What Doesn’t Kill Me Makes Me Stronger

Most people over 50 have some kind of joint and back pain.  We think that when we gain weight, there is more pressure in every step, more strain on the joints, and it makes our arthritis worse.  But the truth is stranger than this.  In fact, exercise helps to prevent and to relieve arthritis [Ref1Ref2, Ref3Ref4].  (The only exception is extreme, punishing exercise, like the elbow of a major league pitcher or the knees of a lineman in pro football.)  Walking around with a 40-pound backpack has the opposite effect of carrying an extra 40 pounds of belly fat.  The reason that weight gain exacerbates arthritis is that every fat cell is a hormone factory, pumping out inflammatory signals.  Together these signals (called cytokines) tell the blood cells to turn up the heat on the inflammatory attack that is eating away at the cartilage in our joints.

Was mich nicht umbringt, macht mich stärker.
— Friedrich Nietzsche

Maybe the fact that overeating is bad for our longevity is so familiar to you that you no longer think it’s strange.  But believe me, it’s strange.  It’s strange that the harder you work your body the longer it lasts.  And it’s strange that life span in lab animals can be modestly extended not by protecting and coddling them, but just the opposite–by challenging them with one hardship or another.  A list of things that have been found to increase life span include

  • low-dose radiation
  • toxins
  • pathogens and infections
  • heat, and
  • cold
  • hypoxia (oxygen starvation)

Paraquat is a powerful herbicide, and highly toxic to humans.  It is the opposite of an anti-oxidant.  When paraquat was sprayed from the air to destroy marijuana fields in Chiapas, Mexico, 16 people died.

In the McGill University laboratory of Siegfried Hekimi, life span of roundworms is extended remarkably by adding paraquat to the medium in which they swim.  Tiny doses of paraquat have little effect, and high doses kill the worms, but if the dose is adjusted just right, the worms live 70% longer.

When challenged, the body adapts by becoming stronger–this much is no surprise.  What makes us stand up and take note and rethink how we’re put together is that the body “over-adapts”.  It becomes so much stronger that we actually are healthier and live longer in the presence of challenges and toxins and hardships than when we are coddled in an ideal, unstressed environment

The name for this general phenomenon is hormesis, and it was first described in the 19th Century.  But the word “hormesis” dates only from 1943, and it is only in the last two decades that the idea has received some scientific respect.  There are three reasons the scientific community has resisted the concept:

  • Association with the problematic science of homeopathy.  In the early 20th Century, people who promoted homeopathic medicine were prominent supporters of the concepts of hormesis.
  • Polluters and chemical manufacturers seized on the idea to argue, opportunistically, that pollution is actually a boon to public health!  In fact, owners of nuclear power plants argue that leakage of radiation is not a problem as long as it is below a threshold dose*.
  • The true strangeness emphasized above.  Hormesis implies that the body is unable to be fully healthy if it has all the food it needs, and is deprived of poisons and stressors.

 

Examples of Hormesis

  • The most dramatic and obvious examples of hormesis are that less food and more exercise both lead to extended life span.
  • Chloroform is a trace contaminant in toothpaste.  Manufacturers tested the safety of their product by feeding toothpaste to dogs with and without the chloroform.  They were surprised to find that the mortality rate was lower for the dogs that got chloroform [Ref].
  • Repeated, mild burns slow the age-related damage to human skin cells [Ref].  Worms that are exposed to heat shock also live longer [Ref].
  • In an Australian study, people exposed to more sunlight had less long-term UV damage to their DNA [Ref].
  • Rats that were bathed in cold water 4 hours per day lived longer and had lower cancer rates than rats that stayed warm [Ref].
  • Mice exposed to 25 or 50 times the normal background level of gamma radiation lived 20% longer than mice that received only the ordinary background [Ref].
  • Fruit flies exposed to disease enjoyed greater fertility and longer life [Ref].

Don Luckey devoted the last decades of his professional life to documenting the health benefits of radiation exposure, and faced the skeptics to argue that we should all be getting more whole-body radiation exposure than we get from cosmic rays and low background of radioactive elements in the earth [Ref]. The US National Research Council disagrees [Ref].

Edward Calabrese researches the epidemiology of environmental toxins at U Mass.  For 25 years, he reported findings in terms of standard linear models:  If 1 part per million is bad, then we expect half a part per million to be half as bad.  But with accumulating evidence, there came a point where he had to break ranks, and he has been a prominent advocate of the hormetic viewpoint ever since.

From a comprehensive search of the literature, the hormesis phenomenon was found to occur over a wide range of chemicals, taxonomic groups, and endpoints…hormesis is a reproducible and generalizable biological phenomenon, and is a fundamental component of many, if not most, dose-response relationship [Ref].

The Hygiene Hypothesis says that widespread use of disinfectants has reduced childhood exposure to bacteria to an unhealthy extent, and that increased incidence of asthma, irritable bowel syndrome, Crohn’s disease, and various auto-immune disorders has been the result.

Hormesis also has an unusual place in cinematic history. During the 1950s, reports on the capacity of ionizing radiation to stimulate growth inspired the genre of so-called ‘‘nuclear monster’’ movies, which included Godzilla (1954) and Attack of the 50 Foot Woman (1958). Typical of this genre was Them! (1954), in which ants exposed to radiation from atomic bomb tests grow to gigantic proportions and terrorize residents of New Mexico. [Ref]

 

How to make biological sense of hormesis

The reason that hormesis seems so strange to us is that we like to think that we are evolved to be as strong and as healthy as it has been possible for nature to make us.  It doesn’t make sense for us as individuals to hold back on strength and longevity just because we don’t happen to be starved or poisoned at the moment.  But if we think collectively instead of individually, it all starts to make sense…

My principal contribution to evolutionary theory has been the Demographic Theory of Senescence, which starts from the premise that population overshoot is a danger to most animal species.  If animals eat all the food that is available to them and reproduce as fast is they are physically capable, then the environment will be denuded, the next generation will starve, and the species will face extinction.  All animal species are evolved to avoid this.  [Academic references 2012 and 2006]

Another way to describe this same situation is to say that the main causes of death in nature are all clumped together.  When food becomes scarce, everyone starves at once.  When there is an epidemic, everyone gets sick together.  When there are storms or cataclysms or environmental poisons, they affect an entire population at once.

Aging is nature’s way of leveling out the death rate, assuring that we don’t all die at the same time.  Aging puts our deaths on an individual schedule so we can die at different times; other causes of death tend to kill everyone or no one.

Since aging has evolved to complement the environmental death rate, we expect that when the environment is most hostile, there is little or no need for additional deaths from aging.  So aging takes a vacation during starvation or other times of hardship.  Conversely, when life is easy and stress-free, no one is being killed from external causes, aging is out in full force, helping to thin the population and avoid population overshoot.

So the Demographic Theory provides a natural context for understanding hormesis.  In fact, the Demographic Theory is the only theory of aging in which hormesis is actually a prediction.

(Mikhail Blagosklonny agrees, but stops short of saying that aging is programmed.  Peter Parsons disagrees.)

 

Implications for Personal Care and Longevity

Well, eat less and exercise more–that’s a good start.  If I were just looking at the data, I’d have to say that introducing a source of gamma radioactivity in the home, 25 times above background might be justified.  But the idea makes me queasy.  We don’t know how to do it well.  Might it be beneficial at some ages and a risk factor at other ages?  People who live in houses with naturally high radon levels have elevated risk of lung cancer [Ref].

The concept of hormesis has made me relax a lifelong fear of pollution, and I have backed off from Bruce Ames’s program of reduced exposure to natural and artificial toxins. But I’m not ready to do anything pro-active to increase my exposure to toxins or radiation.

 

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* My position on nuclear power is that low-level leaks of radioactivity are the least of its problems.  Nuclear power should be a non-starter because it is uneconomic without huge government subsidies, including the Price-Anderson act which limits liability.  Haven’t we learned anything from Chernobyl, Three Mile Island, and Fukushima?  And don’t get me started on guaranteeing the safe storage of radioactive waste for the next 20,000 years.

pf button What Doesnt Kill Me Makes Me Stronger

Regeneration in Mammals–Ancient Capacity is Not Lost, but Actively Suppressed

It was 1995, and Ellen Heber-Katz ran a busy lab at the Wistar Institute in Philadelphia, at the top of a thriving career in auto-immunity.  Her lab used standard practice to identify individual mice with tiny holes punched in their ears.  In the midst of one experiment, she discovered some un-labeled mice, and she spoke to her post-doc about it.  But Lise Clark said she was sure she had punched their ears.  So Heber-Katz punched their ears herself, and checked back a few weeks later.  She could hardly see the holes she had punched.  Within a few weeks, the ears had healed over, smooth skin, seamless cartilage with nary a scar.  Mice aren’t supposed to be able to do this.

She might have continued the project with an alternate labeling method, but Heber-Katz was more curious than that.  She learned that this particular strain of mouse (MRL mice from Jackson Labs in Bar Harbor) was known for healing over their ear punches.  Other researchers had noticed the “problem” and dealt with the inconvenience, without giving a second thought to the larger implications.

Heber-Katz couldn’t wait to study the phenomenon in depth. But her colleagues counseled against it, urging her not to waste her expertise in the field of autoimmune disease and transplant rejection. They advised her to pursue the disappearing ear holes as “an aside,” like a hobby. But Heber-Katz knew she had stumbled onto something big, and she just had to go after it full force. “I realized, since I didn’t know anything about wound healing, I had better go to a meeting about it,” she says. So she did, and there an expert told her: “Oh no, mouse ear holes absolutely do not close.” So Heber-Katz kept her finding secret. “I was really on cloud nine,” she says.    – Katie Moisse, [Sci Am (2006)]

In early studies with regeneration, she and colleagues found that the hearts of MRL mice heal scarlessly from injury.  When humans suffer heart attacks, heart tissue dies and usually the damage becomes permanent.  Normal mice can’t repair their own hearts either.

Salamanders and zebrafish are among the species that can regenerate limbs and even large portions of vital organs after injury, and the regrown portions of their anatomy are just the same as the original. We mammals cannot do this: we can manage fingernails, occasionally fingertips at a very early age, and portions of the liver, but that is about it. One line of modern regenerative research asks whether it is possible to somehow induce the regenerative biochemistry of salamanders and zebrafish in mammals. Is mammalian incompetence in healing a matter of lost capabilities that originally evolved in a distant shared ancestor species, and thus the necessary biochemistry still exists, but is in some way dormant? [Michael Rae at FightAging.org]

Juan Carlos Belmonte’s Group at the Salk Inst has gotten normal mice to perform the same trick, using a micro-RNA signal to turn normal heart (muscle) cells back into the stem cells from whence they came, so they can make new heart cells. They were able to reactivate

long dormant molecular machinery found in the animals’ cells, a finding that could help pave the way to new therapies for heart disorders in humans. The new results suggest that although adult mammals don’t normally regenerate damaged tissue, they may retain a latent ability as a holdover, like their distant ancestors on the evolutionary tree.
In a [2010 paper in Nature], the researchers described how regeneration occurred in the zebrafish. Rather than stem cells invading injured heart tissue, the cardiac cells themselves were reverting to a precursor-like state (a process called ‘dedifferentiation’), which, in turn, allowed them to proliferate in tissue…

The team decided to focus on microRNAs, in part because these short strings of RNA control the expression of many genes. They performed a comprehensive screen for microRNAs that were changing in their expression levels during the healing of the zebrafish heart and that were also conserved in the mammalian genome.

 Their studies uncovered four molecules in particular–MiR-99, MiR-100, Let-7a and Let-7c–that fit their criteria. All were heavily repressed during heart injury in zebrafish and they were also present in rats, mice and humans.

[News Release from the Salk Inst]

In other words, the surprise is that we didn’t lose something in the advance from fish to mammal, rather we acquired a response that suppresses regeneration.  The ability to regenerate remains intact in mammals, but it is switched off.  This raises the possibility that if we want our bodies to be able to regenerate damaged tissue without scarring, we don’t have to acquire a new mechanism or even re-acquire one that has been lost; all we have to do is to fiddle with biochemical switches.  Switching on or off particular genes in particular tissues has become a reliable technology, using any of several techniques (e.g. CRISPR, RNAi, retroviruses).

the team used adeno-associated viruses specific for the heart to target each of those four microRNAs, suppressing their levels experimentally.

Injecting the inhibitors into the hearts of mice that had suffered a heart attack triggered the regeneration of cardiac cells, improving numerous physical and functional aspects of the heart, such as the thickness of its walls and its ability to pump blood. The scarring caused by the heart attack was much reduced with treatment compared to controls, the researchers found. The improvements were still obvious three and six months after treatment – a long time in a mouse’s life.

In the same vein, Heber-Katz’s group has also concluded that the capacity to regenerate has not been lost in mammals, but is actively suppressed.  Four years ago, they had already identified a gene called p21 which is defective in their MRL mice.  They knocked the p21 gene out of normal mice and discovered that those mice could heal their ears similarly to MRL mice.

Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the rule that mammals do not regenerate appendage tissue…Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse, we show that the unrelated Cdkn1atmi/Tyj/J p21-/- mouse (unlike the B6129SF2/J WT control) closes ear holes similar to MRL mice, providing a firm link between cell cycle checkpoint control and tissue regeneration.  [Ref]

Although Heber-Katz’s group was based on genetically engineered mice, there is no reason to expect they could not do the same with normal mice, using one of the three in vivo techniques I mentioned above to shut off the p21 gene temporarily and locally.  I know of no one who is trying this in humans, but it seems to me that this technology is ready, and if I were a heart attack patient, I would eagerly volunteer for early trials.

This story of regeneration not being lost but suppressed fits beautifully with the song that I have sung so often on these pages and elsewhere–that there is no fundamental limit to life span in our metabolisms, but that evolution has programmed a fixed length of life for the purpose of stabilizing ecologies.

One thing that doesn’t fit so well is the story that Heber-Katz has been focusing on the last two years: inflammation is an essential part of the regeneration process [ref, ref, ref].  This could be an example of antagonistic pleiotropy.  Suppressing inflammation is an important anti-aging strategy, and it may have to be pried apart from wound healing in order to make further progress.

 

Porpoises and other marine mammals

Adult porpoises can repel a large shark, but are frequently injured in the encounter.  It is estimated that 40% of poropoises in the ocean have survived a shark bite, but they don’t carry scars from the event.  Porpoise skin and the blubber layer underneath recover in a matter of days from lacerations up to a foot long.

A Georgetown University pediatrician published this information a few years ago in a dermatology journal.  “Reports of the survival after severe traumatic injury of other marine mammals, such as the southern elephant seal [ref] and the Hawaiian monk seal [ref], suggest that efficient healing of soft-tissue injury might be widespread among marine mammals.”

What do the porpoises have that we don’t have?  I think the proper question is likely to be, by what signals have we suppressed the porpoise’s capacity to heal?

 

pf button Regeneration in Mammals  Ancient Capacity is Not Lost, but Actively Suppressed

Three Technologies to Watch

1. Thymus Regrowth with FOXN1

The thymus gland is a time bomb that would kill us at a certain age, if nothing else got us first.  It shrinks (the medical word is “involution”) gradually through life, beginning in childhood and culminating in disastrous results in old age.

The thymus is a small gland located just behind the top of the breastbone.  Among your white blood cells, your first-defense cells are the T-cells, named for their association with the thymus.  The thymus is training ground for the T-cells, where they learn to distinguish friend from foe.  The body has many types of cells, and the T-cells must not attack any of them; but they also must reliably identify invading microbes.

These immune functions are related to many aspects of health, and not just attacking invasive microbes.  The immune system is continually eliminating errant, pre-cancerous cells before they can become cancers, as well as cells in the body that have been taken over by a viral infection.  Rampant inflammation and auto-immune disorders are the consequence when the immune system begins to turn against self late in life.

As the thymus shrinks year by year, the immune system breaks down.  A 90-year-old thymus may be one tenth the size it was in the bloom of childhood, and this goes a long way toward explaining the vulnerability of older people to viral infections that would not be serious for a young person.  Arthritis is well-characterized as an auto-immune disease, but there are auto-immune aspects of other diseases including Alzheimer’s

There is good reason to think that if we can preserve or even regrow the shrinking thymus, then there will be benefits that echo through many or all the diseases of old age.  Human growth hormone has been used with some success, but reactions to HGH vary, and there is reason to worry about its long-term effects.  There is a recent breakthrough in treatment for the thymus that looks very promising.  A transcription factor is a coded chemical signal capable of switching the expression of many genes at once, turning some on and others off in one sweep.  FOXN1 is a transcription factor that has been isolated from the thymus of young mice, and by re-introducing it to old mice, a Scottish research team succeeded in consistently stimulating the thymus to regrow [ref].  The larger thymus looked and functioned much like the thymus of a young mouse.

The most glaring absence in the blood as we age is naive T-cells, cells that are not pre-trained to fight any specific infection from the past, but are primed to look out for new invaders.  So it is most promising that the thymus glands regenerated with FOXN1 produced copious naive T cells.

In the Scottish experiments, mice were genetically engineered with extra copies of the FOXN1 gene that could be turned on with a drug as trigger.  You and I don’t have these extra copies, so we need another means to get FOXN1 into our aging thymi.  FOXN1 is not something we can take in a pill, because it is a large protein molecule that is routinely chopped up for recycling during digestion.  A research group at University of Texas is injecting little snippets of DNA (called plasmids) containing the FOXN1 gene directly into the thymus with some success [ref].  Turning on the cell’s own FOXN1 gene would be ideal, and there are already candidates that can do this.  There is no reason to doubt the feasibility of FOXN1 drugs, but for now we have only rumors that they are under development.

 

2. New Anti-Inflammatory Drugs based on ARF6 Inhibitors

Inflammation has been a recurring theme in this blog, because inflammation is the most obvious and ubiquitous mode by which the body destroys itself.

The fact that simple, “dumb” NSAIDs lower mortality in older people and increase life expectancy is very promising, but the promise is limited because inflammation has an important positive function as well as its self-destructive role.  That’s why the more powerful NSAIDs have side-effects that limit their use.  To make real progress in this area, we will need smart anti-inflammatories that go selectively after the destructive role, and leave the protective function intact.

Dean Li and his research group at University of Utah have been addressing just this challenge.  Their breakthrough paper came in 2012, when they announced the discovery of a signaling pathway that controls just the destructive inflammation, and is not involved in the good kind.  In petri dishes, they identified a target signal called ARF6, and for therapy they constructed a protein that contained the last 12 units at the tail end of ARF6.

Have you ever broken off half a key inside a doorknob?  Not only can’t you turn the knob, you can’t pull the key out, and you can’t get another key in there either.  You may have to give up on the lock and get a new doorknob.  The tail end of ARF6 works like half a key.  It fits neatly into the same receptor as the full ARF6 molecule, but once inside it doesn’t change the conformation of the receptor the way that the full molecule does.  It won’t open the lock, and it stays stuck in the keyhole, blocking access to the real, working key.

The tail stub of ARF6 worked like a broken key to interfere with the real ARF6, preventing it from doing its job.  The Li lab was able to block the inflammatory reaction that responds to ARF6 without affecting the course of inflammation that is beneficial and protective.

They went on to inject their tail stub molecule intravenously in mice.  They report exciting initial successes, treating mouse arthritis without gumming up the other important functions of inflammation.

Some bacteria kill the host not directly but by inducing such a violent inflammatory reaction that the patient dies of his own inflammation.  Dr Li’s team challenged mice with LPS, which is the chemical that induces this fatal inflammation.  Mice protected with their ARF6 tail stub had reduced inflammatory responses, and mostly survived, while those without the tail stub mostly died after being poisoned with LPS. [ref]

This is a discovery that has yet to make front page headlines, but Dr Li’s team is fully aware of the potential for changing the way we treat the inflammatory basis of arthritis and other diseases of old age, especially coronary artery disease.

 

3. Telomere Length Directly Affects Gene Expression

Short telomeres cause cell senescence, which pulls a stem cell out of circulation and, worse, causes the cell to emit signals that damage neighboring tissues and the body as a whole.  This has been the basis of the theory that telomeres act as a kind of fuse for an epigenetic time bomb.  This month, a paper came out of Woody Wright’s Univ of Texas lab that adds a mechanism by which telomeres can affect aging even before cells become senescent.  Telomeres affect gene expression, which is the epigenetic state of a cell.  The same chromosome tends to express and repress different sets of genes depending on length of its telomeres.

It has long been suspected that telomere length affects gene expression.  As far back as 1990, Telomere Position Effect (TPE) was noted as affecting gene regulation.  But until this month’s study, there was no coherent idea how this occurs.  In order to study the effect systematically, the Wright team had to create a culture of cells all with the same telomere length.  They were both able to image the conformation of the chromosomes and also measure the genes they expressed as a function of telomere length.  Wright introduces the acronym TPE-OLD, for Telomere Position Effect Over Long Distances.  What they found was that

  • Telomere length affects the folding and conformation of the DNA
  • Telomeres wrap back over coding DNA and have effects extending at least 10MB from the end
  • Telomere length affects the transcription of at least hundreds, perhaps thousands of genes.

(To have a sense of the scale, keep in mind that a human chromosome is hundreds of millions of base pairs long (108), that the length of a telomere is only about 10 thousand BP (104), and that there are about 25,000 genes in the human genome.  So, even though telomeres are 0.01% of the length of the chromosome, they may affect the transcription of 3% of all genes.)

Gene expression changes with age in some ways that are regular and others that are random.  I would say that as we age, our epigenetic state changes toward a self-destructive, inflammatory mode, and also drifts randomly out of tight regulation.

Telomere length varies greatly from one tissue to another, from one cell to another within a tissue, and from chromosome to chromosome within a cell.  It is difficult to make sense of this within a picture of a tightly-regulated aging program.  But the idea that the random portion of telomere length contributes to epigenetic drift seems plausible to me.

In any case, the present study opens a door to a new science, and gives added credibility to the idea that telomere length plays a fundamental role in human aging.

pf button Three Technologies to Watch

Nicotinamide Riboside — Where’s the Beef?

NR is a supplement that affects energy generation in mitochondria and gene regulation through the same pathway as resveratrol and caloric restriction.  It has been promoted in recent months, and this month is featured in Life Extension Magazine.  But evidence for its life expectancy benefit is indirect.  There have been no positive results for fruit flies, let alone mice.  If it works in humans, benefits will likely be limited to people who are overweight.  And there are reasons to expect only limited benefits from the pathways through which NR works.

Reading about a new life extension supplement, I get excited when I see “we fed it to mice and they lived X% longer”, or better yet, “In preliminary human trials, mortality was found to be Y% lower.”  The articles about NR are full of biochemical pathways and chains of genes that promote other genes.  In my way of thinking, all the biochemistry is important for generating ideas, but the proof of the pudding is in life extension trials.  Lab experiments on live mice run hundreds of thousands of dollars to test a single compound.  We can’t be testing everything under the sun, so we rely on biochemistry for plausible candidates.  But jumping from biochemical theory to marketing of a supplement is a leap of faith that leaves me behind.

Worms and flies are much cheaper to breed than mice, and the experiments last weeks instead of years.  Furthermore, genetics of these lower animals is well-understood, and easy to manipulate.  Experiments with worms and flies provide an intermediate proving ground for ideas before the expensive life span trials with rodents.  The ultimate yield is low.  There are many interventions that work well to extend life in flies that don’t work in mammals.

 

NR and Resveratrol

Resveratrol, which works along similar biochemical pathways to NR, was all the rage from about 2003 to 2006.  First discovered in yeast, its mechanism of action was mapped out.  Len Guarente at MIT and others from his lab put the SIR gene on the  map, and coined the term “sirtuins” for substances that activate these genes.

Excitement mounted as resveratrol was shown to extend life span in worms, and then flies.  A young scientist in Italy launched his career by introducing a short-lived African fish to laboratory genetics.  Nothobranchius lives only a few months, one of the shortest life spans of any vertebrate.  For his PhD dissertation, Dario Ricardo Valenzano (2006) safaried to Africa to bring back samples of Nothobranchius, figured out how to breed them in the lab, and demonstrated they live 60% longer with resveratrol in their food.

Incidentally: Valenzano found best results for an intermediate dose of resveratrol, not the highest or the lowest dose.  This has been a recurrent theme in resveratrol research: a little is better than none, but a lot isn’t better than a little.

Soon after Valenzano’s fish, it was reported that resveratrol failed to extend life span in mice.  We were all disappointed.  The result came from the Harvard lab of David Sinclair, Guarente’s most famous student, who was highly motivated to get good results because he had commercial ambitions for resveratrol derivatives.  Sinclair reported that overweight mice that were fed a high-fat diet could be brought back to a normal life expectancy with resveratrol, but that normal-weight mouse received no life extension from the same treatment.

 

NR in experiments with lab animals

Almost all the literature on NR is about yeast cells.  I can’t find a single study on flies or fish.  I found one study of Alzheimer’s Disease in mice that did not look at life span, but the measured the plaques in the brain that are a symptom of AD.  These are mice that are genetically engineered to be vulnerable to AD, because normally AD is absent in mice.  They showed that feeding these mice NR slowed the progress of their mental decline, a good result that traces dietary cause all the way to behavioral effect, its ultimate benefit.  Another mouse study showed metabolic benefits for mice that were fed to obesity.  This was similar to the result for resveratrol, but not as strong because life extension for obese mice was recorded from resveratrol, but not from NR.  The only study in worms showed a 16% life extension.  This kind of performance would be impressive in mice, but there are many ways to double and triple the life span of worms that don’t work in mammals.  (the record is tenfold increase in a genetically modified worms).;

 

Biochemistry of NR and NAD+ / NADH

Biomolecules are a huge variety of different geometric structures, based mostly on covalent bonds between carbon and carbon or between carbon and hydrogen.  But the body’s energy metabolism is based on ionic bonds, because they store more energy in each bond.  Ionic bonds form between atoms that are very different from each other, like sodium and chlorine in table salt.  The standard biological energy repository is in phosphate bonds.

Every cell has hundreds of mitochondria, which are tiny energy factories that burn sugar and produce  phosphates for the cell’s use.  This energy generation process is an ancient biochemical trick called the Krebs Cycle, and is shared by all plants and animals today.  NAD+ has a role to play in the Krebs Cycle, where it absorbs an electron to become NADH, and then is recycled to NAD+ again.

As we age, we lose mitochondria, and the mitochondria we have become less active.  We have less of all the chemical intermediates of the Krebs Cycle, including CoQ10 and NADH.  CoQ10 is an important anti-oxidant, soaking up ROS and converting their energy to useful form.  CoQ10 has been found to improve heart health, but it has failed to extend life span in mice.

In addition to its role in the Krebs Cycle, NAD+ works through sirtuins.  These are high-level chemical signals that can close up DNA into tight balls (facultative heterochromatin) selectively in certain places to block expression of many genes at once.  NAD+ can turn on sirtuins in order to turn off a panoply of pro-aging genes.  This has been shown to work well to slow aging in obese lab animals, but not normal animals.  It works by some of the same pathways as caloric restriction, but without the restriction.

 

Saturation of the CR pathway

Life span is programmed in a flexible way, so as to respond to external mortality.  Famine is one of the deadliest dangers for populations in nature, and so evolution has provided extra ruggedness in the face of starvation.  Death from aging takes a vacation just when the death rate from starvation is highest, helping to level out the overall death rate and protect against extinction.

The fact that life span is extended by hunger was first discovered in the 1930s, and many years later, the genes and biochemical pathways associated with sensing food scarcity have proven to be the most accessible, the easiest to manipulate.

Underfeeding, and tricking the body into thinking it is underfed, are the simplest, most fertile, and most reliable strategies for extending life span.  On a percentage basis, these strategies work best in short-lived species.  With caloric restriction we can double the life span of worms, add 40% to the life span of mice, but only 15% to dogs and 5% or less in Rhesus monkey experiments reported last year.  So 3 to 5 years is an optimistic range for the available flexibility in humans via the caloric restriction pathway.

There are many ways to activate this pathway, either by eating less, exercising, or taking metformin or resveratrol, for example.  The benefit you get from each of these do not add together; rather you are getting the same 3 years over and over again.  So NR is likely to work best for people who are overweight and not taking metformin or resveratrol.

 

The bottom line

It may be that there have already been experiments feeding NR to mice or rats, but sometimes negative results don’t get published.  I am going to wait and see before jumping on the NR bandwagon.

pf button Nicotinamide Riboside    Where’s the Beef?

Quick Notes from Quebec

 (or “Short Takes from Sherbrooke”),
Center for Research on Aging, Symposium Nov 2-4

Why does the cell appear to be shooting itself in the foot?” asked Andres Kriete of Drexel Bioengineering Dept.  All through the conference, I heard people puzzle that our bodies seem to miss opportunities to save themselves from aging, or worse, that they seem to be pouring gasoline on the fire.  Invariably, researchers sought to reconcile what they were seeing with their faith that the body really is evolved to protect itself as best it can.  Everything that looks on its face like a suicide mechanism is re-interpreted to have some hidden benefit.

I was invited to the conference as an advocate of programmed aging, the only one in the room.  I found everyone to be more than polite–listening with an open mind and eagerly engaging with me.  I spoke on a subject that I find exciting, and which has seen an explosion of results in recent months: the possibility that aging is controlled by a biological clock based on epigenetic programming.

 

Experts in diverse fields, hailing from La Jolla to Poland were represented, and I made several new friends, while renewing acquaintance with Siegfried Hekimi, whose lab I visited four years ago.  I woke up this morning visited by a muse, and penned this before I got out of bed.

Ballad of the Sherbrook Gerontologists

When joints and arteries become inflamed,
The body yields to nature’s conflagration
The standard culprit (as always) is blamed.
The problem must be some dysregulation

We scratch our heads, we wonder what went wrong.
To clearly programmed death we pay no heed…
And comfort find we in familiar song:
“Respect the body’s wisdom” is our creed.

The muscle’s satellites that proudly grew
Retire now and yield to cell senescence
Forsake their given mission, to renew…
But we question not their motives nor their essence.

We scratch our heads, we wonder what went wrong.
To clearly programmed death we pay no heed…
And find we comfort in familiar song:
“Respect the body’s wisdom” is our creed.

And even in the face of apoptosis,
The body’s good intent we must abide.
We tender our familiar diagnosis
And whisper not the phrase “cell suicide”.

For evolution is our benefactor
And we must never question her intent
We blame some tradeoff, or an unknown factor
Though on our own demise she is hell-bent.

We scratch our heads, we wonder what went wrong.
To clearly programmed death we pay no heed…
And comfort find we in familiar song:
“Respect the body’s wisdom” is our creed.

– JJM, 2014 Nov 4


Here are some teasers for things I found most interesting in this brief symposium:

One study in Scotland found diabetics who take metformin live longer than non-diabetics who don’t!  (There’s no data on non-diabetics taking metformin, because there are so few of us.  But in studies with normal, non-diabetic mice, metformin extends life span.) (from presentation of Nir Barzilai)


Centennarians don’t have healthy eating habits, don’t exercise more than others in their cohort or smoke or drink less.  They also don’t have genes that are associated with protection from cancer or heart disease or AD.  What they do have is genetic pre-disposition to long life, and it is specific genes that slow aging.  There are specific genes that are necessary to make to age 100, and without them your chances are slim.  (This is different from longevity between ages 70 and 90, which is affected much more by life choices, environment, etc.) (also from Nir Barzilai)


During the last 2 years of life of a centennarian, health costs are ⅓ what they are for the last 2 years of someone who dies at 75. (also from Nir Barzilai)


Burning ketone fuel instead of sugar helps protect the brain against Alzheimer’s Disease.  Fasting a few days, of course, shifts the body to ketosis.  A low-carb diet is ketogenic, but even better are medium-chain triglycerides, often refined from coconut oil for experimental diets. (presented by Alex Castellano)


The Free Radical Theory of aging has it all backwards, says Siegfried Hekimi.  ROS are not a cause of the oxidative damage that accumulates with age, but rather a signal that turns on the body’s protection against that damage.  In his McGill laboratory, worm life span has been increased almost twofold by exposing them to a strong pro-oxidant chemical.  In biology experiments, it is called “paraquat”, but the Vietnamese knew it as Agent Orange.  Of course, large doses of paraquat poison the worms, and their lives are shortened.  But a range of low doses is beneficial.  This result comports with genetic experiments.  The all-time record for long-lived, genetically altered worms is a worm that lacks the ubiquinone gene, so that its energy metabolism is completely disrupted and it is unprotected from ROS.


Children conceived to starving women in Netherlands 1944 had higher rates of metabolic syndrome 50 and 60 years later, due presumably to epigenetic patterns of methylation laid down at conception. (presentation of Irene Maeve Rea)


Michael Kobor of UBritColumbia shared my enthusiasm for the epigenetic clock. He cited recent work of Steve Horvath, demonstrating a set of epigenetic changes that are characteristic of the aging human.  Some of his own work documents the influence of childhood deprivation on epigenetics that affect health, psychology and longevity much later.


And in preparing my own presentation, I un-learned something that I been taught long ago.  DNA is supposed to be the same in every cell in our body (except for a small number of random mutations).  But a recent paper actually samples tissue from different organs and finds big differences.  Could it be that the body is re-configuring its own DNA, as well as epigenetics, when differentiating?  If this is real, it implies an ability we didn’t know cells possess.


Rumors are the most fun

Alan Cohen (from the home team at University of Sherbrooke) told me that he was in touch with Vaupel, whose work I wrote about back in January.  Vaupel had just published a paper comparing the aging patterns of 48 different animals and plants, mostly animals.  Some age gradually, some hardly age at all until the end, and they all die suddenly.  Some age “backwards” in that they become less and less likely to die as time goes on.  Alan told me that Vaupel and his group at Max Planck Inst have been expanding this list, drawing a more representative sample of 10,000 species, and there is a great deal more “non-aging” than anyone expected.


For at least 10 years, it has been known that senescent cells are “bad actors”, not just shirking their duty to the body but spewing out toxins that destroy neighboring cells and contribute to systemic inflammation, ultimately to cancer. In 2011, Jan van Deursen of Mayo Clinic in Minnesota published a paper that demonstrated this dramatically.  Mice were genetically modified to attach a self-destruct signal to the p16 gene, which is a marker of senescence.  The mice could then be dosed with a signal, and the senescent cells would eliminate themselves cleanly via apoptosis.  The mice with their senescent cells removed had a 20 to 30% greater mean life span and even better results for health span.  Even though these cells are less than 1 in 10,000, they do damage far out of proportion to their numbers.  (To my way of thinking, cell senescence is clearly part of the aging program.)

Van Deursen was there to explain and update his work.  The rumor is that there are at least five companies around the world working on drugs that will remove senescent cells without harming other cells, and that these drugs show promise for treating all the major diseases of old age.

pf button Quick Notes from Quebec

Open Letter on Research Priorities in Aging

Last week, I had the honor of speaking with Cynthia Kenyon, who has been recruited by Google to direct research activities at their new venture into aging medicine, called CALICO, for California Life Co.  She was kind enough to listen to my thoughts on research priorities seeking near-term breakthroughs in human life extension.  Here is what I said to her, paraphrased with some added background and comments.


 

It is my belief that the timing of development and aging is determined by chromatin* state.  The body knows how to be young, and it knows how to be old.  The difference is coded in chromosomes, especially in telomere length of stem cells and epigenetic markers in endocrine cells.

* Chromatin is the DNA in the cell nucleus, together with the histone spools around which it is wrapped and all the proteins and side-groups that are loosely and temporarily attached.  Spooled DNA is called “heterochromatin” and it is mostly silent.  Unspooled DNA is termed “euchromatin” and it is more likely to be active.  All the protein markers, the methyl groups and acetyl groups strategically placed, together determine when and where particular genes are expressed.  This phenomenon is called “epigenetics”.  How is epigenetic programming effected?  The cell’s epigenetic language if much more complex than the Genetic Code, and is yet poorly understood.

I am proposing that aging is, in large part, a matter of epigenetics.  A different set of genes is turned on when we are young compared to when we are old, and that makes all the difference.  Here are four references on the subject, including my own #4 [Ref1, Ref2, Ref3, Ref4].

 

Background assumptions

I believe that aging is controlled by several biological clocks.  This is a strong claim, but I think it has good support, outlined in the references above.  Biological clocks certainly control development, puberty and related schedules early in life.  How the body knows its own age is yet incompletely understood.  It’s a good bet that the same clocks that control development have been re-purposed to control aging.

There are three clocks we know something about.  These are the epigenetic clock, cellular senescence (telomere loss), and life-long shrinkage of the thymus, master gland of the immune system.

A common way to construct a clock is with a feedback loop.  A clock looks at itself to determine its next move.  The body has a feedback loop between epigenetic state (at a cell level) and circulating hormones and RNAs (at a systemic level).

  • The epigenetic state determines which hormones and RNAs are expressed.  Endocrine glands in particular are sending hormones out into the blood which are selected by their epigenetic state.
  • The circulating hormones feed back to cells and re-program the epigenetic state. All cells in the body are constantly receiving signals from the blood that guide them in continually reprogramming their DNA to express some genes and silence others.

There is evidence that telomere length in stem cells constitutes an independent aging clock.  Studies have shown that people (and other mammals and birds) with shorter telomeres have shorter life expectancies than people with longer telomeres.  Extending telomere length is simply a matter of signaling the body to express telomerase, which is always available in the genome but normally is expressed only in embryos.

The thymus is the organ where white blood cells are trained to attack foreign invaders and lay off the body’s own cells.  The thymus shrinks beginning in childhood, accelerating with age.  Late in life, the thymus becomes seriously deficient in its function, with the result that white blood cells make two kinds of mistakes.  Type I errors cause the T-cells to fail to attack invading parasites, with the result that we get sick more often as we age.  Type II errors cause the T-cells to attack healthy cells, leading to the auto-immune diseases of late life such as arthritis and exacerbating inflammatory damage.

 

Strategy

 

1) There is intriguing data from parabiosis that circulating factors may be able to reprogram the body’s age state.  (This is the “back end” of the feedback loop described above.)  If we’re looking for quick progress against aging, the circulating hormones are more accessible and make a more convenient target than trying to get inside the cell nucleus to reprogram epigenetic state directly.

Some of the blood factors most important for aging have already been identified.  For example, as we get older, we have too much NFkB, too much TGF-ß.  We have too little GDF11, too little oxytocin.  Irina Conboy has led me to believe she knows a few more, and identifying these factors is at the center of her research.  It’s a good bet that Tom Rando, Amy Wagers and other parabiosis researchers are compiling their own lists.

If we’re lucky, then adding some factors to the blood while blocking others will have a long-lasting effect of re-programming epigenetics, and the body will take over by continuing to secrete a “young mix” into the blood stream.  If we’re not so lucky, it may be necessary to perform some epigenetic re-programming more invasively.  CRISPR technology holds promise in this regard.

2) I believe that telomeres will also have to be extended in a fully-effective anti-aging program. Many herbs and supplements are known to have small activity in promoting telomerase (e.g., cycloastragenol, silymarin, carnosine).  Bill Andrews claims to have a synthetic telomerase promoter that is 50 times more potent than any of these.  Mike Fossel and others are also pursuing the search for telomerase activators.

3) Multiple treatments have been documented over the years to increase thymus size in humans and in animals.  These include growth hormone, zinc, melatonin, and thymic peptides.  A recent breakthrough from Univ of Edinburgh suggests a particularly effective treatment.

 

Roadmap

Telomerase activators are ready for safety tests and human trials now.

Various techniques for thymus regrowth are ready for clinical trials.

Based on encouraging results with mice just last spring, Tony Wyss-Coray of Stanford Med School has just begun human trials (for Alzheimer’s Disease).  This work should be rapidly expanded if his preliminary results are promising.

GDF11, oxytocin and other blood factors should be tested for rejuvenating potential in rodents.  Drugs can be developed that block NFkB and other pro-inflammatory signals.

pf button Open Letter on Research Priorities in Aging

Poking Fun at Longevity Science

“In science one tries to tell people, in such a way as to be understood by everyone, something that no one ever knew before. But in the case of poetry, it’s the exact opposite!”
                                — Paul Dirac

Gretchen Reynolds, in her chart on “Longer Living Through Science” does a good job of making science into poetry.  Full of qualifications and afterthoughts and 180o reversals, longevity research makes an easy target for satire.  Reynolds herself has established herself as a consistent advocate for some of the clear messages concerning exercise and diet that come from this research.  As we smile, let’s remember that our lives and our health hang in the balance, and through all the contradictions, there are some persistent truths.

NYTimes Reynolds Poking Fun at Longevity Science

This chart was published in the New York Times Magazine on Sunday, summarizing the last four years of scientific studies concerning longevity.

The point of the chart is to convince us that longevity science is a hodge-podge of contradictory results.  The things that consistently lead to better health and longer life are beyond our control (genes, pollution, wealth).  Among things that are under our control, mere mortals cannot know what is effective (diet, exercise, smoking and drinking).

There are many reasons that specific items in the chart are not as inscrutable as they appear.  Reynolds cites only studies of the last four years, and current research is always focused on the unresolved questions, not the well-established basics. Studies based on human longevity are the gold standard, but they must be interpreted with care since they cannot be properly controlled.  (You can’t put humans in cages and vary one factor at a time.  This makes it difficult to disentangle the many correlated variables and draw conclusions about root causes.)  Studies of mice and rats are generally the best indication of what will work in humans.  Studies of flies and worms cannot be directly extrapolated to humans.  They are valuable for biochemical understanding and suggestions for further study; but most treatments that work to extend life in flies fail in humans.

Every result cited in the chart is, in fact, a subtlety, a nuance at the edge of what we already knew about behaviors that affect longevity.  Absent from the chart was the one result that is new, and a reversal of what doctors had been recommending for decades.  Standard doctors’ advice has been to minimize salt intake, and last year it was found that higher salt intake is associated with lower mortality.

Perhaps the most contentious area involves weight loss.  It’s an issue frought with emotion for most of us.  On the one hand, caloric restriction has been the most robust technique for life extension in lab animals for the last 80 years.  On the other hand, using will power to eat less doesn’t work for most of us, and in fact willpower has been found to backfire and produce weight gain more often than not.  Further complication comes from social prejudices against heavy-set women.  For most women, appearance is a stronger motivater than health, and this has produced an epidemic of unhealthy dieting.

I believe this phenomenon has a lot to do with why studies of BMI have failed to show any advantage to being skinny.  In fact, these results always underestimate the damage that is done by overeating.  

People’s weight is determined by a combination of genetics with diet and exercise.  But being congenitally overweight is not a health risk, while overeating and under-exercising are clear health risks.  There are “lucky” people who can overeat without gaining weight, and “unlucky” folks who are disciplining themselves to eat less and exercise more, because they fear that extra weight will make them unattractive.  These two people may have the same BMI, so they are lumped together in the statistics, but the latter will have much better health prospects than the former.  It’s a kind of poetic justice—regardless of cosmetic appearance, nature has been even-handed in rewarding temperance with health.

BMI studies should be re-scaled to separate genetics from life style.  In support of this idea, results from genetically obese mice indicate that they have exceptionally long life spans when calorically restricted, even though their appearance is not at all lean.


Here are some uncontroversial recommendations from the community of scientists who study human longevity:

  • For most people, smoking is a health risk and shortens life expectancy.
  • Exercise contributes positively to every aspect of physical and psychological health, as well as longevity.
  • Conversely, overeating, especially carbohydrates, has a negative effect on health and longevity.
  • Community, engagement, love and relationships of caring have as great and robust a benefit for health and longevity as any physical factor.
  • Anti-inflammatory foods and supplements have shown consistent benefits.

There’s much more on my Aging Advice page, including my personal recommendations that are not yet standard medical advice.

We all need help laughing at ourselves, and I’m happy to accept a poke from Gretchen Reynolds. But let’s not forget that we live in a culture that seduces us into the obsessive earning of money, consuming of food and entertainment, all distracting us from the basics of our health.

 

pf button Poking Fun at Longevity Science