells.Each ferritin molecule is capable of seizing 4500 atoms of iron.

    The senescent cell has a perceived iron deficiency as the iron is all bound up in ferritin and the cell remains in iron acquisition mode.This is all explained in a landmark report published in Redox Biology.It is not surprising to learn that individuals taking iron supplements and iron-overloaded subjects (hemochromatosis – increased absorption of iron) exhibit shorter telomeres, the end caps of chromosomes.

    Senescent cells are experimentally produced by subjecting them to radiation and they immediately accumulate iron in the post-radiation period.These rusty cells can no longer replicate.Under experimental conditions, when an iron chelator (key-lay-tor) is instilled into cells that are subjected to radiation, the chelator inhibited the intracellular iron accumulation in ferritin but did not reverse cellular senescence.The only way iron-overloaded ferritin can be naturally disposed of is to dispose of these rusty cells by macrophage ingestion and thus kill off these zombie cells altogether.

    Normally living cells via lysosomes enzymatically conduct a “self-eating process” called autophagy.Reduced autophagy impairs the turnover of the iron storage protein, ferritin.

    Fasting (absence of incoming iron) can induce autophagy.It is the loss of autophagy (enzymatic clearance of cellular debris including ferritin and iron) that precedes cell senescence.

    Iron also accumulates in lipofuscin, the cellular debris that piles up in cellular lysosomes.Lipofuscin starts to accumulate after full childhood growth is achieved.

    Cell senescence also disarms internal antioxidant defenses in living cells.When cells are subjected to biological stress (heat/cold, radiation, starvation) they switch on a genetic switch called Nrf2 to internally activate enzymatic antioxidants (glutathione, SOD, catalase).In senescent cells, the Nrf2 switch is muffled by 45-65%.

    The use of Nrf2 stimulators activate protease, an enzyme that removes damaged proteins (like ferritin) apart from the cellular cleansing achieved by enzymes in lysosomes.The use of Nrf2 activators has been shown to reverse this senescent process.Quercetin, resveratrol and other polyphenols extracted from plant sources are known Nrf2 activators, being molecular mimics of fasting.

    While there is overwhelming evidence of iron buildup in cells as a factor in cell senescence given that iron is the most abundant metal stored in the body (mostly in hemoglobin of red blood cells), biologists also identify copper accumulation as a “universal feature” of cell senescence.Following injection of copper, tumor cells show typical signs of senescence.Provision of sub-toxic amounts of copper induces premature senescence in a lab dish.

    As cell repeatedly undergo mitosis (doubling) the activity of the Sirtuin1 survival genes decreases.Sirtuin1 is a primary gene target to mimic a life-prolonging calorie restricted diet.The addition of copper to aged cells decreases Sirtuin1 gene activity.Resveratrol, a copper chelator (binder), raises Sirtuin1 gene activity.Copper induced cell senescence results in reduced SIrtuin1 gene activity.Resveratrol is a Sirtuin1 gene activator.

    The dose of resveratrol determines the capability of resveratrol to diminish cell senescence, with doses that exceed dietary intake but are not pro-oxidant mega-doses (100-350 mg) being appropriate.Resveratrol induces autophagy, the degradation and disposal of damaged cellular parts.

    Another interesting finding is that the ratio of copper over zinc in human tissues is considerably higher in senescent individuals compared to middle-aged adults.Zinc is identified as a regulator of autophagy.Biologists, knowing zinc deficiency in aging is common, suspect there may be a connection between a shortage of zinc and senescence.On the other hand, copper is known to induce senescence.Sub-toxic levels of copper have been shown to induce cell senescence.Supplemental zinc counters the effects of copper.

    Of interest, resveratrol helps to restore the proper zinc/copper balance.

    Dasatiniib, a drug used to treat leukemia (cancer of the blood), used in combination with quercetin, is a protein kinase enzyme inhibitor.Resveratrol inhibits protein kinase C and therefore would make a good companion with quercetin.

    After full childhood growth is completed, around age 18, some cells in the human body cease division and renewal (called mitosis) and become senescent — that is they retire and grow old.These senescent cells instigate low-grade inflammation, develop gene mutations, accumulate cellular debris called lipofuscin and cell energy compartments (mitochondria)

    Don’t grow old waiting for senolytic drugs.

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