Report from Rejuvenation Biotech Conference

Fifteen years ago, Aubrey de Grey organized the first SENS roundtable–Strategies for Engineering Negligble Senescence.  It was a small group of out-of-the-box thinkers, heretics who talked about attacking head-on the idea that aging is just part of the human condition, looking for medical (and beyond-medical) treatments that would restore strength, stamina, and alertness, and lower the risk of all the diseases of old age at once.

There followed five more SENS conferences in Cambridge, UK.  Now, SENS HQ has moved to Silicon Valley the series has been absorbed as a summer Rejuvenation Biotech conference in California.

This is the mainstreaming of anti-aging science, the product of many long years of work and relationship-building, largely by Aubrey himself.  As Joni Mitchell wisely warns, “Something’s lost and something’s gained…our dreams have lost their grandeur coming true.”  There is a lot more money, a lot more data, well-established people and funders are involved.  But there is less daring, out-of-the-box risk-taking than in the past, and my personal judgment is that we are still at a stage of understanding where high-risk science is essential.

At one point, a young man posed a question in a session devoted to cancer strategies.  The most common cancers attract the most funding, he said, and there has been little progress over the years in survival percentages in these cases.  Meanwhile, there has been dramatic progress in rare cancers, though they are the province of fringe research with little mainstream funding.  Perhaps there is an inverse correlation between funding and scientific progress.  Perhaps funding distortions favor repeat funding of long-term projects, with a resulting bias toward failed ideas.  Perhaps funding makes scientists more conservative, and impedes discovery.  This was a perspective that no one could digest, and audience and speaker moved on with embarrassed laughter.  

At the end of this page is the most exciting thing I learned at the conference, which is also the most far-flung and likely to be an artifact.

 

Alzheimer’s Trial using Infusion of Blood Plasma from Young Donors

Tony Wyss-Coray of Stanford has what I consider the boldest and most promising program for rejuvenation today.  He discovered last year that mice given 8 infusions of 0.1 ml blood plasma from a young mouse showed dramatic improvements in cognitive performance.  (This is the equivalent of about ½ pint of blood per infusion in human scale.)  Tony told us that there was an unpublished experiment in which similar benefits were achieved with blood from young humans infused into older mice.  The cognitive improvements last at least a few weeks, but were not tested beyond that time frame.

Take a moment to appreciate how unexpected this was.  Even for those of us who are enthusiastic about the ability of blood factors to reprogram the body’s age, we expected that many repeated treatments would be needed, and that it would be necessary to remove pro-inflammatory factors from old blood as well as adding pro-growth factors from young blood.  Most blood factors are constantly being generated and destroyed, so their lifetime in the bloodstream is only a few hours or even minutes.  It was beyond optimistic to think that so short a course of treatment would have a measurable effect.

The result was so promising that Wyss-Coray is leapfrogging over the animal testing phase.  He has formed a for-profit spinoff, proceding right to clinical trials.  (This is possible because plasma transfusion is already a mature technology, long approved for safety in other contexts.)

 

Thymus Regeneration

Georg Hollander presented a cogent and enlightening exegesis of the thymus, from basic function to ongoing projects.  The thymus is a small gland under the breastbone that is responsible for a crucial function of the immune system:  traing white blood cells (T-cells) to distinguish between self and other, so they can consistently attack the latter and spare the former.  In adulthood, the thymus atrophies (“thymic involution”), and in old age there is almost no thymus left, with the disastrous result that T-cells not only fail to protect our bodies from invaders, but treat our bodies as the enemy, leading to autoimmunity.  The training is performed by web-like epithelial cells, shaped like crumpled blankets, each epithelial cell in contact with up to 60 developing T-cells.  Epithelial cells must express every single protein in the genome, and there is a transcription factor called AIRE that binds to DNA, promoting “promiscuous expression.”  Curiously, AIRE works best for genes that are normally turned off by methylation or acetylation.  15% of genes are expressed only in the presence of AIRE.  There are micro-RNAs that are also necessary for promiscuous expression of all genes.  

Hollander has been working on the hypothesis that each epithelial cell succeeds in programming only a random subset of the genome, so if you have fewer epithelial cells late in life, the cells collectively will not express every single gene in the body; there will be holes in the set of all genes represented in the thymus, and as a result there will be autoimmunity.  He said we need a minimum 200-300 epithelial cells for a fully-functioning thymus that protects the body against itself.

At Wake Forest Inst, John Jackson is working on growing epithelial cells in a petri dish, then forming them on a scaffold, integrating blood vessels (vascularization) and structural (stromal) cells.  His intern Blake Johnson made remarkable progress in a single summer toward creating a functional mouse thymus.  Mice (like other small animals) have much larger thymi in relation to body size; and (like humans), they lose most of their thymic volume over their short lifetimes, with the result that their immune systems are disabled and they are vulnerable especially to cancer.

FOXN1 is a transcription factor that may be a key to thymic reactivation.  Last year, a Scottish group announced growing a fully-functional thymus and transplanting it into a mouse.  A Pittsburgh group is working on similar techniques.  Greg Fahy of 21st Century Medicine is conducting a tiny clinical trial in the coming year, using growth hormone and other blood factors to regrow the thymus in people 50-65 yo.  (Enrollment is closed; they are not seeking test subjects.)

 

Two paths to longevity
(Dataheads can skip this and the following section. They are just philosophy.)

Very broadly, there are two approaches to anti-aging medicine, which might be called “bioengineering” and “endocrinology”.  The question is, how much of the change that takes place with age can the body reverse with its internal resources, given the appropriate chemical signals (that’s endocrinology)?  And how much remains that must be rebuilt or replaced with prosthetics (bioengineering)?  From the beginning, SENS has emphasized the bioengineering approach–its middle name is “engineering”.  I am more optimistic about what the body might be able to do on its own, if only we can master its biochemical language.  

Significant advances have been made in bioengineering in the 15 year history of SENS.  A prosthetic limb no longer needs to be a peg leg, but can be designed to respond to neural signals.  Prosthetic eyes and ears have come down from the clouds into the realm of the feasible.  The first organs grown cell-by-cell on scaffolds in the lab have been re-implanted successfully in human patients.

But even more stunning and promising breakthroughs have appeared in the realm of chemical signaling.  In 2000, before the Bush Ban, all stem cell research depended on embryonic stem cells harvested from foetal tissue; but turning muscle or skin cells back into stem cells has turned out to be surprisingly easy (though the process is still being refined).  “Epigenetics” was an abstract noun in 2000, and it is now the fastest-growing area of biological science.  Epigenetic signaling may be the organizing principle of whole-body aging [ref, ref, ref].  Signal proteins have been identified that turn on whole systems of genes that retard aging.  Better yet, pathways that promote inflammation (e.g. TGF-β, NFkB) can be blocked, while some blood factors (e.g. FOXn1, oxytocin) turn on regenerative pathways, with the promise of rejuvenation.  Steve Horvath has pioneered a bioinformatic approach to identifying the epigenetic differences between old and young humans.

 

Broad strategies

Business is averse to risk.  Science is all about exploring the unknown.  It’s not exactly a match made in heaven.

Chas Bountra is deeply tied to the establishment, but radical in his own way.  He is a veteran of many years as head of research at Glaxo Smithkline, and now directs the Structural Genomics Unit at Oxford.  His focus is Alzheimer’s Disease, and tells us why:  We have a basic understanding of cancer, stroke and heart disease, and are making steady, incremental progress toward prevention and higher survival rates.  If current trends continue, dementia will be the scourge of the next generation, exacting an unaffordable social cost as patients survive for years, unable to contribute to society, to care for themselves or even to enjoy social interactions with others.

He is interested in “novel targets”.  He will not consider amyloid beta or Tau protein aggregates because, “we have spent tens of billions of dollars researching A-beta plaques and we still can’t Bountra makes an impassioned plea for open source researching.  He boasts of doing research that drug companies shun as too risky, and having succeeded in identifying more than 40 new targets that drug manufacturers have pursued and brought to the market.  His research unit publishes all data, takes no patents, and shares all ideas in academic journals.   His model: Universities take all the risk, using public monies; pharmaceutical giants make all the profits.  (Big Pharma then uses its considerable leverage in lobbying Congress to increase funding for biochemical research.)

For a commie like me, this model is tainted with corporate welfare, but while I choke on the social injustice, I admit that it is practical and effective in today’s political environment.

 

Oldest Aging Scientist Still Active

That title probably goes to George Martin, at 88 still deeply thoughtful and open to new ideas in his U Washington lab. I visited George a week earlier, on my way to San Francisco.  Len Hayflick, 87, works at UCSF.   At 86, Bruce Ames is still active and doing good work.  After the conference, I was privileged to visit his lab in Children’s Hospital Oakland Research Institute (CHORI).  Ames has been doing innovative biochemistry since the 1960s, and by now has persevered to see some of his heresies absorbed into the canon of public health.  After a 32-year career at UC Berkeley, he moved to emeritus status and opened his present lab in 2000.   

Bruce Ames

In 1972, Ames launched his career by investing a quick and easy lab test for mutaogenicity (and presumptive carcinogenicity) that has saved millions of dollars and countless rabbits and mice.  

In the 1980s, Ames was an early influence on my diet and helped form my understanding of aging.  In that era, we all thought about buildup of toxins and cumulative effect of carcinogens.  Ames was at the forefront, ranking carcinogens by a scheme he called HERP, which took proper account of potency and average public exposure.  The conclusion that surprised him and alienated many advocates of natural medicine was that natural carcinogens are common in the foods we eat, overwhelming the risk from pesticides and preservatives for which we were seeking tighter regulation.  Always an evolutionary thinker, Ames headed off the argument that we might be evolved to deal with natural carcinogens but not manufactured carcinogens, demonstrating that diets and lifespans of our hominid forbears made that conclusion unsupportable.

Ames was one of an elite group at the first SENS roundtable discussion in 2000, forerunner of the RB2015 conference that I attended last week.

Today, Ames argues that dozens of micronutrients are essential for both day-to-day metabolism and for long-term health.  When any of these micronutrients are in short supply, the body prioritizes the former, and the latter is shortchanged, with consequences for longevity.

In Bruce’s lab, I met Rhonda Patrick, a dynamic young post-doc who both does innovative nutritional science and has a uniquely nerdy and well-informed video blog, FoundMyFitness.com of health advice, broadcasting biochemistry, nutrition and metabolism for the masses.  

I can’t resist noting how pleased I was to find support in Bruce’s lab for my contrarian idea that aging is controlled in part by an evolved genetic program.

 

Metformin Update

I have been an advocate of metformin for everyone, and enthusiastic about Nir Barzilai’s trial of metformin as an anti-aging drug.  Last week, I learned from Brian Hanley that metformin has a dark side, to wit, a statistical association with higher frequency of Alzheimer’s disease [ref, ref].  There is a biochemical mechanism that makes the epidemiology more compelling.  B12 supplementation may mitigate the risk.

Other studies [ref, ref]  have found that diabetes patients have elevated risk of dementia, and that that risk is reduced when they take metformin.  So it’s fair to say that there is contradictory evidence, and the direction of the effect may depend on individual variation.  Here is a balanced view of both sides.

A reader of this blog, George Goldsmith has written to me that berberine is a good herbal substitute for metformin.  Everything we know about berberine looks really good–it is an anti-inflammatory as well as helping preserve insulin sensitivity, acting through the AMPK pathway.  But we have much more experience with metformin, both clinically and in the lab.  Metformin increases life span in mice, and to my knowledge, this test has yet to be performed with berberine.  Magnesium supplements also can help prevent insulin resistance, and there are other good reasons to take magnesium.  

Gynostemma pentaphyllum, sold by LEF under the brand name AMPK Activator, is another herbal alternative to metformin.

 

Telomeres

Bill Andrews was a major sponsor of the conference and a ubiquitous presence, though he did not make a presentation.  Curiously enough, the only spokesperson for telomere biology was Judith Campisi.  While Andrews has taken the position that lengthening telomeres is more than a good thing, possibly a key to reversing aging, Campisi has cautioned us that telomerase is rationed by the body, and there must be a good reason for this.  For two decades, Campisi has been the principal advocate of the thesis that telomeres are permitted to shorten in order to protect us from runaway replication of tumor cells.  

My judgment is that Andrews has it right, and Campisi is clinging to a flawed theory   At this point, overwhelming evidence tells us that short telomeres cause many more cancers than they prevent.  To her credit, Campisi has backed away from the cancer theory which she had so long propounded.   But she has yet to embrace the radical truth that telomere shortening is an evolved mechanism of programmed death (and has been since the dawn of eukaryotic life).  Campisi is a good scientist who knows as much about telomere biology as anyone on the planet; but she has afforded too much deference to the prevailing evolutionary perspective, though it is contradicted by evidence that she can (and does) recite from memory.  So her more recent papers stress the (sometimes) beneficial role of inflammatory signals in promoting wound healing, and she pursues a theory that she hopes will someday explain the devastating consequences of telomere shortening as a necessary price to pay for the signals that call forth repair and renewal.

Meanwhile, flawed evolutionary theory continues to be the principal obstruction that impedes progress toward an effective telomerase activator which, I believe, will add years to our lives.  Neither VC investors nor NIH funders have given this subject the priority it deserves.

 

 

Rejuvenation from an extract of umbilical blood
(Here is the promised most exciting, and most speculative thing I learned.)

Wuyi Kong is a researcher in regenerative medicine who spent 15 years at Stanford before returning to her native China five years ago.  She now has a private for-profit business, incorporated in Silicon Valley and relocated to China, with enough funding from the Chinese government to get tantalizing results, but not enough to do clinical trials.

She describes particles in umbilical blood that confound a basic principle of biology: that every cell comes from another cell.  She calls these medium-size particles NPRCP, for non-plasma RNA-containing particles, and has observed them in electron micrographs, as they agglomerate into stem cells.  

Time sequence shows particles aggregating into cells. This is either a Nobel Prize or an anomaly.

Time sequence shows particles aggregating into cells. This is either a Nobel Prize or an anomaly.

For 15 years, Kong has been filtering these particles from umbilical blood and injecting them intravenously, first into mice and then into humans, with spectacular results.  In her most complete and convincing paper, she damages the kidneys of mice by cutting off blood supply, then demonstrates regrowth of the kidneys after infusion with NPRCPs.  The problematic claim is that NPRCPs are non-living particles, yet they agglomerate to form stem cells, which are then ennucleated with DNA from the recipient mouse.  This is indeed strange science, but isn’t this all the more reason to replicate her experiments?    

Kong claims anecdotal evidence for erasing wrinkles and white hair turned to black.  More substantively, she says patients have improved energy and faster healing.  One semi-comatose patient with advanced AD recovered not just her consciousness but also her short-term memory.

This is the kind of speculative, creative science that I have come to expect at SENS conferences.  Most such reports do not pan out, but some of them lead to spectacularly disruptive technologies.  We can survive with no less.

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Orcas and Elephants–Aging and the Taboo Subject of Population Regulation

One species has come to sit atop the biosphere in much of the world, to dominate and transform the world’s ecosystems.  A complex of environmental crises looms, and they can’t count on evolution to change their genetics fast enough to catch their fall.  The crisis will have to be negotiated with social agreements.  Will their political organizations be up to the task of establishing a sustainable culture without a population crash of unthinkable proportions?  In all the history of life on earth, there is no precedent for this situation.

…or maybe there is…maybe it has happened before that a species has encountered the productive limits of a finite planet, and responded with widespread and peaceful cooperation to avoid ecological collapse.


 

My main theoretical contribution to the field of aging research has been the Demographic Theory of Aging.  It says that aging evolved in order to level the death rate in good times and hard times, so individuals don’t all die at the same time, risking extinction in periods of famine or epidemic.

The mathematics of populations is about reproduction in proportion to present numbers.  This implies either exponential growth or exponential decline.  Stable ecosystems cannot be built from populations that are growing exponentially or collapsing exponentially; and no animal species can live (for long) without a stable ecosystem. There are two common objections to this simple, straightforward logic.  

The first is that evolution doesn’t work like this.  “Evolution is about one mutation at a time, and either that mutation produces more copies of itself or less copies.”  My response is that this statement is not a law of nature but a hypothesis.  It is a picture painted not by Darwin, but by evolutionary mathematicians of the early 20th century, including R. A. Fisher and J. B. S. Haldane.  Though this particular model of evolution has been the basis of much theory for the last hundred years, the products of evolution demonstrate that group fitness frequently counts as much as individual fitness.

The second is that animal populations can be stabilized by simple feedback.  When there is plenty of grass on the plain, the rabbits increase in number; and when there is not enough grass on the plain, the rabbits starve, and their numbers diminish.  My response is that this process is too violent to produce viable ecosystems.  The problem is that deaths tend to clump together, and populations overshoot so far that they are bound to vanish to extinction.  The rabbits keep eating and reproducing as long as there is grass to eat.  After that final generation of rabbits has eaten the prairie bare, their offspring–far more numerous even than they–are born into a world devoid of grass, and they all die.  

The tool of my art is computer simulation, (and I wish R. A. Fisher had had computers to support his insight).  Computer models show consistently that ecosystems relying on starvation to regulate their populations are subject to violent swings.  In simulations, animal populations will bloom to hundreds of times the level that can be supported in the long run, only to collapse suddenly to extinction.  The same simulations show that aging is able to stabilize this dynamic.  Each individual’s death occurs on an independent schedule, so they don’t die all at once, and extinction is avoided.

In the 19th Century, the Rocky Mountain Locust was a great success in the American Midwest.  Huge clouds of ten trillion locusts covered the sky for miles in every direction.  Locusts fell from the sky and covered the ground, so thick that a man could not walk without crunching them.  Every green leaf was devoured, and the midwest became a dust bowl.  The locusts drove themselves extinct, victims of their own spectacular success.  The last locust was observed in 1902.

Population regulation is an idea that has been considered and decisevly rejected by the mainstream of the evolutionary community.  The consummate British naturalist V. C. Wynne-Edwards published (in 1962) a book about natural, evolved population regulation that was at once the denouement of his life work and the end of his career.  His theory was ridiculed and dismissed, and two generations of evolutionary scientists could not breathe the words “population regulation” or “group selection” for fear they would suffer the same fate.  But these ideas have begun to resurface in the 21st Century, and in fact it is impossible to understand natural ecologies without them.

Stabilizing population dynamics with aging…

The lion cannot chase down a gazelle in the prime of life–not fast enough.  We might imagine a time in the past when some proud, tragic lion evolved enough speed that he could easily catch any gazelle in the herd.  The genes that allowed her to do this enabled her to provide more meat for her offspring, and they flourished and crowded out the slower lions as the lion population grew.  Plentiful food assured that the population of super-lions grew and grew, until the herd of gazelles was diminished, the herd was picked clean, and the lions died all at once.  This race of lions disappeared.  Elsewhere, the lions that were just a little slower continued to live sustainably with their prey.  What we are left with is a productive and stable demographic structure.  Each gazelle matures through the prime of life, runs fast enough to escape its predators, raises a family.  Then with age, the gazelle’s speed begins to lose its edge.  The lions are able to catch the older gazelles that have already replaced themselves, but not the young ones in the prime of life.  This is a stable population dynamic, and it is made possible by aging of the prey.

…and with social behaviors

Like almost all predator birds and mammala, lions use territorial social behaviors to limit their population sizes and protect their prey.  There are a few spectacular fights to the death, but for the most part, the system is maintained through voluntary submission.  One family will hold a territory, and several non-mating individuals may lurk in the wings but not reproduce and not challenge the territory-holder, sacrificing their individual fitness entirely, waiting for an opportunity like a pool of unemployed workers waiting for a job offer.

Carl Safina: Beyond Words

This week I have been reading Carl Safina’s wonderful new book about the inner lives of animals, and the languages and social structures of three groups in particular:  elephants, wolves, and cetaceans.  He is an engaging story-teller, and after hearing one drama after another of intelligent, collective actions, I came to a new appreciation of animal societies.  Because population regulation is the center of my research, I found myself melding Carl’s ideas with my own, and thinking about conscious, communal responses to overpopulation.

 

Elephants and orcas have much in common.  Both orcas and elephants are apex predators, with no natural enemies.  They are also nomadic, traveling huge distances and foraging over great territories.  They use sound in ways that we might find difficult to imagine, communicating over huge distances.  Both elephants and orcas recognize hundreds, perhaps thousands of individuals, their personalities and social relations, and have names for themselves, can call to specific others over distances of many miles.  Both are guided in their migrations by elder matriarchs who accumulate decades’ of experience about feeding prospects in many and widely-dispersed locations.  Leadership in elephant tribes and orca pods is established via an elaborate political system of social relations, supported by communication modalities that a few devoted scientists, studying them for decades, have only begun to decode.

Because they live much longer than the species on which they depend, their demography must be tuned to plan ahead, or else they are in danger of devastating the species on which they depend for food.  A bloom in the orca population could wipe out salmon, so that the salmon would not recover for a long time; elephants range over many thousands of square miles, and can devastate the foilage in a region because of their prodigious demand for food.

I learned that orcas divide into two cultures.  Some orcas eat fish but not mammals; others eat mammals but not fish.  Both are highly social, and are extremely friendly, gentle, playful and careful in encouters with humans.  Fish-eating whale pods might meet other pods of fish-eating whales and greet them as old friends, talking and touching.  Likewise with mammal-eating whales.  But fish-eating and mammal-eating clans ignore one another utterly.  They overlap in territory, but they do not interact.  They don’t fight, and they don’t talk.  They swim right past one another.

Warning – the rest of this column is my own speculation, and is not established or tested science.  My theory fits the facts, but it is out on the edge.

A species may gradually evolve population regulation built into its life plan, co-evolved within an ecosystem.  This is a long, slow process.  But when a species becomes social, it may learn to hunt with suddenly far greater efficiency than when individuals were hunting separately.  Social learning is much faster than the “genetic learning” that is accomplished via natural selection.  The genes don’t have time to catch up.  So when a species of animals learns to hunt socially, it must also learn to control its population socially.  Through territoriality and other agreements–through culture and communication–the population group must maintain restraint, or it will devastate its food supply and starve to extinction.

I imagine that orcas and elephants each faced this problem many tens of thousands of years ago, perhaps hundreds of thousands of years ago.  They hunt cooperatively with devastating effectiveness.  As they learned to hunt together, they must also have learned some scheme for apportioning the privilege of reproduction, an essentially political process.  Neither species is territorial in the usual sense; they roam over huge, overlapping territories.  Via communication and enforcement systems unknown to science, they have maintained their populations at levels that allow them to feed their prodigious biomass comfortably and with little fear of starvation.

The impact of humans

All this must have changed in the 20th Century, as humans blundered into their ecologies, killing huge numbers of whales and elephants, and laying waste to their food resources.  At the same time that new political agreements, new negotiations and cultures were necessary for their survival, we have killed the oldest, largest, and wisest matriarchs who might have guided this process. 

In my fantasy, the worldwide Orca community ate only fish until they faced a crisis in the mid-20th Century precipitated by human overfishing.  They shared information and held meetings about the extent of the damage.  They were shocked and saddened by the oblivious, blundering behavior of humans, but they were too wise to try to go to war, to take retribution against humans.  Perhaps they knew that this would trigger an extermination campaign that went beyond harpoons to machine guns.  There was a deep divide in opinion; some orcas thought they had no choice but to expand their hunting to walruses, seals, and porpoises in order to continue to live with the freedom they had once known; others must have thought that hunting mammals was barbaric, akin to cannibalism.  Perhaps the two orca cultures agreed to disagree, and have lived in separate communities for decades, though their territories are not at all separate.

Can humans learn from animals?

Man is in uncharted territory because in the last 150 years we have learned to increase our life span to the point where our population growth far outstrips the growth of our historic food species.  We have made up the difference by harnessing fossil energy sources to expand our habitat, and by farming on a global scale, transforming natural ecosystems into artificial ecosystems.  We don’t know how long this process can continue, and we don’t know whether our engineering can secure the fragility of artificial ecosystems.  We have not yet begun to face the Law of Unintended Consequences.   Hence “uncharted territory”.

But perhaps we have something to learn from the orcas and the elephants.

Jon Lomberg — Intelligent Life in the Universe

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The Mystery of Aging, Solved at Last!

How many headlines have you seen that purport to reveal THE secret of aging?  Just in the last few weeks,  there have been several fundamental, earthshaking, paradigm-shifting, game-changing, disruptive discoveries–and they were very different one from another.

Why do these headlines keep popping up?  Is there truth in any of them?  …and, most interesting to me, What is it that they are all missing?

I’m a culprit in this game, too.  My publisher wants to call my forthcoming book Cracking the Aging Code.

I’m going to cover seven of these news releases below; I trust you’ll let me know if you want to hear more about any of them in particular.

What to Eat while FastingI have posted a page of recipes for my variation on Longo’s Fasting-Mimicking Diet.  These recipes are not endorsed by Dr Longo, but they have the same profile of macronutrients (calories, protein, fats, carbohydrates) as the products soon to be available from L-Nutra.

These recipes are based on fresh foods, and the fiber content is much higher than the FMD that Dr Longo has tested.  Intuition tells me that fiber can only add benefit, but this is untested.

Delay of Aging by Remote Control

“UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems.”  [Science Daily from last fall]

AMP Kinase is a key chemical workhouse for energy production and regulation.  In this study, the AMPK gene in fruit flies was found to be a signal that controls autophagy throughout the body.  (Background: Autophagy is recycling at the cellular level.  It declines through the life span, with the result that molecular gunk accumulates and production of properly-formed proteins declines.)

Life span and health span of the flies were increased when the gene for AMPK was activated in the nervous system, and independently in the digestive system.

 

Role of Mitochondrial Damage vs Epigenetics

Jun-ichi Hayashi of Tsukuba University was an early enthusiast of the mitochondrial free radical theory of aging, who became convinced by his own lab results that the theory doesn’t work.

Background: Mitochondria are thousands of organelles inside a cell that burn sugar for electrochemical energy that the cell can use.  They have their own DNA and their own reproductive cycles within a cell.  They generate reactive oxygen species (ROS) as a byproduct, and it was an attractive theory to attribute aging to damage and mutations they suffer because they are at ground zero for high concentrations of ROS.

Over the last two decades, we have learned that mitochondria do indeed play a central role in aging, but the story is not about simple damage.  In his latest paper [research article, Science Daily report], researchers from Hayashi’s lab show that there is no difference in the amount of DNA damage in mitochondria from cells of young people and from old people.  Why then do mitochondria perform less well, and provide less energy in older people?  They go on to propose that it is the epigenetic programming (in the cell nucleus, not the mitochondria) that makes the difference, and they identified two genes (GCAT and SHMT2)  that may be all that is needed to restore youthful function to the mitochondria.  These genes control production of glycine, the simplest of the 20 amino acids that are common protein constitutents.  Simply feeding the cells with glycine also improved mitochondrial function.  (You can buy glycine tablets as a supplement, but the body already has a lot, so it’s a good guess you would need a lot of it to make a difference.  Food sources rich in glycine include gelatin, shrimp, spirulina, and raw ostrich meat.)

 

Simple Flip of a Genetic Switch

Johnathan Labbadia at Northwestern University has discovered an epigenetic switch, a set of genes that is turned on that begins the aging process in lab worms [Research article from the Morimoto lab, Science Daily summary].  Worms begin aging at the tender age of 3 days, just a few hours after adulthood, with a switch that represses Heat Shock Protein.  HSP is not jus for heat, but a high-level signal that invokes a set of responses that create resiliency in response to stress of many kinds.  In worms and in other animals, stress resistance is closely associated with longevity, and HSP is associated with longer life span in worms [ref].

Scientists who see aging as a purposeful, programmed event, myself included, look to mechanisms of epigenetic control, as we are hopeful that signaling can be modified to avert aging.  But traditional evolutionay biolgy denies that there can be such direct control of aging.  According to theory, such switches could only be flipped if flipping them increased reproduction in a way that more than offsets the loss of reproductive opportunity from aging.  In keeping with the standard theories, Labbadia and Morimoto, looked for a connection to reproduction in the epigenetic switch they discovered.  They found one, but–undermining the theory–they found that the benefits for reproduction and the costs in the form of aging could be easily separated.

“In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.”

Why doesn’t the worm do this, and get the best of both?  Must be some kind of mistake, the Northwestern team asserts.  “Dysregulation” has become a favorite word, though many have enough integrity and insight to be scratching their heads, wondering why there should be so much “dysregulation” involved in aging, when we rarely find anything else about the metabolism that is consistently dysregulated.

 

Older Blood Vessels are Better Protected against Oxidative Stress

This press release from University of Missouri descirbe evidence that cells of the arterial lining (epithelium) are more resistant to oxidative damage when they are older.  Research from the lab of Steven Segal used hydrogen peroxide (H2O2) as a stressor.  Peroxide is also known to be a multi-purpose signal molecule that can induce cell suicide (apotosis) in high concentrations, and can induce protective anti-aging response at lower levels [ref, ref].

The article is framed within an old and discredited view of that regards aging as a simple result of oxidative damage [ref].

Although the causes of many age-related diseases remain unknown, oxidative stress is thought to be the main culprit. Oxidative stress has been linked to cardiovascular and neurodegenerative diseases including diabetes, hypertension and age-related cancers.

It should no longer surprise us that anti-oxidants are not anti-aging [ref], or that pro-oxidants can be anti-aging [ref], or that aging is an active process controlled by central signals, not a passive process of damage [ref].

 

Getting to the Bottom of Aging

This article claims to find the root of aging at the cellular level.  In particular, it is in the endoplastic reticulum [background in a Kahn video]. The ER is a transport network inside the cell that directs each protein molecule to a targeted location.  It does more than this–it finishes and folds the protein after it is manufactured.  The new study finds differences between the ER of old and young cells, studied in lab worms and in cultured human cells.  [Here is a Science Daily summary.]  Proteins tend to be misformed and misfolded by the ER of old cells..

In direct contrast to the article just above on blood vessels (“oxidative stress is thought to be the main culprit” ), the claim here is that there is not enough oxidation in the ER of old cells.  It is the reduced state of the ER that is responsible for misfolding of proteins.

 

Diverging Paths from Parabiosis Experiments:  GDF11 and TGF-β

In the early 2000s, Irina Conboy and Amy Wagers were grad students in Tom Rando’s Stanford University lab, studying parabiosis in mice.  They learned that tissues in an old mouse could be rejuvenated by exchanging blood plasma with a young mouse.

Blood plasma is the liquid, containing dissolved signal molecules but no whole blood cells, no stem cells.  The implication was that the old tissues could receive instructions from other parts of the body (an epigenetic clock?) causing them to get older or to revert to a younger state.

Following up on this work: Now Irina and her husband Mike Conboy have a lab at UC Berkeley, where they are focusing on TGF-β as one of the signals that causes aging.  They are experimenting with a drug that blocks TGF-β receptor, and found that it has rejuvenating effects both on muscle and brain cells [press release, research article].  The implication is that excessive TGF-β in the blood is a source of aging.

Wagers is at the Harvard Stem Cell Center, where her biggest trophie so far is the discovery that GDF11 has rejuvenating effects in muscle and nerve cells.  The implication is that there is not enough GDF11 in the blood in the blood of older mammals, and this is a source of aging.

The irony is that GDF11 is a form of TGF-β.  The findings of Wagers and Conboy have diverged to the point where they have focused on the same signal as pro-aging (Conboy) and anti-aging (Wagers).

I don’t have the expertise to take sides in this disagreement, but others have noted that Wagers’s claim seems counter-intuitive. Doubts were expressed about Wagers’s findings by researchers at Novartis (a Cambridge, MA pharmaceutical lab), where David Glass claims he has been unable to duplicate Wagers’s work, and that in his experiments with mice, GDF11 seems to decline with age.

Wikipedia says, “GDF11 is a myostatin-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin.” [emphasis added].  Myostatin is an inhibitor of muscle growth whose structure is 90% homologous to GDF11.

Images of cells in the brain’s hippocampus show that the growth factor TGF-beta1 (stained red) is barely present in young tissue but ubiquitous in old tissue, where it suppresses stem cell regeneration and contributes to aging.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”

 

Keeping your Brain Active with Balance Exercises

A pilot study by Ross and Tracy Alloway of Univ North Florida suggests that balance exercises improve working memory and protect against neurodegenerative disease. [UNF press release]  The focus of the study is termed “proprioception”, awareness of body position.

We all lose brain cells with age, and I think of Alzheimer’s dementia as one end of a spectrum.  Some herbs have been studied for neuroprotective effects.  Vigorous exercise is neuroprotective.

In parallel to my life as a scientist, I have always practiced yoga and I have taught one yoga class each week for almost 40 years.  Balance exercises are an essential aspect of yoga.  Intuition tells me there is an anti-aging benefit in yoga practice, and there is implicit evidence for this.  I think the connection between yoga and aging deserves a lot more study, but of course it cannot be done with animals, and blinded, controlled experiments are not feasible.

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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.

Rod-bacteria-multiply

 

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.

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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.

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

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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.

 

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* 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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