Funding Policies Distort Science

Capital shuns risk .  —— The essence of science is exploration of the unknown.

Science and Capitalism is not exactly a match made in heaven.  Government and foundation funding has always been behind the curve of innovation, but the recent contraction in US science funding has engendered an unprecedented intensity of competition.  This has translated into a disastrous attitude of risk aversion.  A “hard-headed” business model prevails at the funding agencies, and they are now funding only those projects that they deem “most likely to succeed.”

The difference between science and engineering is that scientific research starts without understanding and tries out various hypotheses until one seems to work; while an engineer works with a paradigm that she knows to be reliable enough to be a basis for results of her innovations in advance.

A high failure rate is inseparable from good science.  But NSF prefers to fund low-risk work, which is really engineering.  


One irony is that capitalism is pretty good at allocating funds for engineering.  Once the science is well developed, the marketplace isn’t a bad model for deciding where to invest engineering resources.  We probably don’t need NSF to fund the “D” half of “R&D”.  But the reason that we need NSF (and NIH and NIA) as public funding institutions is that the rewards of science are difficult to predict.  I venture to propose Mitteldorf’s Law of Experimentation:

The more unpredictable the result, the more important the experiment.


Perverse Incentives and the Law of Unintended Consequences

Government funding pays a minor portion of each contract for salaries, equipment, and operating expenses.  The major portion is called “overhead”, and it goes back to the university (or other institution, some of them for-profit) that houses the research.  The proportion allocated to overhead “ranges from 20% to 85% at universities, and has an even wider spread at hospitals and non-profit research institutes.” [from a 2014 article in Nature; also, background and recent news here]

At a prominent midwestern medical school where I was visiting last week, my host had just received word of renewed funding for his research, breathed a sigh of relief.  For the first time in many months, he was able to put grant-writing in the background and devote his attention to the substance of his research.

There were cranes and bulldozers and signs of new construction everywhere.  It looks like healthy expansion in the health sciences.  But the reality beneath the surface is that the existing buildings were less than 70% occupied.  Why was the university building more space when they couldn’t fill the space they had?  Because the “overhead multiplier” is negotiated with NIH for the university as a whole, and has enormous consequences, dwarfing the cost of any one building.  This university had an overhead rate of 53% and the new construction was part of a push to justify raising it to 54%.  If they succeed, the University will be a little richer, and each of their research scientists will be a little poorer.


Pharmaceutical Companies are the Worst Case

Private companies are motivated to research the drugs that can be sold most profitably, not the ones that can provide the most good to the public at the least cost.  So there are orphaned drugs and there are untested nutraceuticals that are unpatentable and therefore unprofitable, but may be safer and more effective than the patented drugs—how will we know?  This represents a huge distortion of spending priorities, a sacrifice of health to profit.

There is a well-documented tendency of pharmaceutical companies to research small tweaks to their competitors’ successful drugs, rather than strike out in new areas with new ideas.  The former has a lower risk, and if the program is successful, the company can take over an entire profitable market from a competitor, with a drug that is only marginally better.  And even if the new drug is not even marginally better, frequently the company finds a way

The system that we have provides that pharmaceutical companies are responsible for testing their patented products for safety and efficacy.  This is an invitation to corruption.  In Phase III trials, a company has already invested so much in their product that if the trial results are negative then the company is on the hook for hundreds of millions of dollars.  It is too much to ask scientists to be objective under these conditions.  How can they make unbiased judgments about the message of their data, let alone design experiments and tests and criteria, when their funding and their boss’s funding depends on a favorable result.  Does anyone believe that scientific data reported under such circumstances can be reliable?  Among the horror stories of fraud and suppressed data in the pharmaceutical industry, antidepressants top the list because criteria are subjective and markets are huge.  In addition to antidepressants, many of the drugs on this list are psychiatric drugs that have been promoted “off-label” for depression because this expands their potential market.

Pain medications are sold in a shadow street market.  Arthritis drugs have been promoted despite the dangers they pose for cardiovascular damage.

Abuse of antibiotics and the unfolding global crisis of antibiotic-resistant bacteria is too big a topic even to summarize.

The right way to fund pharmaceutical research is through university grants to target high-priority specific diseases, including aging.  All patents accruing from this work should be placed in the public domain, and pharmaceutical companies can compete at what they do best, which is devising inexpensive ways to manufacture and distribute known chemicals.


Positive directions

The best prospects for future scientific breakthroughs lie in the direction of things that we already  know but don’t understand–things that don’t make sense.  Most of these will turn out to be mistakes in experimental technique or interpretation; but there are some that have such broad corroboration from diverse laboratories that this is unlikely.  I have a personal passion for collecting stories of scientific results that defy theory, and a portion of my research and reading time is always devoted to looking for neglected or fringe science that just might lead someplace new and interesting.

Within the field of aging research, readers of these pages already know that my dark horse favorites are telomerase, decoding the language of epigenetic programming, identifying the relevant blood factors from parabiosis experiments, and replication of promising Russian experiments with epithalon and other short peptides.  Here are a few topics that have piqued my interest from further afield in biology.

  • Cell phones and cancer.  I don’t know whether the risk from RF radiation is small or large, but I do know that it ought to be zero from everything we know about biology and physics.  Interactions between RF radiation and biological systems took the entire scientific community by surprise, and whatever the mechanism turns out to be, it is likely to open doors into new fields of research.
  • Animal navigation.  From salmon to monarchs, from whales to homing pigeons, the means by which animals know where they are and where they want to be are just beginning to be elucidated.  Some are amazingly reliable.  Surprising uses of quantum physics by plants and animals have already been a fruit of this research.
  • Perhaps related is (presumed) epigenetic inheritance of acquired cognitive information.  Knowledge (as far as we know) is coded in synapses in the brain. How can it be transmitted in DNA?  The case of monarch butterflies “remembering” the tree 2000 miles away where their great great great great grandmother overwintered is a well-known example.  Less known is this article on metamorphosis and learning from PLoS One.
  • Anomalous cures.  For every “incurable” disease, there is some small percentage of people who manage to cure themselves.  These cases are ignored by most medical scientists because they don’t fit the model of statistical evidence and “one disease ⇒ one cure” that predominates in the community.  But perhaps we can learn some basic biology from studying them.
  • Lamarckian inheritance.  Darwin believed that the individual traits of your offspring depend on your activities as well as your genes.  “Use and disuse” was his term.  But for 100 years since August Weismann, bedrock evolutionary science tells us that the genes you inherit are the genes you pass on, with only purely random mutations.  In recent decades, there are exceptions to this law.  One is epigenetic inheritance, through which your life experience can affect your children and grandchildren and perhaps great grandchildren through their inherited gene expression.  The other is what James Shapiro calls natural genetic engineering.  He has documented the ability of bacteria to alter their genes in response to stress, and in a way that responds explicitly to the kind of stress that is experienced.  Is anyone looking to see if higher organisms can do this, too?


I could go further…

I could say that “professional scientist” is already a oxymoron.  Scientists work best when they are driven by curiosity and a passion to find out, when they are doing what they love.  How can that be consistent with centralized decision-making and bureaucratic control of research priorities?  If we pay a scientist to do science, we should not make the payment contingent on studying anything in particular.

No one in a government bureaucracy has the wisdom to predict next year’s breakthroughs, or to single out the scientists most likely to achieve them.

Since 1996, I have pursued the science of aging without funding or support or a university appointment.  (Every year or two, I ask a colleague to arrange for an unpaid “courtesy appointment” so that I can have a university affiliation behind my name when I submit papers for peer review.)  Some of my closest friends are at universities, with large research staffs and successful careers.  I envy their daily contact with colleagues, access to seminars, and (aboe all) the opportunity to mentor and supervise the next generation of researchers.  They tell me I am lucky to avoid grantwriting, faculty meetings and academic politics.  Most of my academic friends and colleagues have paid for their success with their health in one way or another.  I am privileged to manage my time so as to make self-care a priority–nutrition, exercise, meditation, and sleep.

In the late 1970s, when I was a low-level researcher at a government contract research house on Route 128, we always worked one year ahead of our funding.  By the time a proposal was written, we had worked out the science in sufficient detail that we knew the results.  If the proposal was funded, we would use the proceeds to support us while we worked on next year’s proposal.

We may be outraged at 70% overhead rates for administration, and think of this as “slush money” that is ripe for abuse.  I agree that bureaucrats receive too big a share of the pie, and scientists too little.  But there is some portion of the overhead money that finds its way back through departments to the researchers themselves, and offers them some slack between contracts, their only real freedom to think and to innovate.

I asked my collaborator at Prominent Midwestern U whether he had funding for the exploratory, groundbreaking work on population dynamics that he was doing with me, but I already knew the answer.  He was doing it with soft funding for a follow-on to previously successful research.  He had prudently kept the funders in the dark about this specific project.  There’s plenty of time to tell them about it if we succeed.

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Aging in Microbes

Aging is very old.

Long before there were plants and animals, aging was fully-developed in one-celled eukaryotes and before that in bacteria.  This seems strange–almost paradoxical.  In fact, for a long while, biologists would have said for aging to exist in bacteria was somewhere beetween “impossible” and “meaningless.”

In 1957, George Williams published what has since become the standard, accepted theory of why aging exists and how it arose.  In a seminal article, he listed eight numbered predictions of the theory, six of which have not fared very well.  But the prediction that met the most direct and flagrant contradiction was the one he probably felt was the surest bet: “There should, therefore, be no senescence of protozoan clones.”


With and Without Sex

The rules of the evolutionary game are different in sexual and asexual communities, and consequences for the strategies by which the game is played are dramatic.  In a sexual community you can be pretty sure that if you succeed in mating and your offspring survive, then your genes have a future.  Some of them will continue on, and others will be out-competed, and some of them will succumb to genetic drift and disappear.  Successful individuals will pass a lot of their genes into the future, and unsuccessful individuals will leave only a few.  Conversely, looking back in time, you have two parents, four grandparents, eight great grandparents, etc.  By the time you get to 20 generations, that’s a million people, and probably they’re not all different.  (People marry their sixth and fifth and even fourth cousins all the time and never know it.)

But in asexual communities (this may not be obvious) it’s winner-takes-all.  If you have a stable colonty of a billion bacteria, the laws of population genetics (essentially just statistics) say that within 100 generations, descendents of all but one of that original population will have disappeared with no legacy.  Everyone alive 100 generations from now will have been descended from a single individual alive today.  Bacteria breed rapidly, and 100 generations of bacteria might be about two weeks.


Aging in Bacteria

Because of this winner-take-all competition, bacteria are using every trick in the book to get ahead, or even get a tiny edge.  For example, their genomes are far more compact and economical than yours and mine because the time it takes to copy the DNA can limit the speed of their reproduction.  One trick for getting ahead is asymmetric reproduction, and asymmetric reproduction was the first form of aging, the “birth of death” if you will.

Let’s say you were one of these bacteria, trying to beat the billion-to-one odds and be the one and only great-grandfather of the future.  You want to split in two, and as quickly as possible.  The quicker you divide, the quicker your odds go from 1 in a billion to 2 in a billion.  You can do a little better yet if you divide asymmetrically, giving a little boost to one of your two progeny at the expense of the other.  If the lesser twin loses, it’s no great loss–after all, losing is what you expected anyway.  But if the greater twin has a little extra juice, that could make all the difference.  This is especially true, since the better offspring of the better offspring is doubly endowed, and might have an advantage that grows from one generation to the next.

Some rod-shaped bacteria actually perform this trick.  Each new half-rod has one end that used to be an end and one end that used to be a middle.  It retains a subtle memory of its history, and if it has recently come from an end, it is stronger than if it has recently come from a middle.  In this diagram, the generations of bacteria are arrayed as though they stayed close together, strung in a line.  This is just for illustration–in fact they are living and moving separately; but they retain a memory of where in the line they belong.



The bacteria whose virtual positions would have been on the ends are the strongest.  The ones in the middle become weaker and weaker, and eventually this lineage dies out.  This asymmetry in replication of bacteria is the oldest, most primitive form of senescence.

From here, it is a short step to an asymmetry that is more like parent and child.  The “mother” bacterium buds with a smaller version of herself, and again and again.  But the mother won’t keep this up forever–if she is not first killed by something external, she will age–bacterial senescence–and stop reproducing after awhile.  This is real, full-bore aging, in its earliest and most primitive instance.


Aging in Protists

Protists (or protoctists) are single-celled life but much larger and more complex than bacteria, the first eukaryotes.  Aging and programmed death in protists is already highly-developed, multiformed, adaptive, and plastic in response to the environment–with all the ecological functions ascribed to aging in animals and plants.  I presume that aging was fully developed in this way long before there was multi-celled life.  There are two principal forms of programmed death in protists.  One is apoptosis, and the other is cellular senescence (telomere attrition).



Apoptosis, or cell suicide, was discovered in the 19th century, and for more than 100 years it was understood to be a multipurpose mode of eliminating cells in the body that are either diseased or merely unwanted.  Before a cell dies “unwillingly” of external causes (e.g., starvation), it goes to every extreme to keep itself alive.  All its protective machinery is engaged in high gear, and when it fails, it fails spectacularly.  The cell is in complete disarray.  Apoptosis is just the reverse.  When the cell receives a signal (either from the outside, or within) it begins an orderly process of closing down its operation, recycling its biochemical stores, and fading gentle into the that good night.  The cell slices up its own DNA, digests its own proteins, and turns itself into useful pieces that other cells might ingest.

During development of the foetus in the womb, much of the body’s shape is sculpted by subtraction (the way Michelangelo did it).  For example, fingers on the hand take shape as cells in webs between the fingers eliminate themselves via apoptosis.  More surprisingly, the brain develops via a process of selection.  Starting with a thousand times more neurons than it needs, they grow connections to one another, and those that remain poorly connected (almost all of them) die via apoptosis.  This process continues after birth, so that an adult has fewer brain cells than an infant.  It is unclear whether this should be regarded as an early form of aging or as part of ongoing brain development.

Later in life, cells that become cancerous detect that they are a danger to the body and fall on their swords, using apoptosis.  Cells that are infected with a virus similarly figure it out early and kill themselves to limit spread of the virus.

All this fits well with theory, and is easy to understand.  Somatic cells have no evolutionary future, no long-term interests of their own apart from the welfare of the body as a whole.  Since they share 100% of their genes with the germ line, they are happy to live and die as appropriate to the needs of the body.

But microbes are independent evolving units, and according to evolutionary theory they are locked in competition with one another.  A yeast cell would never voluntarily sacrifice its own chances for those of another yeast cell…or such was the thinking until 2004.

Readers of this blog are familiar with Valter Longo and his work on fasting and caloric restriction.  In the 1990s when Longo was a grad student at UCLA, he discovered that a starving colony of yeast cells adapts by pruning itself.  95% of the cells die, not of starvation, but via apoptosis.  They digest themselves and turn themselves into food for the remaining 5%.  This was so surprising and counter to evolutionary theory, that early versions of his paper were dismissed and sent back to him with a patronizing message that there must be some error.  Time and again, he returned to the lab to measure all the different biophysical and biochemical signatures of apoptosis.

It was a great education for Longo, both in the biochemistry of apoptosis, and also in the politics of science.  By the time his paper was accepted for publication in the Journal of Cell Biology, Longo was done with his PhD, done with his post-doc, and a young professor at University of Southern California.  And now, 11 more years out, there are many known examples of apoptosis in protists, and the biology community acts as though “we always knew that.”


Cellular Senescense

Cellular senescence was discovered by Leonard Hayflick in the early 1960s, and, like Longo, Hayflick had to overcome a great deal of skepticism and dogma to get his work accepted.  Before Hayflick, the flawed experiments of Alexis Carrel had been accepted for half a century as proof that (even though bodies as a whole are subject to aging) cells could continue to propagate forever.  The mechanism behind the “Hayflick limit” was discovered a few years by Carol Greider and Elizabeth Blackburn.  Every time a cell divides, it loses a little DNA from the ends of its chromosomes, the telomeres.  The telomere is made of repetitive DNA, and carries no information, so it can easily be replenished.  But, curiously, the enzyme that performs the replenishing (telomerase) is locked up epigenetically in most cells most of the time, and so the cells’ telomeres are permitted to shrink until the chromosome becomes chemically unstable, and the cell dies.

The biology community discovered this phenomenon in multi-celled higher organisms, and had a ready explanation for cellular senescence.  Greider herself [1990] supplied the rationale:  cells that divide too many times are probably dividing out of control.  They are cancerous, and cellular senescence is there to put a check on their rogue adventure.  This explanation is accepted overwhelmingly today, though there was never a shred of evidence for it, and in fact cellular senescence in humans actually increases cancer risk.

But long before there was cancer, before there were plants and animals, cellular senescence and the rationing of telomerase evolved in cilliates for quite another purpose.  Ciliates (e.g. paramecia) are some of the most “advanced” protists.  Their cells are surrounded by tiny hair-like cila that they use like oars to propel themselves through the water, and do so in shockingly intelligent ways, pursuing food or fleeing from a predator or locating a mate.

In most protist communities, sex is optional.  Reproduction is via meitosis, simple cell division.  Sex is an entirely separate function, accomplished via conjugation, in which two cells of the same species sidle up to one another, merge their protoplasm, and then exchange DNA, with individual genes swapped between homologous chromosomes.  By the time that two individuals emerge from this process, they have lost their identities, so that each one is “half me and half you”.

The key to understanding cell senescence is that, in ciliates, telomerase is kept under lock and key during the process of mitosis, so the telomeres are permitted to shorten in generation after generation of clones.  But during conjugation, telomerase is freely expressed, and telomeres are restored to their full length, ready for dozens or even hundreds of cell divisions.

What is the purpose of this form of aging?  There can be but one answer:  cell senescence evolved in ciliates in order to enforce the sharing of genes.  In an asexual community, competition is cutthroat, and the winner takes all.  In a sexual community, genes are combined and recombined, diversity reigns, and evolution can follow a far more creative path.  But what’s to stop a particularly macho young stud from opting out of the sex game, reproducing fast and furious, regarding his co-conspirators only as competition and wiping them out?  All the diversity and potential of the community would be lost if this happens.  So cell senescence evolved to prevent rogue individuals from opting out of sexual sharing.

Aging in ciliates evolved for the purpose of promoting a diverse community and enhancing the evolutionary response in adapting to changing environments.  And in higher organisms, aging continues to function in these same ways.


The Bottom Line

The present evolutionary theory of aging was formulated in the 1950s, before any of this was known.  It was designed to apply to higher animals that age gradually.   Not even plants (which often don’t age) were considered, let alone semelparity (instant death after reproduction) or any of the topics on this page–cellular senescence and apoptosis and asymmetric division in bacteria.  Hardly anyone ever notices that the standard theory assumes implicitly that aging evolved “late” (after the Cambrian explosion) and for reasons that only apply to multi-celled.

Not only the function and mechanisms are the same, but many of the same genes that regulate aging in microbes also regulate aging in multi-celled animals and plants.  But if the currently-accepted theory of aging is correct, then aging in one-celled life forms must be completely unrelated to aging in higher organisms.  From our present vantage, this seems absurd, but that’s not the way it happened historically.

I believe that aging in one-celled and multi-celled life serves similar purposes to aging in microbes, and the purposes have to do with ecology.  One purpose is population regulation, to keep a population from outgrowing its food supply; the second is to promote diversity and evolutionary change, to keep the population adapting and innovating.

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Fasting-Mimicking Diet – A Disclaimer

Last week, I suggested a do-it-yourself version of Dr Longo’s FMD diet, and offered sample recipes. I want to clarify that this version was not authorized by Dr Longo or his associates at USC. In fact, they have a large team with expertise in different aspects of health, nutrition and aging, and they have developed a specific package of prepared foods and micronutrients, intended to be administered under a doctor’s supervision.

The package will soon be available as a kit from L-Nutra Corp, marketed under the brand ProLon.  This specific diet has been tested in a clinical trial, and the results reported in a research article last month.

I designed the recipes on a spreadsheet, and adjusted quantities to recreate the calorie content and the proportions of macronutrients (protein, carbohydrate, and oils) closely matching the FMD. But I know nothing about the actual ingredients in the Pro-Lon package, or the supplements they contain. The ingredients have not yet been announced, and my recipes haven’t been tested in a clinical trial.

I am enthusiastic about the FMD idea, and I am trying it myself this week. I certainly encourage you to do the same, and I believe that five days of light vegan meals with limited protein and a high proportion of fat is likely to be safe and healthy. This is my recommendation, and not endorsed by Dr Longo.

(I will add recipes to the list as I progress through the week, and they will appear on the original page, if you scroll down from here.)

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Can anything be done about Parkinson’s Disease?

There’s nothing that will help everyone.
But there’s probably something that will help you.

This is the emerging paradigm of individualized medicine.  We are in transition from a past when we looked for “the cure” (antibiotics, vaccines) that would work universally to a future in which blood tests and computer analysis will determine exactly the right treatment for your individual metabolism.  While in that in-between space, the key will be personal experimentation.  Seek out reports of “miracle cures” in which something worked spectacularly well for just a few patients, while failing to help the others.  Find ten such miracles, and try them on yourself, one at a time.  Experiment to see what works for you.

Today’s column is motivated by news I received Friday about a long-time friend whose Parkinson’s is creeping out from medical control.  At 68, George is active and young in outlook.


Parkinson’s Background

Symptoms of PD include tremors, slow and uncertain movements, loss of motor control, shuffling.  There often is cognitive impairment, especially at later stages.

The cause of PD is the loss of neurons in a particular region of the mid-brain called the substantia nigra (SN), where nerve signals are translated into chemical signals.  One of the functions of these nerve cells is to secrete dopamine, a neurotransmitter.

We’re all losing neurons, but we don’t all have symptoms.  Maybe at age 50 our hand isn’t quite as steady as it was at age 30, but it’s nothing we would talk to a doctor about.  By the time “symptoms” appear, over 70% of the dopaminergic neurons are gone.

[LEF article on Parkinson’s]
[Background and new ideas from the Buck Institute’s SAGE web site]

It is agreed that the cause of PD is the loss of these nerve cells.  We might assume from the fact that that they are nerve cells in the brain that they perform their secretion function in a way that is smart, in response to activity and stimuli.  And yet, the standard medical treatment for Parkinson’s does not address the loss of this population of nerve cells, with the many functions they perform, nor does it even attempt to deliver dopamine in a smart and targeted way.  The best treatment medicine has to offer is to flood the brain with supplementary dopamine.

A few decades ago, it was thought that no new nerve growth takes place in the brain after adolescence.  We now realize that nerve growth continues lifelong, although neurogenesis slackens with age and does not keep up with nerve loss.  There are stem cells in the brain, and these can mature as neurons, or as glial cells or astrocytes that contribute vitally to brain chemistry.

A real cure for PD would be to re-grow the lost nerve cells of the SN.  Why not use stem cell therapy to regenerate the nerves?  This was a promising line of research about a decade ago [in rats, in people].  But when stem cells were injected into the brains of Parkinson’s patients, they withered on the vine.  They were perfectly good stem cells, but something was telling them to slack off.

This is the converse of a theme that researchers have encountered in many contexts.  Put an old cell in a young environment, and it acts young; conversely, put a young cell in a old environment and it acts old.  There are signal molecules–presumably carried in the blood plasma–that carry messages about age.  (This leads us back to the work of Amy Wagers and Mike and Irina Conboy and Tom Rando and Saul Vileda and Tony Wyss-Coray, all building a foundation for anti-aging therapies based on blood factors.  I have repored on the subject here, here, and here.)

Although enthusiasm has waned for stem cells as a one-stop cure for PD, the research community is continuing to refine the technology.  A transition is in effect from fetal stem cells, limited in availability by Bush-era regulations, to stem cells derived from the patient’s own cells, which have the advantage of being a perfect genetic match.  Stem cells do not have to be injected into the brain, because they have a remarkable ability to find their way to the place they are needed.  The most effective delivery at present is through the nose, or (more invasive) guided via a catheter that is threaded through arteries that lead to the brain.


Cell Senescence and PD

Are the lost brain cells that cause PD dying simply because their telomeres run out?  This would not seem a likely connection to make, since telomeres shorten with cell replication, and in the brain, cell replication is slow compared to blood, skin or even muscle cells.  But in a new article from Buck Institute last week, Megumi Mori reviews an unexpected connection between cell senescence and PD, documented by Judy Campisi’s research group.  Astrocytes are star-shaped glial cells, the background support substrate for the brain which create the proper chemical environment for neurons.  Astrocytes grow and are replaced continually during a lifetime, and hence their telomeres shorten with age.  Aging astrocytes become senescent cells, and secrete inflammatory toxins–the so-called Senescent-Associated Secretory Phenotype, or SASP.  Senescent astrocytes and these toxins have been linked to PD.


What can be done to prevent and to treat Parkinson’s Disease?

Returning to the theme at the top of this page, I ask what options can people try to prevent PD or to slow its progression.

  • Selegiline (aka deprenyl, or Emsam) was a standard treatment for PD in the 1980s.  It has since fallen out of favor because of inconsistent results, but I think it deserves consideration and personal experimentation, especially since there are no outstanding alternatives.  Selegiline acts in two ways, addressing both the symptom and cause of PD.  Its primary action is an MAO-B inhibitor, which slows the chemical breakdown dopamine, so that the existing dopamine remains available longer*.  Secondarily, Selegiline is neuroprotective.

The main reason I am enthusiastic about Selegiline is because of its potential as a life extension drug.  Selegiline is on the short list of drugs that have succeeded in extending life span of rodents.  [my blog in the subject from 2 years ago]

  • Stem cell therapies are working well for some patients, and new experiments are likely to make the treatment more effective for more people.
  • Glutathione (standard abbreviation=GSH) is the only one of the body’s natural anti-oxidants that I believe has anti-aging potential.  Levels decline with age.  GSH depletion is both a cause and an effect of the loss of neurons in the SN [ref, ref].

GSH is a short protein molecule, a tripeptide.  It does not survive digestion in the stomach, but the molecule is small enough that with finesse it can be delivered orally.  There are new products with liposomal encapsulated GSH that purport to survive the stomach so that more GSH is delivered to the bloodstream.  GSH can also be absorbed in a nasal spray.  A more traditional product is to ingest N-Acetyl Cysteine (NAC) which is a precursor to GSH.

I have a friend, a vibrant 86-year-old MD who tells me he has a Parkinson’s tremor which is well managed and controlled with liposomal glutathione.  One small study of intravenous GSH for Parkinson’s showed inconsistent benefits that were not statistically significant overall, but might be interpreted as promising for a larger study.

  • There is anecdotal evidence for benefits for PD from telomerase therapy (cycloastragenol, TA65, Product B, etc).  No study has been done.  Here is a video from Ed Park.
  • Rapamycin is a powerful anti-aging drug with powerful side effects.  It has been effective in vitro and in preliminary animal trials against Parkinson’s.  It is probably a powerful neuroprotector, and has been proposed for trials delaying progression of PD.
  • Not to harp on the issue, but intermittent fasting and caloric restriction are powerfully neuroprotective.  This article from Johns Hopkins Med School reviews the evidence.

Researchers at the National Institute on Ageing in Baltimore said they had found evidence which shows that periods of stopping virtually all food intake for one or two days a week could protect the brain against some of the worst effects of Alzheimer’s, Parkinson’s and other ailments.

“Reducing your calorie intake could help your brain, but doing so by cutting your intake of food is not likely to be the best method of triggering this protection. It is likely to be better to go on intermittent bouts of fasting, in which you eat hardly anything at all, and then have periods when you eat as much as you want,” said Professor Mark Mattson, head of the institute’s laboratory of neurosciences.

Cutting daily food intake to around 500 calories – which amounts to little more than a few vegetables and some tea – for two days out of seven had clear beneficial effects in their studies, claimed Mattson, who is also professor of neuroscience at the Johns Hopkins University School of Medicine in Baltimore.

…the growth of neurones in the brain could be affected by reduced energy intakes. Amounts of two cellular messaging chemicals are boosted when calorie intake is sharply reduced, said Mattson. These chemical messengers play an important role in boosting the growth of neurones in the brain, a process that would counteract the impact of Alzheimer’s and Parkinson’s. [The Guardian]

Experimenting on yourself–the one-person trial is the only one that matters

If you have Parkinson’s Disease or Parkinsonism or early Parkinson’s symptoms, then each one of the above suggestions offers some small chance of improving your condition.  Start by keeping a daily diary of symptoms, a baseline of at least two weeks.  Then try the above suggestions, one at a time.  Continue the diary so you can look back and determine what works and what doesn’t.  If you believe you have found a benefit, go off the treatment for a week, then back on, to see if your diary reflects a response to the treatment, or if it was just a fluke.

Don’t give up.  It is unlikely that any given treatment will work for you, but it is likely that patience and persistence and controlled experimentation will be rewarded with something that helps.



* Dopamine, like all neurotransmitters and many other hormones, is continually being manufactured and simultaneously destroyed by the body.  The body regulates the amount of dopamine from moment to moment by adjusting both the rate of production and the rate of breakdown.

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One Week, Two Innovations in Aging and Health

Incremental advances in understanding the genetics, epigenetics, and biochemistry of aging are gradually pushing the field forward.  In addition, there are occasional new ideas that have the potential for quantum advances that change the nature of the game.  Last week, there were two game-changers, originating from the US East and West coasts.

  1. Caloric Restriction has been the surest and best-documented way to add a few years to human life expectancy, with additional benefits for health and vitality along the way.  But few people have the discipline to stick with a restricted diet year after year, and in fact average BMI has been increasing for decades in America and Europe.  Valter Longo (U of S Calif) has been promoting the idea that intermittent fasting offers most of the benefits of CR, while demanding less discipline.  Last year, he documented impressive benefits from periodic fasting on water for 3 to 5 days.  Most people who try this practice compensate when the fast is over, and quickly gain back the weight that they lost; nevertheless the benefits persist.  This week, Longo offers us a 5 day diet that induces many of the same benefits as fasting, but need not disrupt anyone’s life, comfort, or energy level.
  2. The search for drugs that extend human life has been held back bureaucratically by the FDA’s  outdated idea of what a drug is for.  A drug can only be recognized or approved if it treats a disease, and aging is not a disease.  In fact, there are existing drugs that modestly slow aging (e.g., aspirin, melatonin) but they have been approved on a different basis, for different uses.  Nir Barzilai (Einstein College of Medicine) is a respected and well-established researcher who has thrown his reputation behind an initiative to change the FDA’s position.  He has designed a drug trial for metformin, the oldest and best treatment for Type 2 diabetes, to determine whether it can slow aging.  Of course, a great deal of pre-existing data suggests it will pass this test, and Barzilai will then propose that metformin be approved as a prescription for people not diagnosed with diabetes, as a preventive for cancer, diabetes, Alzheimer’s Disease, heart disease and stroke.


Allowing People to Eat While They’re Fasting

I got my start in aging science in 1996, after reading an article on Caloric Restriction by Richard Weindruch.  My first act as a researcher was to write a letter (USPS, not an email–this was 1996) to Weindruch and ask whether the timing or the kind of food mattered for life extension. “Not at all,” he answered, “calories are the bottom line.  Just make sure you get all necessary nutrients.”

Weindruch was well-informed, and what he said was state-of-the-art science in 1996, but today we know better.  Restricting protein and restricting particular nutrients have been shown to deliver some of the same benefits as a CR diet; and intermittent fasting has been validated as a life extension program in rodents, with strong evidence that it will work in people, too.  It’s a good thing, because sticking to a low-calorie diet is hard for most people.  Now Weindruch is approaching retirement and his compatriot Roy Walford left us in 2004.  Valter Longo  has picked up the mantle of practical CR research where they left off.

As I have come to expect, Longo does his homework.  The new publication is convincing because it combines theory and history with longevity studies in mice and yeast, and metabolic data from a new short-term trial in humans.


The Diet

The FMD (fasting-mimicking diet) is ketogenic, with restricted protein and a high percentage of calories from fat.  “Day 1 of the diet supplies 1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate).”   The diet is predominantly fat.  The closest single food that approximates these macronutrient ratios is the avocado.  The diet approximates two avocados per day.  But you could construct the same macronutrient ratios using rice or apples and adding vegetable oil or small quantities of nuts.  I assume that green leafy vegetables could be added to the diet without changing its effect, while making it more palatable and filling and giving you a vehicle for the vegetable oil.

Here are three sample menus of my own construction (don’t blame Longo), each designed to give you ⅓ of the FMD nutrients for Day 1 or ½ the nutrients for Days 2-5. Each recipe has about 360 calories.  While these recipes mirror the macronutrient content of the FMD, they don’t have the same micronutrients, and they generally have a lot of extra leafy-green bulk (fiber).  My recipes haven’t been studied in a clinical trial.

Sample Meal One:
4 oz salad greens + 4 oz cucumber
1 tbsp vegetable oil
1 tbsp vinegar
½ apple (~4 oz)
½ oz almonds

Sample Meal Two:
6 oz cauliflower
1.5 oz sesame tahini
1 oz lemon juice
4 oz blueberries

Sample Meal Three (red cabbage salad):
4 oz shredded red cabbage
3 oz shredded carrots
½ oz cilanthro
½ (mushed) avocado (~3 oz)
1 tbsp lime juice
2 tbsp apple juice
¾ oz walnuts
garlic and mustard to taste

Sample Meal Four (gazpacho):
12 oz canned or fresh tomatoes
4 oz fresh onion
1 tsp olive oil
4 oz black olives
2 tbsp vinegar
4 oz cucumber
3 oz snap peas
salt, black pepper, cayenne
(Blend together, leaving it chunky or smooth to taste)

Spice to taste–the effect on calories and macronutrients is negligible.  Salt freely and supplement with magnesium.


The Data, mice

Mice were put on the FMD for 4 days, twice per month, starting when they were already middle-aged (16 months for mice ~ 50 years for humans).  They lived 11% longer than control mice (median) though maximum life span was not increased.   There was some indication that the mice were unable to tolerate the FMD intervals when they were really old, that it was triggering their death, and the experimental protocol was modified so that FMD intervals were stopped when the mice were 29 months old (the human equivalent of 90 years).

Test mice fully compensated for the lost calories when they were returned to ad libitum feeding, but still they weighed less–same lean mass but less visceral fat.  FMD mice had improved cognitive performance, stronger immune systems, lower markers of inflammation, and lower fasting blood sugar.  When they died, it was less likely to be of lymphoma, which is what usually kills lab mice.


The Data, humans

Humans were on the FMD diet 5 days out of each month, in a preliminary test that ran for three months.  Like the rodents, humans compensated for the lost calories when they returned to free eating, but still lost weight (not lean mass, but body fat).

Blood sugar and markers of inflammation were down; fasting insulin and IGF-1 were lower.  The article made no mention of HDL or LDL cholesterol.  Longer term trials with more criteria for metabolic health are planned.

In case you can’t tell, I’m really impressed with Longo’s work.  I think he has advanced the practice of human nutrition in the last few years more than anything that has been done in decades.


Legitimizing Research in Anti-Aging Medicine

We already have, incidentally, a great deal of information about the benefits of metformin in people with Type 2 diabetes (T2D, or metabolic syndrome).  It has been the first-line drug for T2D for fifty years, and about 150 million people are taking metformin worldwide.  The huge numbers have made it easy to collect data on other diseases.  People taking metformin have lower rates of cancer, heart disease and dementia than people taking other diabetic drugs.  It is tempting to conclude that metformin forestalls the diseases of old age generally, but rates of all these diseases are already elevated in people with T2D.  The new question being asked is whether metformin will offer benefits for people who don’t have diabetes to begin with.  There is one Scottish study reporting that cancer rates for diabetics taking metformin are depressed below the rate for non-diabetics who don’t take metformin.  Now that’s promising.

Nature reported last week that FDA had scheduled a hearing on Wednesday past (6/24) to consider a proposed drug trial for metformin as an anti-aging remedy.  The protocol would be to identify patients who have symptoms of one of three age-related disease:  cardiovascular disease, cancer and dementia.  People with T2D would be excluded by design.  Subjects would be prescribed metformin or a placebo, and the researchers would look for an effect on the other two diseases.  This design is a clever compromise between bureaucratic requirements and clean experimental methodology.  The bureaucratic requirement is that people assigned to take the drug must already be diagnosed with a recognized disease.  But it is the potential of metformin to reduce risk of the diseases that the subjects do not have that is the target question for the study.

Barzilai already has a small, ongoing trial for metformin and aging registered at  Just 15 patients will be enrolled, and the plan is to look at their gene expression profiles to see if metformin has an anti-aging effect.  A growing number of researchers (including me) thinks that gene expression drives aging, and last year, Steve Horvath of UCLA published a protocol for measuring physical age of the human body by combining epigenetic markers (methylation) from hundreds of different chromosome sites that empirically appear most sensitive to age.  They use the acronym MILES for Metformin In Longevity Study.

The new study is far more ambitious.

Plans call for the trial to enrol 3,000 people aged 70–80 years at roughly 15 centres around the United States. The trial will take 5–7 years and cost US$50 million, Barzilai estimates, although it does not yet have funding.

That’s $17,000 per patient, for a drug that costs pennies.  Certainly the cost will hold up this project, and monitoring patients for diseases that are already covered in their annual physicals.  Why does it need to be so expensive?

I have written to Barzilai about the Wednesday meeting with FDA and he would only say to watch for an article in next week’s Science magazine.


In the Larger Scheme…

The shortcut to modest gains in longevity is to work with the body’s adaptation to caloric restriction.  CR is known to work in many different animals, and is known to offer health benefits in humans, (although human longevity studies are probably completely impractical).  So the search is on for “CR mimetics”, drugs that will put the body into a calorie-deprived state without actually having to eat less.  Intermittent fasting, the Longo diet, and metformin all work on the same pathway as CR.  Some researchers believe resveratrol works on this same pathway, and even for rapamycin there is significant overlap with the CR mechanism.

It is understandable that researchers should be investing their time and pharmaceutical companies their money in this area, because this is where returns on investment are surest.  But the potential of this approach is limited to a few years of life extension, and layering metformin on CR on fasting on resveratrol on rapamycin will not add more years, just the same few years many times over.  As I have said in previous columns, there is immediate potential in telomerase activation, and longer term my highest priority would be to understand the epigenetic changes that come with age.

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Correlation and Causation–Nuts and Chocolate

Nuts are a big part of my diet.  It’s my habit to eat handfuls of nuts through the day, and a few times a week to incorporate almonds or cashews or peanuts into a main course.  Perhaps I should be cheering that a headline in ScienceDaily last week told us, “Nuts and peanuts (but not peanut butter) linked to lower mortality rates, study finds”.  So, is the study good news for me?  I can answer with assurance: “Probably.”  

The headline referred to this study, just published in the Journal of Epidemiology.  The researchers in Maastricht looked back at data from a Dutch survey on diet and mortality conducted from 1986-1997.  They found mortality rates of nut-eaters were 23% lower than people who reported eating no nuts.  23% lower mortality corresponds to 2½  years of life extension [how to calculate].  Threshold for the benefit was quite low at a few ounces per week, and more was not better.  (Past studies indicated that perhaps more is better.  I eat about 2 pounds of nuts in a week, perhaps over the top, because I like them and because I’m on a low-carb vegetarian diet.  There is no data in that range.)  Peanuts were found to be just as good as “tree nuts” (almonds, cashews, walnuts, Brazils, etc.) but peanut butter had no benefit whatever.

By itself, a finding like this is hard to translate into a dietary recommendation.  There are qualitative problems with methodology.  People are different, and a diet that is right for one person may be all wrong for another.  And if we eat more nuts, are we adding more calories?  Or are we eating less of something else?

There is also the quantitative problem of cross-correlations–correlation does not necessarily imply causation.  People who eat nuts are likely to be richer and better educated and more careful about their diets, likely to be eating less unhealthy snacks, less meat, less carbohydrates.  Any of these things could produce an incidental statistical association between nut consumption and longevity, with no indication that eating nuts confers a benefit.

Nut consumers were on average somewhat younger, leaner (in women), drank more alcohol, ate more vegetables and fruits, were less often hypertensive or never smokers (women), but were higher educated and more often used supplements, or postmenopausal hormone replacement therapy (HRT). Women with the highest nut consumption less often reported diabetes. [ref]


Cross-checking and corroboration

It’s common to correct with multivariate analysis, but multivariate analysis doesn’t work very well if there are more than a few variables, and it’s hard to know in advance which are the relevant ones.  Statistics ends up being an art as much as a science.

So the study gains credibility when previous studies, with different methodologies in different populations, come to the same conclusion.  There are several, the biggest and best of which are this one and this one.  With write-up of the new study, the authors include a “meta-analysis” of these past studies.  This is another layer of statistics which combines previous results to come up with a conclusion stronger than any one study could draw.  Meta-analysis is a pursuit that can keep a data geek happy and productive for weeks on end.  Happiness and productivity are both positively correlated with life expectancy ☺.

Though a self-identified stat geek, I confess to being unfamiliar with Cochran, Begg and Orsini; nevertheless a paragraph like this adds to the credibility of a study in my eyes:

In these analyses, the HR estimate for each study was weighted by the inverse of the variance of the log HR to calculate the summary HR and its 95% confidence interval (CI). Heterogeneity between studies was estimated using the Cochran’s Q test and I2 (the proportion of variation in HRs attributable to heterogeneity).  Publication bias was assessed by the Begg test.  In addition, we performed dose-response meta-analyses using generalized least squares regression described by Orsini et al. with restricted cubic splines (four knots, at 5th, 35th, 65th and 95th percentiles) to investigate potential nonlinearity in the dose-response relationship.

The multi-study meta-analysis results closely paralleled the present study.  All the diseases of old age were lower in people who ate nuts; cancer was marginally lower, and cardiovascular disease much lower.  Some of the older studies found less benefit for peanuts than for tree nuts, and beyond a few ounces a week, there was ambiguity about whether more nuts offered more benefit.



There is comparable statistical evidence for the benefit of eating chocolate!  For years, I have refused to take these studies seriously, figuring that they are funded by a consumer industry that is eager to rehabilitate its junk-food image.

And in fact, just last month there was a spoof done by a science journalist, intending to remind us how easy it is to lie with statistics.  The headline was “Slim by Chocolate”.  Here is  John Bohannon’s account of what he did, and what morals we should draw.  His main point is that we all should use our common sense and be skeptical of sensational health claims.  Who can argue with that?

But the topic he chose incidentally illustrated other points as well.  There are legitimate claims for health benefits from chocolate.  People are complicated, and no two bodies are alike.  Not only do foods affect our metabolisms differently, but even more various are the psychological effects of foods.  There are people who find a little bit of chocolate uniquely satisfying, and it helps them to eat a leaner, healthier diet in many other ways.  There are other people who find chocolate addictive, and the more chocolate they eat, the more they want.

I find it completely plausible that some people are better able to lose weight with chocolate than without.


The psychology of eating is the most individual thing about diets, and it plays an essential role.

Time after time, human psychological studies have demonstrated that for the great majority of people, will power is worse than useless in trying to control weight.  (Present company, of course, is excluded.  You and I both have perfect control over what we eat, regardless of what the statistics may say.)  People who set out to lose weight by adhering to a set of rules generally succeed for awhile, then well over 90% bounce back to a weight higher than they started.  Habits in themselves are hard enough to change; but in addition we have powerful and persistent homeostatic impulses whispering in our ears.  The body gravitates to a “set point” in weight and percentage of fat.  The most successful diets all manipulate those signals of craving and satiety with alterations to the body’s biochemistry.

We joke about pregnant women having aversions to some foods and cravings for others.

Methionine is an essential amino acid, and it is normally part of all protein that we eat (though some sources have more than others.)  There have been a lot of studies of methionine restriction, in which mice are fed an artificial diet of re-constituted proteins in which this one amino acid is missing.  Despite the fact that methionine has no distinctive flavor or smell, mice know at some level that they are missing methionine.  Some researchers report that the mice refuse to eat unless there is methionine in their food.

The moral of the story is that our bodies know what they want, and will nag at us until they get it.

For some people, phytochemicals in chocolate can play a positive role in regulating gut biota and controlling anxiety that can lead to nervous eating and other destructive behaviors. This new study comes from University of Aberdeen in Scotland, and was published last week in the British Medical Journal.  All-cause mortality was not compiled, but the study claims that eating more chocolate is associated with less cardiovascular disease, and the group with highest chocolate consumption enjoyed 23% less heart disease.  Here is a meta-analysis of studies in the past that have been less clear and consistent than for nuts.  The average is that people who ate the most chocolate had 25% fewer cardiovascular events compared to people who ate the least.  No studies have been done about cancer, or all-cause mortality.

Interestingly, the non–chocolate-eating group had the highest mean body-mass index, the highest percentage of participants with diabetes, and the highest levels of inactivity. On the other hand, “higher chocolate intake was associated with a higher energy intake, with lower contributions from protein and alcohol sources and higher contributions from fat and carbohydrates.” [ref]

Translation: chocolate eaters weigh less despite eating more.  Did Mr Bohannon stumble onto something that none of us expected?  Probably not.  Here are two studies [one, two] that find just what we would expect, that eating chocolate is associated with weight gain.


The bottom line

People who eat nuts and chocolate have lower rates of cardiovascular disease and live longer than people with comparable amounts of body fat who don’t.  If you can adjust your diet to add chocolate and nuts without gaining weight, you will probably benefit.  Remember always that diets are individual and the response of your own body is not the average response.

This is the era of big data.  We are awash in data.  What fun for people like me, who love to extract meaning from numbers!  Still, answers to basic questions remain elusive.  Finding correlations between single foods and particular diseases is a start.  But researchers might remember that our goal is to design diets and life styles that are healthy and adapted for each individual.  We have a long way to go.  More creative and ambitious study designs for the future might help.  I’ll have two examples for you next week.

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Dreams of a Pill to Enable Regeneration

Eight years ago, I assumed erroneously that the chute of my food processor was longer than my fingers.  I lost a quarter inch from the tip of my right middle finger.  Today, my finger has grown back, right down to the pattern of the fingerprint.  I am fortunate to be a good healer.  This is the extent of regeneration that adult humans can normally expect.

Many “lower” animals can regenerate large parts of their bodies when damaged.  This includes not just the legendary cases of starfish and planaria worms, but also zebrafish and salamanders.  Porpoises that have suffered deep and severe lacerations in encounters with sharks regenerate their skin quickly, without scarring.  So why can’t we?

It has long been assumed that mammals have “lost” the capacity for large-scale regeneration, and the cellular machinery is no longer present.  But 20 years ago, Ellen Heber-Katz (then at Wistar Institute in Philadelphia) noticed that a strain of mice in her lab routinely erased the ear punches that her lab used to identify them.  There was no scar or mark where the hole had been punched a few weeks earlier.  She was curious enough to investigate what was different about these mice, and traced the ability to a defective gene–a defect in a gene that shuts off regeneration.  She turned on a dime, put aside her research on immunity, and set about to breed this mouse, to study the biochemistry of this defect, and the latent power of the mouse to heal itself cleanly.  The defective gene was p21.  (read more from my blog from last year)



p21 plays a role in apoptosis, the elimination of cells that self-detect that they are damaged or dangerous or cancerous.  We might suspect that eliminating p21 would increase cancer, but that seems not to be true.  Apparently, p21 has both pro- and anti-cancer effects, and in fact, inhibitors of p21 have been studied as a strategy for treating cancer.  Mice lacking p21 can heal more effectively, and there seems to be no downside.


Prostaglandin inhibition

A headline in Science Daily this week announces identification of a drug that can dramatically increase healing capacity by blocking the enzyme that degrades prostaglandins.  Prostaglandins are eicosanoids, fats and oils that serve as signal molecules.  (Usually we think of signal molecules as proteins, or less commonly RNAs.)  Hormones circulate through the bloodstream and reach the whole body, but eicosanoids circulate locally, which is the definition paracrine signals.

If the word “prostaglandin” is familiar to you, it may have an association with headaches.  E2 is the most famous prostaglandin (PGE2), and PGE2 is associated with pain and fever.  NSAIDs including aspirin inhibit the COX enzymes (cyclo-oxygenase) which have a primary role in creation of prostaglandins.  This is not a side-effect but an important mode of action of aspirin.  Prostaglandins are pro-inflammatory.

We think of inflammation as destruction of tissue, and regeneration as renewing or re-building tissue.  So it seems surprising that prostaglandins should be involved so deeply in both processes.  But PGE2 is known to be associated both with inflammation and with anabolism, stem cell activity, and tissue formation.

Prostaglandins are constantly being created and degraded, signaling on a short time frame.  The amount of prostaglandin in the system is determined by a balance between production and destruction.  The new drug has already been promoted with the catchy name SW033291, and it is an inhibitor of 15-PGDH, which is the enzyme that degrades prostaglandin.

A team of scientists at Case Western (Cleveland) and U of Texas (Dallas) were searching for ways to enhance PGE2, based on preliminary evidence that it could promote healing.

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. To date, therapeutic interventions have largely focused on targeting two PGE2 biosynthetic enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), with the aim of reducing PGE2 production. In this study, we take the converse approach: We examine the role of a prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a negative regulator of tissue repair, and we explore whether inhibition of this enzyme can potentiate tissue regeneration in mouse models. [ref]

They noted that mice lacking the gene for 15-PGDH had twice as much PGE2, and these mice recovered more rapidly after exposure to radiation, or surgical removal of part of the liver.  They also had stronger immune systems, with more white blood cells.


Preliminary Findings from Heber-Katz Lab

Also new last week was a paper from the Heber-Katz lab, recently moved to the Lankenau Medical Center.  They have identified the protein HIF-1α as a target for therapy, and have preliminary, positive results for an injectible drug that enhances healing power to the level of the p21-null mice by promoting HIF-1α. “Increased expression of the HIF-1α protein may provide a starting point for future studies on regeneration in mammals.”  The chemical name of the drug is in the article, but it is not enlightening.

In a press release, Heber-Katz reports indications that the drug she is applying de-differentiates some “end-user” cells and restores their ability to act as stem cells.

“Our experiment shows the possibility of taking mature cells and, with addition of HIF-1a, causing dedifferentiation to a highly immature state where the cells can proliferate, followed by redifferentiation upon withdrawal of HIF-1a,” says Heber-Katz. “Many researchers in the field see tissue regeneration as a very complex set of events, but some of us look at it more as a process that needs to be turned on and allowed to go to completion. This is what is so exciting about what we saw with drug-induced stabilization of HIF-1a.”


So, What’s the Prognosis, Doc?

NSAIDs including aspirin have well-estalished benefits that lead to substantially lower mortality from heart disease, stroke and cancer.  NSAIDs work in two ways:  (1) reducing blood clotting, which is the proximate cause of most heart attacks and strokes, and (2) reducing inflammation, which is a deep cause of cancer, damage to arteries, and other ailments associated with age.  All these benefits are associated with reduced PGE2.

The new drug increases PGE2, and demonstrates some promising benefits that also have potential benefits against aging.  My guess is that this is a hint of something important, but that SW033291 itself is unlikely to have a net benefit for longevity, because its action is opposite to aspirin.  (Garret FitzGerald expresses this caution in a Perspective piece accompanying this week’s Science article.)

The benefit will come when next-stage science learns to tease apart the benefits of enhanced regeneration from the liability of increased systemic inflammation.  There is every reason to believe this is possible, but the intervention will have to come at the next level down from PGE2.

As for the HIF-1α stabilizers, the challenge at this point is that this approach requires repeated injections of time-release capsules of the drug, which has a short lifetime in the body.

Where are the p21 inhibitors?  I can find no literature on p21 drugs being studied for regeneration.


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