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.

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

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.

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.

Link to list of recipes, created with data from USDA nutritional database, in cooperation with Enid Kassner.

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.

• Most people living above the tropics don’t get enough vitamin D.  There are large individual differences in absoption and need for Vit D.  Low vitamin D levels are statistically associated with Parkinson’s.  [another ref]

• Exercise is good for every aspect of aging, including PD.

• 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.

• Melatonin might help some people.

• Curcumin (from turmeric) has been used with some success.

• It’s a long shot, but Magnesium Threonate might be neuroprotective.

• If you are taking statin drugs, consider alternative means to lowering your risk of heart disease.  Statins double the risk 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.