Levamisole: metabolite aminorex

I would strongly recommend not including levamisole in any course of research into  possible use as a senolytic.


Why is cocaine adulterated with an animal dewormer? Mystery solved?

Aminorex, a metabolic of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters. Hofmaier T et al. Neurochem Int 2013 Dec 1


Wide exposure to levamisole due to contaminated black-market cocaine has lead to cases of hematologic and vascular side-effects.

Vasculopathic purpura and neutropenia caused by levamisole-contaminated cocaine.




A cautionary note for users of antioxidants


In cells, some oxidants are needed: Reactive oxygen molecules cause damage in diabetes and many other illnesses, but also can warn cells to defend themselves

Within our bodies, high levels of reactive forms of oxygen can damage proteins and contribute to diabetic complications and many other diseases. But some studies are showing that these reactive oxygen species (ROS) molecules sometimes can aid in maintaining health — findings now boosted by a surprising discovery from Joslin Diabetes Center researchers.

Led by Keith Blackwell, M.D., Ph.D., Associate Research Director and co-head of the Section on Islet Cell and Regenerative Biology at Joslin Diabetes Center and Professor of Genetics at Harvard Medical School, the scientists studied a protein known as IRE-1 in the outer membrane of the endoplasmic reticulum (ER), an “organelle” in the cell that synthesizes proteins such as insulin. IRE-1 stands guard over the ER, triggering alerts when these synthesized proteins are misfolded and thus allowing cells to take corrective measurements.

The Joslin scientists discovered that this membrane protein also can react to ROS molecules surrounding the ER, kicking off an antioxidant response that increases the cell’s resistance to stress.

“It’s surprising to see the same molecular sensor doing two different things, like a combination smoke/carbon monoxide alarm,” says Dr. Blackwell, senior author on a paper published in the Molecular Cell journal and Professor of Genetics at Harvard Medical School. “A major sensor of misfolded proteins in the ER turns out to be a major sensor of ROS, acting in a completely different molecular pathway with a completely different function.”

The discovery highlights the need to consider ROS molecules not just as protein-wrecking machines but as links in the chains of cell pathways, Dr. Blackwell says.

“It’s clear that at high levels, ROS molecules can damage proteins, promoting aging and worsening disease states,” he says. “But over the past several years, there’s been a growing body of evidence that there are also ROS molecules that appear to be physiologically normal and act as normal cell signals.”

The Joslin team studied IRE-1 first in the cells of the simple nematode C. elegans and then in human cells, where the molecular pathway works in essentially the same way.

“IRE-1 really has two faces,” Dr. Blackwell says. “On the one hand, it senses misfolded proteins inside the ER, and it turns on a corrective mechanism called the unfolded protein response (UPR). On the other hand, when IRE-1 gets a signal from ROS molecules outside the ER, it shuts off the UPR response and turns on an antioxidant response. Also surprisingly, this functional switch is mediated by a single oxygen molecule, which attaches to a single amino acid at a very critical place in IRE-1 — and this relatively subtle alteration has a dramatic effect.”

The protein, which has long been studied for its role in ER health in many diseases, can now be analyzed for its role in ROS pathways as well.

As Dr. Blackwell notes, high levels of ROS molecules are associated with diabetic complications. It’s possible that these molecules worsen complications not only by catastrophically damaging proteins but by obstructing normal gene regulatory pathways, he suggests.

Another potential key action for IRE-1 in diabetes arises in pancreatic beta cells. These cells synthesize insulin in the ER, and the ER may be placed under stress if it produces high level of the hormone while trying to handle insulin resistance or a type 1 diabetes autoimmune attack. “Beta cells then would rely on IRE-1 to protect the ER, and this could have a negative effect on antioxidant defenses,” Dr. Blackwell says.

His lab is probing deeper into IRE-1’s ROS and ER pathways, and studying how they might eventually be targeted to improve treatments. Among their work, the investigators are looking at how ROS affects gene regulatory responses in cells that are exposed to elevated glucose levels or other stimuli.

As Dr. Blackwell points out, the Joslin study also sounds a cautionary note for people who take antioxidants in the hope of protecting themselves against damage from ROS.

“In clinical trials, therapies with antioxidants have been pretty much a bust, and it’s not entirely clear why,” he says. “But blindly consuming large doses of antioxidants is probably not the best idea, because while your intent would be to protect yourself from damage, you’re also potentially interfering with normal ROS signals that are helpful and important.”


Story Source:

The above post is reprinted from materials provided by Joslin Diabetes Center. Note: Content may be edited for style and length.

Doubts on the role of free radicals in aging


Forget the antioxidants? Researchers cast doubt on role of free radicals in aging

February 17, 2009
For more than 40 years, the prevailing explanation of why we get old has been tied to what is called oxidative stress. This theory postulates that when molecules like free radicals, oxygen ions and peroxides build up in cells, they overwhelm the cells’ ability to repair the damage they cause, and the cells age.

An industry of “alternative” antioxidant therapies — such as Vitamin E or CoQ10 supplements in megadose format –has sprung up as the result of this theory. However, clinical trials have not shown that these treatments have statistically significant effects.

And now researchers at McGill University , in a study published in the February issue of the journal PLoS Genetics, are calling the entire oxidative stress theory into question. Their results show that some organisms actually live longer when their ability to clean themselves of this toxic molecule buildup is partially disabled. Collectively, these molecules are known as reactive oxygen species, or ROS for short.

Dr. Siegfried Hekimi of McGill’s Department of Biology, said most of the evidence for the oxidative stress theory is circumstantial, meaning oxidative stress could just as easily be a result of aging as its cause.

“The problem with the theory is that it’s been based purely on correlative data, on the weight of evidence,” explained Hekimi, McGill’s Strathcona Chair of Zoology and Robert Archibald & Catherine Louise Campbell Chair in Developmental Biology. “It is true that the more an organism appears aged, whether in terms of disease, or appearance or anything you care to measure, the more it seems to be suffering from oxidative stress”.

“This has really entrenched the theory,” he continued, “because people think correlation is causation. But now this theory really is in the way of progress.”

Hekimi and postdoctoral fellow Jeremy Van Raamsdonk studied mutant Caenorhabditis elegans worms. They progressively disabled five genes responsible for producing a group of proteins called superoxide dismutases (SODs), which detoxify one of the main ROS. Earlier studies seemed to show that decreased SOD production shortened an organism’s lifespan, but Hekimi and Van Raamsdonk did not observe this. In fact, they found quite the opposite.

None of their mutant worms showed decreased lifespan compared to wild-type worms, even though oxidative stress was clearly raised. In fact, one variety actually displayed increased lifespan, the researchers said.

“The mutation that increases longevity affects the main SOD found in mitochondria inside the animals’ cells,” said Hekimi. “This is consistent with earlier findings that mitochondria are crucial to the aging process. It seems that reducing mitochondrial activity by damaging it with ROS will actually make worms live longer.”

The researchers hasten to point out that they are not suggesting that oxidative stress is good for you.

“ROS undoubtedly cause damage to the body,” Hekimi said. “However, they do not appear to be responsible for aging.”

More information: dx.plos.org/10.1371/journal.pgen.1000361

Provided by McGill University


‘one of the most important aging discoveries ever’


The science news circuits have been buzzing about Jan van Deursen’s recent paper, in which mice stayed younger, longer when their senescent cells were removed.  They’re right to call this technology a game changer for anti-aging medicine.  They’re wrong to say this is new—in fact, the recent paper advances only incrementally over van Deursen’s stunning results from 2011.  But what they don’t explain very well is that so far this technology only works for specially-prepared mice.  The mice are genetically engineered (before birth) to make their senescent cells vulnerable to a trigger that can be administered later, when they are old.  We don’t yet have a way to selectively kill senescent cells in a natural mouse, or a natural human.

(Background is in my blog post of last spring.)

As we get older, a tiny minority (~1 in 10,000) of cells becomes senescent, usually through telomere shortening that goes so far as to compromise the integrity of the chromosomes.  The number of cells is small, but they do outsized damage, by secreting signals into the surrounding region and even into the body as a whole that turn on inflammaging, which is one of the primary modes by which the body destroys itself.  Chronic, systemic inflammation is linked to all the diseases of old age, especially arthritis, cancer, arterial diseases and Alzheimer’s.

The original paper from 2011 reported on a novel idea to test the hypothesis that getting rid of this tiny number of cells could have a positive impact on the whole body.  The experiment required genetically engineered mice.  That means their genes were modified in the egg stage, when the incipient mouse is still a single cell, and there’s only one set of genes to modify.  Mice could be prepared in such a way that a particular gene called p16 was associated with an added gene that made the cells extremely vulnerable to a drug that wouldn’t otherwise have damaged them.  This was done because senescent cells express p16, while normal cells don’t.  So administration of the drug would kill just the senescent cells, while leaving normal cells alone.

The results of the experiment were dramatic.  Animals that had their senescent cells removed lived 20-25% longer, and were healthier and more active at an age when other mice were in steep decline.  In the recent paper, life extension was bumped up marginally to 24-27%.

From my perspective as theorist, I take this as confirmation of the idea that aging is part of the developmental program, not an unavoidable side-effect or “accumulated damage” as standard thinking allows.

  • The body is assassinated by signaling, not by damage.
  • Much of the signaling comes from a tiny minority of cells that the body could eliminate, but doesn’t.
  • And furthermore, there is no need for this minority to become senescent in the first place.  They become senescent for want of telomerase, despite the fact that every cell in the body includes the telomerase (TERT) gene, and has the potential to produce telomerase, if it were instructed to do so.  (There are many species that DO produce telomerase through their lifetimes, including mice, pigs, and cows.)

Most scientists have yet to assimilate this paradigm shift, and the popular press glosses over it with glib quotes.

This seems perverse, but there’s method to the body’s madness. Cells undergo senescence because they accumulate damage that could potentially lead to cancer, and the molecules they secrete prompt the immune system to come over and clear them. “It’s a very potent anti-cancer mechanism,” says Baker. But as we get older, the immune system falters, and senescent cells accumulate. Now, the molecules they secrete become problems rather than solutions.

Even then, senescent cells have benefits. Last year, Campisi showed that these cells help to heal wounds. And sure enough, Baker and van Deursen found that their mice heal more slowly after such cells were removed. [quote from TheAtlantic]

But (1) the cancer hypothesis has been abandoned even by its principal proponent, Judith Campisi.  Senescent cells cause a net increase in cancer deaths.  And (2) the idea that secretions from senescent cells may marginally increase wound healing efficiency cannot explain their evolutionary provenance if the small good is outweighed by a larger harm.  The net result is that they kill us.  (I wrote a related column last year.)


The Future

This technology holds up the possibility of a quick avenue toward life extension in humans that could be delivered in a treatment starting in middle age or even later. But promising as this idea is, it remains an idea and not a treatment that can be tested.  Up until now, it only works in genetically engineered animals, and not in natural mice or you or me.  What we need is a medication that will kill senescent cells while leaving normal cells undamaged.  This is akin to the idea of chemotherapy, but perhaps somewhat easier because we have already identified a single genetic marker (p16) to identify the cells we want to kill, and because the cells are not proliferating and mutating as they are in a cancer patient.  Nevertheless, there is a substantial challenge in finding the medication that can kill almost all senescent cells while leaving almost all other cells undamaged.

The word for such an agent is senolytic.  Last year, two effective senolytic agents were reported: quercetin, a common botanical extract, and Dasanatib, a chemo drug [my blog post from last spring, including reference].  Though they prove the principle, they don’t distinguish senescent cells efficiently enough to offer an attractive therapy.

Some promising anti-aging technologies are being ignored by researchers and pharmaceutical companies, but this isn’t one of them.  The good news is that there is a race on to test senolytic agents, with at least half a dozen labs competing to find powerful and non-toxic senolytic agents.  Oisin Biotech is a start-up with a liposomal technology.  Van Deursen and Campisi have their own for-profit spinoff, called Unity Biotechnology.  This is now a problem of synthetic chemistry and testing, and we should know within a year or two if they are finding success.

How Soviet scientists did gene modification to grain long before the West had an understanding of the phenomenon.

Many plants that grow in climates with a cold winter require growth for several months at low temperatures—a process called vernalization—to promote flowering in spring, when days lengthen and temperatures increase.

  • Epigenetic memory impacts gene expression over short and long timescales.
  • Epigenetic memory perpetuates altered gene expression or alters the potential for gene expression.
  • Different mechanisms of epigenetic memory require distinct, chromatin-based changes.

Although genetics has an essential role in defining the development, morphology, and physiology of an organism, epigenetic mechanisms have an essential role in modulating these properties by regulating gene expression.


Genetic memory (biology)


how plants remember winter

J. Exp. Bot.-2006-Sung-3369-77

How plants erase the memory of winter

Plants decide when to flower in response to environmental cues through a complex gene regulatory network. In some species, flowering requires the plant to be exposed to prolonged periods of low temperatures, like winter cold. This process is known as vernalization and it is crucial for growing several crops such as wheat, barley and all the Brassicaceae family (rapeseed, mustard, cabbage, broccoli, etc.).

Vernalized plants are able to remember winter by keeping silenced a floral repressor during subsequent growth at warm temperatures in the spring. This “epigenetic memory” is erased and the floral repressor is reactivated during seed formation. This process ensures that the next generation of plants maintain a vernalization requirement to flower. However, the genetic mechanisms which control this resetting process remained unknown until recently. A study by Pedro Crevillén from CBGP working with colleagues from John Innes Centre (Norwich, UK) and The Chinese Academy of Sciences published in “Nature” has discovered how this memory of winter is erased between generations.

Epigenetic marks are heritable chemical modifications that regulate genome function without altering the DNA sequence. For example, twins share the same DNA sequence, but a fine analysis of their genomes reveal that they are marked differently by epigenetic modifications accumulated throughout their lives. This fact explains, to some extent, the observed differences between identical twins.

In the model plant Arabidopsis thaliana, there is gene called FLC that acts as a “floral brake”. This floral brake is silenced during the winter. After the cold, this gene remains silenced by epigenetic mechanisms in the absence of cold allowing the plants to bloom in spring. Later, this gene is reactivated in the seeds and the new plants require to overwinter (vernalize) to flower again.

Vernalization is a process of great importance for a number of crops. In the case of wheat, different varieties must be sown in different seasons depending on their vernalization requirement. In recent years, due to the effects of climate change, winters are less cold than they use to be. This reduces crops yield because some plants are unable to flower at the right time. Dr. Crevillén said that the results of this study, led by Prof. Caroline Dean from John Innes Centre, may allow us to get more productive plants varieties in the current environmental conditions.


The study, published in Nature entitled “Epigenetic reprogramming that prevents transgenerational inheritance of the vernalized state”, characterized how the epigenetic memory of vernalization is erased at the molecular level. The authors also show that ELF6 gene is required for this epigenetic reprogramming. This research work was made possible by the isolation of a mutant ELF6 gene which made the plant able to “rememeber” vernalization across generations. This mutant is one of the few examples of transgenerational epigenetic inheritance that has been studied in plants. “This work recalls the ideas of Lysenko, the Soviet botanist who wrongly claimed that the progeny of vernalized wheat would flower increasing their production,” said Dr. Crevillén. “However, he was wrong and we now know that vernalization is needed in every generation for plants to flower.”

Epigenetic changes also affect humans. Scientists have recently discovered that epigenetic transgenerational inheritance affects not only plants but also animals and therefore humans. Initially, it was thought that epigenetic changes could only be inherited from cell to cell within the same organism, but not from one generation to another, ie from parents to children. However, numerous studies are suggesting that a small part of this epigenetic information is not erased and is transmitted to the offspring. For example, malnutrition in expectant mothers causes epigenetic changes that affect not only their children, but may have consequences for their grandchildren growth. This is a hot topic nowadays which has caught the international community attention, although more research is still needed.

The next step to complete the study, according to first author Dr. Crevillén, would be to deeper into the mechanisms of how plants regulate flowering in response to changes in ambient temperature. “These studies become more important today if we want to prevent the adverse effects of climate change, because we know that increasing temperatures cause epigenetic changes that regulate flowering time”, says Crevillén, who has recently been awarded with a Ramón y Cajal contract to continue his research.

Original Paper:

Crevillén, P; Yang, H; Cui, X; Greeff, C; Trick, M; Qiu, Q; Cao, X; Dean, C. “Epigenetic reprogramming that prevents transgenerational inheritance of the vernalized state“. Nature. DOI:10.1038/nature13722


Centre for Plant Biotechnology and Genomics U.P.M. – I.N.I.A. Parque Científico y Tecnológico de la U.P.M. Campus de Montegancedo
28223 Pozuelo de Alarcón (Madrid) Tel.: +34 91 4524900 ext. 1806 / +34 91 3364539 Fax: +34 91 7157721. Contact



Plants must be able to forget the epigenetic memory of winter in order to adapt to unpredictable weather.

Current Biology


The Legacy of Lifestyle

Individuals born during the Dutch Hunger Winter of 1944–45 have altered epigenetic programs that may render them more susceptible to conditions such as diabetes than their siblings born before or after the famine. Credit: Nationaal Archief.

Kids are full of surprises, right down to the coded biological programs they inherit, which may contain subtle chemical reminders of their parents’ lifestyles. But if our parents’ lifestyles are encoded in our biology, as some scientists speculate, then the way we think about health and lifestyle will change dramatically.

The general assumption is that our parents’ lifestyles reach our genes only in the womb, through biochemical factors associated with maternal behavior during pregnancy. New research indicates, however, that we might actually inherit our fathers’ lifestyles through a genetic mechanism that would come into play before the prenatal period.

The study, led by Duke University geneticist Adelheid Soubry, is the first to describe a correlation between a father’s obesity prior to conception and changes in chemical marks on a gene known as IGF2 (insulin-like growth factor-2) in his offspring. The biological significance of the changes is as yet unclear, but the findings raise important questions about our inheritance of health.

The chemical “marks” Soubry and colleagues examined consist of methyl groups, which latch on to DNA in a process known as methylation. In animals, lifestyle factors such as diet can alter genes’ methylation status, and in some cases those alterations have been found to stick, being passed from parent to offspring and even to generations beyond (see my previous post on transgenerational epigenetic inheritance for more detail).

The inheritance through generations of chemical, or epigenetic, modifications acquired during a parent’s life before the conception of offspring offers an intriguing explanation for nature-nurture, or gene-environment, interactions. The prospect of its existence in humans is tantalizing, especially because of evidence that chemicals in our environments, including substances in food and household products, can alter gene expression without causing direct mutation in DNA. Those changes in gene expression might, in theory, increase our susceptibility to conditions such as diabetes or autism.

Epigenetic modification plays a key role in embryonic development by influencing the process of differentiation, in which cells are assigned gene expression profiles that guide their specialization, determining whether they become skin or muscle cells, for example. Modifications involved in development occur on imprinted genes, which come with parent-specific methylation marks. In a zygote (fertilized egg cell), those pre-existing modifications are erased and then established anew following sex determination. The zygote recreates the marks according to the inherited “epigenetic memory,” the program coded by the modifications in parental egg and sperm. The types of modifications that might be linked to lifestyle and acquired by the mother or father presumably become part of the epigenetic memory, or they might escape erasure altogether.

For humans, direct molecular evidence for the fetal uptake of epigenetic change, even from the mother, with whom the fetus shares an intimate environment, remains elusive. The most convincing proof is with a gene known as PPARGC1A, methylation of which in newborns has been linked to maternal body mass index, suggesting a potential role for methylation status in metabolic regulation.

Observational data, on the other hand, are more abundant, and they reveal compelling correlations. For example, in 2008 a team of scientists led by Columbia University epidemiologist L.H. Lumey reported that IGF2 methylation in adults who had been exposed prenatally to famine during the Dutch Hunger Winter of 1944–45 was reduced compared with methylation in younger or older siblings. Six decades later, those individuals who were exposed prenatally to famine were found to be at increased risk of insulin resistance, which frequently is associated with diabetes.

The Dutch Hunger research suggests that the health affects of changes in IGF2 methylation might not manifest in offspring for years. Unfortunately, that means that the impact of Soubry’s observations of obesity in fathers and IGF2 methylation in offspring probably won’t be known for some time.

We have plenty to mull over while we wait, however, including a commentary published alongside Soubry’s paper by University College London scientists Gudrun E. Moore and Philip Stanier. The commentary emphasizes the role of IGF2 as an imprinted gene.

Imprinted genes are atypical, and not only because they possess our epigenetic memory. Unlike most other genes, where we inherit two working copies (one from each parent), we carry only a single functional copy of each imprinted gene. In the case of IGF2, we inherit the functional copy from the father, while methylation renders the mother’s copy inactive.

Lumey’s and Soubry’s studies suggest that maternal famine and paternal obesity are both linked to decreased IGF2 methylation. However, maternal famine during the Dutch Hunger likely also coincided with paternal famine, and Soubry and colleagues, Moore, and Stanier speculate that undernutrition in the father, too, may be associated with the gene’s reduced methylation. No one has actually investigated that association, but if this is true, then the relationship between a father’s nutrition prior to conception and IGF2 methylation in his children may be even more complicated.

Deciphering the nuances is critical, because whether famine- or obesity-related, any supposed inherited change in IGF2 methylation raises concern about the possibility of long-term health consequences. Cancer and other chronic diseases have been associated with similar alterations in IGF2 methylation.

While the science is complex, the solution may be simple, if we consider this simple observation: kids adopt their parents’ behaviors, for better or worse. If we want the legacy of our lifestyles to be a healthy one, we need to lead by example, and that takes practice, initiated well before our little ones come along.

The views expressed are those of the author(s) and are not necessarily those of Scientific American.

The Senolytic Manifesto

Senescent Cells gonna’ get yo’ Mama

_The Senolytic Manifesto_

Kill or Be Killed: Senescent cells got plans for you, baby.  They know the future and it is murder.

The war on senescent cells is joined with a small but flexible armory of ‘magic bullets’ to take out the renegade cells that may doom us to cancer, progressive dementing disorders, and plain rotten miserable old age.

These cellular hangers-on have no interest in the collectivity that constitutes “you”, “me”, or us. They stand between us and a virtually unlimited healthy lifespan.

Do we negotiate with this terrible fifth column?  Pshaw no!, and piss on you, Jack!

As for me and the Immortalist International, we are fighting mad and fighting smart.

Our antioxidant armour, vitamins, superfoods, blood-pressure pills, and meditations won’t save us now. As that wondrous cold war piece-of-work Ronald Reagan asserted, “We do not negotiate with terrorists.”

The dying cells within us are not cutting any deals. They leak inflammatory intercellular communications better than a newsroom shop-steward exhausting the employers resources to affect an ultimate victory, even unto the inevitable collapse that will create a wondrous new utopia: a little patch of paradise for the worms whose cysts already populate our flesh.  They will  wait only hours after death to redeem their birthright; our previous bodies, our precious bodily fluids.

Surveillance is a useful measure but would only amount to documenting the advance of aging due to cell cycle arrestees. Mere cell cycle arrest isn’t adequate to control this situation. Only extermination or extirpation can be effective to win us back our lives. Against such a scattered band of opponents, skillful timing may prove the pivotal tactic in our armamentarium.

As in any armed conflict, we would be wise to effect senescent cell clearance when the time is opportune and with all the force and precision our science affords us.  We must learn the calculus of senescent existence and strike when they are most vulnerable.

The only prisoners will be those people that will not fight the onslaught of the forces of decrepitude.

Cower in your bedsit microwaving geri-kibbles as your teeth drop, boobs sag, and sphincters alternately seize and leak?    Do expect coffin vendors, bequest-seeking offspring, and bill collectors to call. It may be a mercy if fortune leaves you too impoverished to afford a phone.  Expect that preachers and insurance representatives will be dickering over your still walking remains. Are you mad?

We are hostage to an insurgent force of decrepit flesh that is nonetheless weakened and vulnerable.

Seniors of the world, cast off your chains!

If you stand any chance of cashing in on that pension (O, you fortunate few!) you had best learn how to stay on your feet, to keep the dendrites turning over, and to keep your eyes and palms open for the chance to grab some ‘tech’ to balance the odds more in your favour. And it now appears that effective anti-cell insurgency substances are readily available for the brave.


The time has come; the weapons have been paid for and the enemy will not be any less formidable in the future.  Fortunately for us, it’s weakness is inherent.

The irons are hot and the time for cautery has arrived.

Senolytic medicines may save your sorry ass, just give them a clear line of fire and keep the ammo coming. We have no reasonable alternative.

Joseph Hogan,

Victoria, BC  14 Feb 2016

We would like to acknowledge that the land we live and work on is First Nations’ territory. The city of Victoria and surrounding area lies on the territories of various Straits and Coast Salish peoples including, but not just, the Esquimalt, Songhees, and WSANEC.

Introductory note

Senolytic Agent


UVic student, retired RN (gerontology),
Long time life-extender (dating from John A. Mann, _Secrets of Life Extension, 1980 ISBN-13: 978-0936602066), more recently a first-time (intermittent) killer of senescent cells, cultivator of telomeres, peptide tinkerer, C60oo experimenter.

Newly returned from forced obscurity, Joseph is now renewing his footprint on the internet and is networking with various talents in the field of radical life extension/health enhancement, and sexual medicine.
Contact Me



“We cannot wait for favors from Nature. To take them from it – that is our task.”

lysenko and joe
Josef Stalin recognizes the revolutionary contribution of the methods and science behind the horticultural innovations of Lysenko, Mascherin, and others.
So spoke groundbreaking Russian horticulturalist Ivan Vladimirovich Michurin.  I endorse his sentiment and copy some of his methods in my quest to create another true “New Soviet Man”.

One particular immune stimulant that excited my attention back in the ‘eighties: Levamisole, available at livestock medicine sections of local agricultural feedstores.


[Edit, 19 Feb 2017:   Two proven senolytic compounds are dasatinib and quercetin. See: Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan ]

As I understood it following a dose of levamisole macrophages go on a killing frenzy. They gobble up every slightly deformed membrane protein then gobble up the cell it damaged doing that and then the whole population of macrophages crashes…death by gluttony.

Sweet, eh?  We should all die so happy!

One is left relatively immune exhausted for a week  until stem cells divide enough to replace the newly departed. Caution is in order with exposure to infectious patients. I was in a very clean presurgical service so this wasn’t a problem.

Levamisole has a rather unique and intriguing side effect: at random moments one is overcome with an olfactory hallucination. I’d never heard of that until Lev delivered a number each day of treatment and got me hitting the books.

The overwhelming odor was of bleach. I like bleach smell very much.  In hospital it means someone’s been cleaning;  not as common an event as we’d hope.

Macrophages do their lethal work with cytotoxins.  I wonder if these cytotoxins are rich in Cl- ions?   What the ‘hallucination’ may have been was my nose turned inward and smelling my own blood awash in macrophage cytokines. Awesome hypothesis, no?

For cell clearance Levamisole is awesomely powerful, cheap, easily available, but from what I read rather indiscriminate. I don’t know if it releases programming to macrophages as to which particular cells it’s going to go gobble up. It might trigger the “gobbling up” of articular cartilage.  That would truly suck bigtime.

I think Levamisole stands another look.

Its use for senescent cell destruction (presuming it actually does trigger that) could be patentable.  Levamisole clocked off patent protection as a livestock dewormer decades ago.  It may  never  have been patented for human use. The crushing expense of clinical trials would be required before medically supervised therapy could be delivered.

With recent discussion of enhancing telomerase to delay a cells entry into senescence I wonder if delaying  is ultimately a good strategy for longevity.  I hypothesize that one is favoring the survival of mutation-carrying and ultimately carcinogenic cells thereby.
If cells remain in the reproductive stage for longer periods due to the protection that extended telomeres give them there is longer for mutation and aberrant chromatin  to result in later disease and dysfunctional cell suicide.  All cells aberrant or not will age into senescence.   Is blocking the exits from the cell cycle a good idea?
Triggering rather than suppressing apoptosis would seem a more promising a strategy. Enhancing apoptosis would in effect crowd the exits, but macrophages and other defense are obviously eager to “punch their tickets”  and even more effectively with timely delivered stimuli from senolytic agents.

I’m going to wait a year to use Epithalon peptide to lengthen any teleomeres after thirty or so cycles of senescent cell clearance with EMIQ.  I don’t want to be adding extended  life to any unfit cells.

Promote longevity  _after_  culling the population of decrepit cells.

  • You may be right.

    In that case it may be better to kill off the senescent cells then.

    We won’t know until we try.

    >I am directing my readings and experiments to plausible mechanisms of SASP population removal.— in this case I believe we cannot afford to wait for evidence.

    In that case the best treatment may be to come with something that identifies cells that are near-senescent (ex: with short telomeres) and instruct them to produce telomerase.

    Giving those cells more telomerase would effectively rescue the unfit.  Take ’em out, let pristine stem cells spawn take over.

    Here starts the Soviet connection:

    Vernalization (a Russian invention) changed frozen wheat to a different phenotype sans genetic mods. I wouldn’t expect to be able to devernalize back to winter wheat (vs. spring wheat). but who knows.

    So descenescence shouldn’t seek to protect current gene-expression by telomere extension, but by simple elimination of the unfit.


    It is possible to devernalize a plant by exposure to high temperatures subsequent to vernalization. For example, commercial onion growers store seeds at low temperatures, but devernalize them before planting, because they want the plant’s energy to go into enlarging its bulb (underground stem), not making flowers.[17]




    Lysenko Lives!

    Vernalization, Competence, and the Epigenetic Memory of Winter

    Vernalization is the process by which prolonged exposure to cold temperatures promotes flowering. Over the past century, this process has been studied extensively at the physiological level. Recent studies have provided some insight into the molecular basis of vernalization. The rich history of vernalization research has been discussed in detail in many reviews (Chouard, 1960; Lang, 1965; Bernier et al., 1981). I will briefly summarize some highlights and classic experiments that I would like to relate to recent molecular advances.


    The first papers describing exposure to cold as the specific climatic aspect of winter that was necessary for flowering in some species were published in the latter half of the 19th century. However, the work of Gassner (1918) is usually cited as the first report that a wide range of plant species require cold exposure to flower (Chouard, 1960; Lang, 1965).

    There are several ways to classify the vernalization responsiveness of plants. One is whether a requirement for exposure to the prolonged cold of winter to flower influences the plant’s life history. Monocarpic species senescence after flowering and setting seed. Monocarpic plants that require vernalization to flower thus typically require two seasons to complete the life cycle and are usually classified as biennials or winter annuals. The term biennial is often used for plants that have an obligate requirement for cold exposure to flower, and the term winter annual is often used for plants with a quantitative cold requirement (Lang, 1965; Figure 1A). Monocarpic species that flower in one growing season without a vernalizing cold treatment are often called summer annuals. Many polycarpic species (i.e., perennials) also require a vernalizing cold treatment to enable flowering.

    The distinction between summer annuals and winter annuals or biennials is not always absolute. It is possible that genetically identical plants could behave as summer annuals in one location and as winter annuals in a different location with a different climate. Furthermore, these classifications do not imply fundamental differences in the mechanisms that control flowering. In Arabidopsis, for example, single-gene changes can convert plants without a vernalization requirement into plants that have either a quantitative or obligate requirement or vice versa; therefore, the relevant molecular differences between plants in various categories can be minor.

    Many winter annuals and biennials become established in the fall, taking advantage of the cool and moist conditions optimal for their growth. The vernalization requirement of such plants prevents flowering until spring has actually arrived. Weather is often variable, so for a vernalization requirement to work as intended, plants must not only sense cold exposure but also have a mechanism to measure the duration of cold exposure. For example, if a plant is exposed to a short period of cold in the fall season, followed by a return of warm temperatures later that fall or in early winter, it is important for the plant not to perceive the brief exposure to cold and the following warm weather as spring. One mechanism to determine that spring has in fact arrived is to measure the duration of cold and to permit flowering only after a period of cold that is sufficient to ensure that winter has passed. Sensing the increasing daylengths in the spring can also play a role. In many perennial species, the release of buds from dormancy only after perception of a sufficient duration of cold exposure is, like vernalization, designed to measure the duration of a winter season. Processes that require prolonged exposure to cold, such as vernalization and the cold-induced release of bud dormancy, stand in contrast with cold acclimation—a process designed to respond to cold as rapidly as possible (Thomashow, 2001).

    Within a given species, there can be variation in the extent to which vernalization affects flowering time. In some species there are varieties that require vernalization and others that do not, such as winter and spring varieties of cereals (e.g., winter wheat and spring wheat). In fact, the term vernalization comes from studies of flowering in cereals. The infamous Russian geneticist Trofim Lysenko, who studied the effect of cold on flowering, coined the term jarovization to describe what we now call vernalization. Spring cereals are called jarovoe in Russian (derived from Jar, the god of spring), and cold exposure causes a winter cereal to behave like a jarovoe (i.e., to flower rapidly). Jarovization was translated from Russian into vernalization; vernal is derived from the Latin word for spring, vernum (Chouard, 1960).

    A useful definition of vernalization is provided in Chouard review (1960, p. 193): “the acquisition or acceleration of the ability to flower by a chilling treatment.” Two types of experiments demonstrate that this acquisition or acceleration is occurring at the shoot apex. One is to locally chill only certain parts of the plant. Another is to graft shoot tips: In most species, if a vernalized shoot tip is grafted to nonvernalized stock, it will flower, but a nonvernalized shoot tip grafted to a vernalized stock will not flower.

    As noted in the above definition, cold exposure does not necessarily cause flowering but rather renders the plant competent to do so. A classic demonstration of this comes from the work of Lang and Melchers (reviewed in Lang, 1965) using biennial Hyoscyamus niger (henbane). Biennial henbane requires vernalization followed by inductive photoperiods to flower. If vernalized henbane plants are grown in noninductive photoperiods, they continue to grow vegetatively. However, if such plants are later shifted to inductive photoperiods, they flower. This shows that the vernalized plants are able to remember their prior vernalization; that is, they had acquired competence to flower but did not actually do so until the photoperiod requirement was met. Thus, vernalization establishes a cellular memory that is stable through mitotic cell divisions. The length of this memory of winter varies among plant species; in some species it is much shorter than in henbane.


    the rest of the read @:





    One of the most highly cited phrases by Michurin is:

    “We cannot wait for favors from Nature. To take them from it – that is our task.”

Human implant


Human implant: broccoli can help beat breast cancer by passing genetic material into human body, scientists in California claim

Stephen Chen chen.binglin@scmp.com

Broccoli may prevent or stop the growth of breast cancer by modifying the expression of certain human genes, according to a new study published in the latest issue of the journal Cell Research.

The vegetable, which is part of the cruciferous, or cabbage, family, has long been known for its health effects, including potential anti-cancer effects targeting the mouth, throat, neck and head.

The latest study suggested that it works by transferring genetic agents called micro RNA (miRNA) into the body. These are short, single strands of nucleic acid involved in genetic coding, decoding and expression, according to the paper.

The research team confirmed for the first time that miR159, which is commonly found in plants but has a particularly high presence in broccoli, can inhibit the growth of tumour cells in the human breast, it said.

The team was led by Dr Emily Wang at the City of Hope Beckman Research Institute And Medical Centre in California.

The study demonstrated for the first time that a plant’s micro RNA (miRNA) can inhibit cancer growth in mammals. A dose of miR159 (pictured) can significantly suppress the growth of breast tumours in mice, it found. Credit: Cell Research

Further experiments with mice showed that feeding them this form of miRNA could reduce the onset and progression of breast cancer.

“Oral delivery of tumour-suppressive plant micro RNA may provide a new non-invasive strategy for cancer prevention and treatment in humans,” Wang said.

But because the animals were not directly fed with broccoli, “it remains to be seen whether therapeutic levels of plant micro RNAs can be reached through consumption of specific foods,” she said.

“If this is the case, then dietary changes may improve currently existing cancer therapies,” she added.

Dr Jiang Peng, a biological researcher with the School of Life Science at Tsinghua University in Beijing, said it would be “really exciting” if the study’s findings were confirmed.

“It means plants can meddle in our genes, and that has long been regarded as impossible,” he said.

RNA is less stable than DNA due to its single-strand structure, but miRNA can be almost impossible to destroy and can be passed from plants to humans to influence gene expression. Credit: SCMP Pictures

Previous studies in the United States have also shown that certain vegetables may have anti-cancer properties.

In December 2012, researchers at the Baylor College of Medicine in Texas found a concentrated form of sulforaphane in broccoli. This compound has been shown in laboratory tests to reduce the number of acute lymphoblastic leukaemia cells – a cancer of the white blood cells common in children.

“There is about an 80 per cent cure rate, but some children don’t respond to treatment,” Dr Daniel Lacorazza, assistant professor of pathology and immunology at the college, said at the time.

“For those cases, we are in need of alternative treatments.”

Nonetheless, the majority of biologists remain skeptical about whether a plant’s RNA can actually enter the human body. Typically, it perishes quickly after exiting a living organism because of its unstable, single-stranded structure.

In order to enter the human body as food, the genetic agent has to go through a number of destructive processes, namely, being cooked, masticated and then digested. If it manages to survive all of these, it still has to contend with the human immune system, which is nothing if not hostile to “alien” genes.

Emily Wang, Ph.D., associate professor in the department of cancer biology at the City of Hope Beckman Research Institute And Medical Centre in California, led the research team. Photo: Handout.

But a few years ago, a team led by Professor Zhang Chenyu at China’s Nanjing University in eastern Jiangsu province discovered for the first time that miRNA can be passed from plants to humans directly.

The team claimed to have found traces of the plant’s physically intact miRNA in the human body, despite the plant having been boiled, fried or steamed before it was consumed and digested.

A follow-up study by Zhang’s team reportedly went on to show how miRNA from the arching shrub honeysuckle could enter the human lungs to bind and kill the flu virus, or common cold.

But attempts by researchers at Harvard and Stanford universities to replicate Zhang’s success failed. Some have argued that if the Chinese scientists’ claims were indeed true, the phenomenon may be limited to Asians.

But the latest study by Wang’s team seems to support Zhang’s results.

Wang detected miR159, which is only produced by plants, in the blood of human donors from Western countries like the US and breast cancer patients.

Farmers harvest broccoli at a vegetable base in Hefei, capital of East China’s Anhui province, last Thursday. A protracted cold spell has taken a heavy toll on the supply of fresh produce in the country. Photo: Xinhua

Her team also found that the higher the level of miR159 found the blood, the less likely a person was to get breast cancer. For patients already afflicted with one or more tumours, higher doses in the blood were found to retard the development of such tumours.

The main problem with previous studies is that they restricted their compass to traditional compounds like sulforaphane because of their stable chemical structure.

Xue Yuanchao, a researcher with the Chinese Academy of Sciences’ Institute of Biophysics in Beijing, said Wang’s results were encouraging for cancer patients, but that much work remained to be done in studying the exact role and function of miRNA.

“This is one of the most controversial topics in biology today, namely, miRNA. They seem to be indestructible, but nobody can fully explain why,” said Xue.

Plants are not believed to be able to pass their genetic information on to animals, which is why some scientists have a hard time believing they can influence humans.

Moreover, this is used a key argument by purveyors of genetically modified food when selling their products as safe for human consumption.

But if future studies confirm miRNA can be passed from plant to person, the safety evaluation codes of GM foods may need to be rewritten, Xue said.