Signal Molecules in the Blood: What do we lose with age?

Two weeks ago I wrote about the hypothesis of Harold Katcher (and others) that aging may be mediated by signaling molecules that circulate in the blood – hormones among them.  Katcher’s idea for rejuvenation is to give older folks transfusions of blood plasma (with the white and red blood cells filtered out) from younger folks.  This could require a large number of young volunteers, I said, so maybe we could make a start by identifying some of the differences between hormones in blood from older and younger humans.  There are some hormones we have too much of, and others we have too little of as we age.  

A timely news item: Steve Horvath, a biostatistician from UCLA, published an article last week in which he analyzed the way gene expression changes with age. A semi-permanent factor in gene expression is methylation of the DNA, and Horvath showed that you can pretty much tell how old a person is by using a statistical template he developed to analyze which genes are methylated.

This week, I explore a few hormones that decline with age.  (Next week, I’ll cover those that increase with age.)  Of those I’ve investigated, melatonin offers the best prospect for life extension benefits.

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I take the position that aging is not a passive process of accumulated damage, but a genetic program, centrally orchestrated through the body on a schedule.  It follows that signaling molecules that broadcast instructions through the bloodstream are likely to be messengers of death as we get older.  There are too many signals to catalog, and biochemists are just beginning to unravel the web of their interactions. Some may be small RNAs and micro-proteins, in addition to the better-known hormones.  Nevertheless, it’s worthwhile looking at those we know about.

Melatonin:

Melatonin is just the kind of circulating factor we’d like to evaluate. It is produced in the brain (specifically the pineal gland), and it is a high-level signaling hormone that affects gene transcription, with a cascade of lower-level effects.

This was the first hormone to be studied for anti-aging potential, and there is good evidence that supplementing with melatonin works to modestly extend rodents’ life span.  Melatonin is an anti-oxidant, but in the tiny quantities that the deploys it, this is probably not significant.  It is best known as a regulator of our diurnal sleep cycle.  Young people generate melatonin in their bloodstream around the same time each evening, signaling the body to prepare for sleep; and melatonin levels stay high through the night, dropping off before it’s time to wake up.  Older people have less melatonin at night.  More older people than younger people suffer from sleep disorders.  And some people who travel between time zones find that taking melatonin at the (new) bedtime helps their bodies to reset their clocks.

(In my personal experience, I find that 1 mg of melatonin helps me fall asleep at night. Side effects include morning “sand” in my eyes, exacerbation of apnea, and possibly an effect on dreaming – it’s hard to tell.)

“It may be that melatonin, when taken as a supplement, can stop or slow the spread of cancer, make the immune system stronger, or slow down the aging process. But these areas need more research,” says WebMD – a properly conservative assessment.

I’ve mentioned Vladimir Anisimov in the past – a Russian biochemist who has studied a large number of anti-aging interventions in his lab, and reports optimistic results, only some of which have been replicated outside his St Petersburg lab.  He may be the world’s authority on the association between melatonin and slower aging.  Here is his 2006 review of studies up to that time.

Melatonin is a potent neuroprotective agent, demonstrated in tests where animals brains are subjected to ischemia (oxygen deprivation). It has been proposed as a no-brainer for Alzheimer’s treatment [Ref1, Ref2, Ref3], and for Parkinson’s there is preliminary data [Ref1Ref2Ref3], though clinical evidence remains shaky.

Taken orally, it is easily absorbed and quickly boosts blood levels.  Melatonin is cheap and convenient.  In the mid 1990s, several books were published promoting broad benefits. Walter Pierpaoli led the charge. There followed the inevitable backlash, but when I review the warnings in these papers now, I find they have little substance.  The worst they had to say was that melatonin needs more study.  This remains true today, and melatonin’s chief drawback in this area is that it is unpatentable and too cheap to motivate any capitalist entity to invest in research.

Thyroxine and thyrotropin

Thyroxin is a hormone generated by the thyroid.  Bet you knew that.  Like melatonin, it is a high-level signal with lots of downstream effects.  And as with melatonin, levels of thyroxine decline with age.  A few studies have found association between low thyroxine levels and mortality, and with risk of brain aging diseases (PD and AD); but others find the opposite.

Thyrotropin is a related hormone, which stimulates the thyroid to produce thyroxine.  There is better data associating low thyrotropin levels with disease in the elderly than there is for thyroxine.  The Leiden 85+ study of mortality in the elderly found that mortality rates were higher in people who had high thyroxine, low thyrotropin. (Yes, that’s not a misprint: high thyroxine levels in older people might be a liability.)

There is no question there is such a thing as too much thyroxine as well as too little, and it is regulated in the body from moment to moment.  Symptoms of too much thyroxine include anxiety, tremors and heart irregularity. So thyroxine is tricky, and it is wisely classed as a prescription drug, though it is a natural hormone.  But there are thyroxine pills, available by prescription, prescribed for hypothyroid conditions; some people also use them for weight loss. Daily dosages in tens of micrograms.  We rarely stop to think how exquisitely sensitive is our bodies’ homeostasis, that a signal far smaller than a pinhead can have major effects.

Carnitine and carnosine are two popular supplements taken for potential life extension benefits that can interfere with thyroxine uptake.  A number of other supplements stimulate and support the thyroid.   Without clinical symptoms, these may be more practical alternatives to thyroxine for now, but maybe someday we will know better how to optimize thyroxine levels in the body.

 

DHEA  (dehydroepiandrosterone)

The most abundant hormone in the body when we are in our 20’s declines to a small fraction of its prevalence when we are old.  At any age, males have more than females.  Manuractured in the adrenals, DHEA is chemically related to sex hormones and steroids, and there is evidence that they are transformed into these forms in our bodies.

There are some studies showing cancer suppression in mice from DHEA. But DHEA is peculiar to human biochemistry, and it is scarce in mice and rats.  This is a reason to question whether there is a basic relationship to aging, and also whether we can extrapolate from studies of DHEA in rodents.

Some human studies show lower rates of heart disease and cancer when DHEA levels are higher; others find no effect.   If there is a benefit, it may be small enough or contingent enough that it is difficult to disentangle from secondary associations.  Smokers tend to have higher DHEA levels.

“An early human study that pointed to possible benefits for DHEA came from Dr. Barrett-Connor’s group. They measured DHEA levels in blood samples taken from almost 2,000 men and women between 1972 and 1974 and looked at how many died from heart disease. In 1986, they reported that men with high DHEA levels were far less likely to have died of heart disease, while women with high DHEA levels were at greater risk. A more detailed analysis published late last year, however, showed that men with above-average DHEA levels back in the early 1970s were only 15% less likely to have died of heart disease, while there was no association between DHEA levels and heart disease in women.” (Ray Sahelian, 1996)

There is better evicence that DHEA has, for some people, a positive effect on mood and energy and possibly favorable body composition (more muscle, less fat).  Life Extension Foundation emphasizes that dosing should be done in conjunction with blood tests, because of individual differences in absorption and in natural DHEA levels.

Mayo clinic says: “No studies on the long-term effects of DHEA have been conducted. DHEA can cause higher than normal levels of androgens and estrogens in the body, and theoretically may increase the risk of prostate, breast, ovarian, and other hormone-sensitive cancers. Therefore, it is not recommended for regular use without supervision by a licensed health professional.”  Nevertheless, it’s sold over-the-counter.

Men and women respond differently to DHEA because it has a greater propensity to be turned into male hormones.  In a UCSD clinical study, hormone levels were monitored in men and women during a six-month course of DHEA.  Male hormones in the women but not the men rose to unnaturally high levels,

 

Others:

I’m not going to talk about growth hormone.  HGH can make you feel good in the short run, but it is a life-shortener in the end.  “Despite more than a decade of finding numerous ways to slow aging in mice, the longest-lived genetically altered mice are still those that lack the genes for growth hormone receptor (GHR),” [Source]

Sex hormones decrease with age, but from a theoretical perspective the evolutionary function is to cut off fertility, not to raise mortality.  A lot of study has been done of post-menopausal hormone replacement therapy and mortality from cancer and heart disease, and the story has no simple message.   The same is true for (male and female) sex hormone levels in males.

Some of the biochemical changes with age take place within the cell, unrelated to whole-body signaling.  For example, CoQ10 (ubiquinone) is manufactured and consumed in each cell.  It does not qualify as a hormone or signaling chemical because it is not circulated.  As for CoQ10, there is less of it as we age, and probably the body suffers for that.  Certainly the capacity of mitochondra to generate energy for us diminishes with age, and a shortage of CoQ10 is a logical candidate.  Oral administration of CoQ10 has not produced life extension in animal experiments.  Vladimir Skulachev (University of Moscow) has an ingenious way to target CoQ10 to the mitochondria, and he has succeeded in increasing life span in lab rodents using what he calls SkQ, which is a CoQ10 molecule modified with a mitochondrion-seeking tugboat on the front.

 

Respecting the wisdom of the body – not!

Editorial comment: There’s a habit of conservatism in medical thinking that has imposed too high a burden of proof for DHEA and melatonin and thyroxine, based on a vague notion that the body knows what it is doing, so if we have less of it as we age, then probably less of it is good for us.  This is the way people think before they realize that the body’s purpose is to kill itself, slowly but surely as we get older.  If we want to live longer, we are going to have to oppose programmed biochemical changes that come with age.

Today and tomorrow

I can recommend melatonin for now, and hope that study in coming years focuses on other promising targets for intervention, especially Anisimov’s small peptides.  There is no barrier to studying difference between blood factors in young and old people.  It could be done now at modest cost.  For example, small peptides could be catalogued in blood samples from 100 young people and 100 old people, and consistent differences would be easy to spot.  The same could be done with short RNAs.  What else to look for?  I’m sure the biochemists have better ideas than I have.

How is sex like Obamacare?

No – I’m serious.  How is sex like Obamacare?

…Good guess, but no – I’m not talking about the health and longevity benefits of sex later in life.

You don’t give up so soon, do you?

A: Sex and Obamacare both offer substantial benefits to the community, but they only work if everyone participates, and it’s not in everyone’s interest to participate.

Not so clear?  Allow me to explain…

 

Obamacare

(What did you expect, I was going to start with sex?  And trust that you’d still read through to the end?)

Insurance works (when it works) by sharing risk, providing a safety net that makes everyone more secure.  But not everyone has the same risk, so it turns out to be a better deal for some than for others.  To the extent that one can know his own risk in advance, people can game the system.  Healthy people choose low premiums and high deductibles, while people who need more frequent medical services will choose the opposite.  For the healthiest individuals – those who are young, don’t smoke or drive motorcycles or pursue rock climbing on the weekend – any kind of health insurance is a pretty bad deal, and it is in their interest to opt out.

Ross Douthat has a column in yesterday’s NYTimes about computer glitches that dragged down the rollout of Obamacare three weeks ago, but he begins by citing a New Republic article by Jonathan Cohen from last May.

Health insurance needs lots of healthy people to sign up for coverage. Their premiums cover the big bills for the relatively small number of sick people. So if the exchanges don’t enroll enough young, healthy people, insurers will have to raise everyone’s premiums. In the worst case, this could create what actuaries call a “death spiral”: Rising premiums prompt people to drop out, causing premiums to increase even more.

When Obama designed Obamacare, the greatest challenge was how to ensure participation.  The obvious solution was universal coverage by a single payer, the system used in Commie countries like Great Britain and Canada and Japan and France and Germany and Spain and Switzerland and…  Obama went to great lengths to avoid that, because it would be the end of fat profits for Aetna and Wellpoint.  So instead of a one-sentence health care bill that welcomed all ages to buy into the present Medicare program, we have a 961-page document full of rules and exceptions and exceptions to the exceptions, and lots of wiggle room for insurance companies and their lawyers to continue charging exorbitant rates for Swiss-cheese coverage.  Whether the Federal government has the Constitutional authority to compel people to buy insurance from private companies was a question posed to the Supreme Court two years ago, and it was resolved on a technicality.

…but I digress.  The point is that the community has a collective interest in universal insurance, but for the strongest and healthiest individuals, insurance is a bad deal, so the community coerces their participation.

Just like sex.

?? !

…allow me to explain.

Sex

When I say the word ‘sex’, you’re probably thinking of male and female, reproduction, that sort of thing.  No?  Were you thinking of something else?  Then you must be a biologist, because to a biologist sex isn’t about reproduction, it’s about combining genomes.  Sharing genes.  Sex is strongly linked to reproduction for us and almost all higher organisms, but it doesn’t have to be that way.

For bacteria, sex consists in plasmid exchange.  Bacteria share genes promiscuously.  A plasmid is a little loop of DNA, and bacteria eat them like candy.  They are constantly shedding genes (in the form of plasmids) for others to pick up, and taking in other genes that they find in the environment, with no regard to where the plasmid came from, or who owned it last.  It’s as if they had no Mommies to teach them right from wrong.  Plasmids are replicated along with the rest of the bacterial genome, and passed on to daughter cells.  In this form, bacterial genes move freely not just between strains but also across species lines*.  (This was discovered in the 1950s, when genes for antibiotic resistance spread through the bacterial world far faster than epidemiologists had anticipated.)

Protozoans (‘protists’) are much larger and more complex than bacteria, and, like higher organisms, they have two copies of each chromosome, but only during some phases of their life cycle.  Protists share genes by sidling up to another protist of the same species, and dissolving the cell wall between them.  They thoroughly mix their cytoplasm, and then their cell nuclei (with the genetic material) merge as well, and they mix up chromosomes, and mix up the genes within each chromosome.  When the two protists separate, there’s no more telling which was (formerly) which.  Each individual is now half and half.

This is called conjugation.  It is a mind-bending process that disrupts our notion of indvidiual identity.  It is also closely related to the way in which sperm and egg cells are generated in animals and plants (meiosis).  But for most protists, reproduction is separate from sex.  Every individual is perfectly capable of reproducing by simple fission of the cell (mitosis), and needs no other individual to do this.

There was a lot of evolutionary history before sex was invented, but it wasn’t nearly so interesting as what happened afterward.  Sex was the best thing that ever happened to evolution.  Sex promotes cooperation, and integration of whole communities of interest.  It is sex that tamed the selfish gene and changed the rules, so that evolution wasn’t merely a race to see who could reproduce the fastest.

Before sex, it was every cell for itself.  There was no motivation to cooperate, because only one cell’s progeny would survive into the future.  Every other cell was a competitor, an enemy.  After sex, there is a community encompassing a gene pool.  Everyone has both an individual stake and a collective stake in the future.  The individual stake is in getting more of my own genes into the communal gene pool.  The collective stake is in seeing that the community survives and thrives.

 

What does this have to do with the title at the top of the page?

Sex made possible a life style that is far more resilient and robust in the long run, adaptable to different environments and robust to changes in circumstance.  Sex ties together the fate of a community (the biological word is a deme) that shares genes.  Sex also makes possible diversity, which protects a deme against extinction, and leads to far more rapid and efficient evolution into yet stronger communities.

But there’s a problem.  It’s not in everyone’s interest to participate.  In fact the “fittest” individuals – meaning those that can reproduce fastest – have no incentive to share the genes that make them superior.  Hey – if they’re winning the game, why would they vote to change the rules?  They would do well to opt out of sex, and just reproduce clonally.

…and if they did that, then the community would fall apart.  Cooperation would give way to a selfish brawl, and the fastest reproducers would win.  No complexity, no resilience, no evolvability.

Somehow, evolution has solved this problem.  Evolutionary biologists haven’t a clue how this happened.  From asexual reproduction (with gene-sharing on the side) to fully sexual reproduction must have been quite a complex transition, with no immediate fitness benefit, but only a very long-term reward for the community that pulls it off.  It is a great and enduring mystery how this long-term communal interest prevailed over the short-term interest of the selfish individuals (for whom sharing genes was a bad deal).

Sharing of genes was made mandatory for almost all higher organisms, and even for some protists.  In protists, the compulsion to conjugate is enforced with telomeres.  Telomeres are protective tails on the end of each chromosome, and with each cell division, the telomeres get a little bit shorter.  Eventually, this will lead to cellular senescence, and the protists will no longer be able to reproduce.  The telomere is only rescued during conjugation, when an enzyme called telomerase is produced, that can restore the telomere to its full length.  So if these protists don’t conjugate, they will eventually die out. [William Clark has a very readable account of this.]

And how is the mandate to share genes enforced in higher organisms?  In most animals and plants, reproduction is tied firmly to sex.  The individual cannot reproduce on its own, but only by finding another individual to share genes with.  This solved the problem, and made sure that the fittest individuals would not opt out of the system, but would share their genes like everyone else.  But how was it arranged?  This linking of sex to reproduction, making sex a mandate, has been called the Masterpiece of Nature.  No one knows how it evolved

 

The inexplicably dunderheaded mentality of the modern evolutionist

Since the 1920s when Darwinian fitness was first fitted to a mathematical formula, mainstream evolutionary scientists have postulated (i.e., they made an educated guess to see where it would take them) that fitness consists in leaving more offspring behind, faster.

(The exact formula is like a compound rate of return on investment, where the investment is one individual and the return is counted in offspring, which enter the formula as if they were a kind of dividend payment.  This measure of fitness is called the Malthusian Parameter, designated lower-case r, and is computed according to the Euler-Lotka equation.)

Evolutionary theorists equate fitness to r, the Malthusian parameter, and base their models and their calculations and their predictions on this assumption all the time.  They assume that the game of natural selection is all about making more babies, the faster the better.  And yet, in another part of their brains, they all know that with two sexes, higher animals and some plants commonly sacrifice a full factor of two in r by being only one sex at a time.  Hermaphrodites (like worms and slugs) have both sexes in the same organism.  They have all the advantages of mixing genes, and add the advantage of being able to reproduce twice as fast.  Twice as many offspring.  Twice the fitness.  Why don’t slugs take over the earth?  Why aren’t we all hermaphrodites?

This is considered by evolutionary theorists to be an abstract mystery, a theoretical curiosity, a subject on which a few deep thinkers write clever papers year after year.  But it is never – never! – a reason to question the fundamental assumption that “Fitness=Rate of Reproduction”, or that Natural Selection always operates to maximize reproductive success.  It is never taken as evidence that Multilevel Selection is the name of evolution’s game, or that the perspective of the Selfish Gene is not the full story.

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Next week, I plan to come back to the question: what blood factors do we lose as we get older, and what destructive blood factors appear in higher concentrations with age?

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*to the extent that ‘species’ can even be defined for bacteria. Read more if you’re interested.

How Young Blood Differs from Old

“Young Blood May Contain Chemical Factors Which Can Prevent or Reduce Some Effects of Aging” read the science headlines after Saul Villeda published his article last year about rejuvenating mice with successive transfusions from young animals. Learning what blood factors we are missing as we get older is a promising new frontier in anti-aging medicine, but more powerful yet is the realization that there are other blood factors that increase as we get older, with destructive consequences for our nerves, our stem cells, and the integrity of our metabolisms. (This entry continues a thread from last March, based on the ideas of Harold Katcher.)

Background

Blood is best known for for blood cells.  Red corpuscles carry oxygen so every cell in the body can breathe.  White corpuscles are legions of the immune system, ready to detect invading organisms or errant internal cells, to search and destroy.  On a smaller scale, our blood also carries hormones, large specialized protein molecules that constitute a signaling system for regulating the metabolism from moment to moment, making us hypervigilant or putting us to sleep, for example.  Smaller yet are signaling molecules that are much simpler than proteins, that are broadcast by various organs but especially parts of the brain, and that constitute the marching orders, directing activities at the cellular level.

We know now that some of what these small chemical messengers do is to orchestrate a process of self-destruction later in life, a function we refer to as “aging”. We don’t yet know how much of the aging process is triggered by these signals, or how reversible the process might be if “young signals” replace the “old signals”, and we don’t know how many separate signal molecules there might be, or which are the ones that are most important. It is vitally important that we learn these things. It is our next step.

Parabiosis experiments

Saul Villeda (formerly at Stanford, now UC San Francisco) is studying the blood signals that trigger and regulate the aging process.

Villeda’s research involved connecting the circulatory systems of two mice by a technique known as heterochronic parabiosis, which is typically used to study immune systems. After the blood of the old mice and young mice had mixed, Villeda found that the older mice showed distinct signs of a slowdown or even a small reversal in the aging process. The brains showed an increase in stem cells, and the connections between neurons had increased by 20%.

In [a not-yet published] study, Villeda and his team also tested the mice’s behavior.  Villeda injected small amounts of blood plasma, the liquid portion of blood, from two-month-old mice into 18-month-old mice eight times over the course of a month. The amount of plasma used was approximately 5% of a mouse’s total blood volume. Villeda then had the mice solve a water maze, an activity in which mice have to remember the location of a platform. Untreated older mice made mistakes as they attempted to solve the maze, such as swimming down blind alleys. Mice who had received the young plasma, however, often found the platform on their first try and performed similarly to mice four to six months of age.

Villeda…believes that treatments based on factors found in youthful blood may eventually be able to help middle-aged people prevent some of the worst effects of age-related deterioration, possibly even Alzheimer’s disease. “Do I think that giving young blood could have an effect on a human? I’m thinking more and more that it might,” he said. “I did not, for sure, three years ago.”
[from The Guardian]

In his parabiosis experiments, Villeda surgically joined the circulatory systems of young and old mice.  One of the effects he discovered was new nerve growth in the old mice receiving young blood.  He went on to ask what substances in the blood triggered this benefit, and homed in on a blood factor called CCL11, a chemokine, a kind of protein signal molecule involved in development and regulation of growth. CCL11 is not a promoter of growth, however – just the opposite.  It is one of those signals that we have too much of as we age, and it inhibits nerve growth. Villeda injected young mice with CCL11 and found that their nerve growth was slowed.  More to the purpose of anti-aging medicine, he was able to stimulate nerve growth in older mice by injecting them with antibodies to CCL11.

Biochemical dramas have few unequivocal “bad guys”, and much depends on context.  Mice without the receptor for CCL11 (called CCR3) have developmental deficiencies.  So the best guess so far is that we have too much CCL11 as we age, but that we wouldn’t want to eliminate it altogether.  (This article by Richard Ransohoff in Nature, summarizes Villeda’s work and places it in context.)

Parabiosis experiments are more than a century old, but have received new attention in the study of aging beginning with Irina and Michael Conboy about ten years ago. Their research continues with their collaborators at Harvard and University of Cambridge.  Parabiosis experiments are important for demonstrating the principle that young blood contains something that rejuvenates, and that old blood contains something that inhibits renewal.  But they are hardly a practical solution for humans.  In this sense, the work of Villeda points to a new path, in which these blood factors are isolated and their pathways understood, so that a cocktail can be prepared which might offer the advantages of “young blood”.

 

The Big Question: Which chemical components of blood are important for aging?

I’ve been compiling two lists:  Blood factors that we have too little of as we get older, and blood factors that we have too much of.  Over the next couple of weeks, I will research these one by one and report in this column what I find.

In the meantime, if you, dear reader, are aware of other blood factors that I should be considering, please help me to augment these lists.

Blood factors that we have too little of as we get older

  • melatonin, from pineal gland, controls daily cycle of sleep and waking
  • DHEA = dehydroepiandrosterone is a precursor of sex hormones and steroids
  • ubiquinone = CoQ10 is an anti-oxidant and electron transporter, used in mitochondria for energy production
  • thyroxine, produced in the thyroid, regulates many other hormones, stimulates activity
  • HSP70, heat shock protein, protects against muscle loss with age
  • progesterone, involved in menstruation, sleep cycle, mood; downregulates growth, increases insulin sensitivity
  • (HGH = human growth hormone)
  • (testosterone) primary male sex hormone
  • (estrogen) several primary female sex hormones

The last three in this list are sex and growth hormones.  They are in parentheses because, even though their prevalence declines with age, I believe that they are actually counter-productive, and may hasten aging.

Blood factors that we have too much of as we get older

  • Wnt, a growth promoter associated with cancer
  • NFkB, a cytokine which triggers inflammation
  • LH (luteinizing hormone) & FSH (follicle-stimulating hormone), associated with ovulation in women and sperm production in men.  Increase late in life for both men and women.
  • Estradiol, a female sex hormone
  • CCL11 (a growth-inhibiting chemokine, see Villeda’s work above)

Combining Biochemical Pathways to Longevity: Toward a Recipe for the Youth Pill

From studies in rodents, we now know dozens of treatments that extend life span modestly.  If we could combine their effects all together, we would have a basis for dramatic life extension!  But some of these have biochemical actions that overlap, while others are likely to be independent, and – if we are lucky – some will be synergistic, so that the combined benefit might be greater than the sum of the treatments individually.  Experiments with combinations of longevity drugs are the next big thing in anti-aging research.

 Deprenyl-mouse-study-summary

Deprenyl is an antidepressant and Parkinson’s treatment (sold as Selegeline, Emsam and Eldepryl).  Dinh lang is the Vietnamese name for an Asian plant (Policias fruticosum, not available to my knowledge in the US),  root of which is a traditional medicine.  In 1990, T T Yen and Joseph Knoll worked together on a study of life extension in mice.  Mice treated with deprenyl lived 22% longer; with the dinh lang, there was 28% life extension; and with the two together, an impressive 35% life extension.

Interpretation:  Life extension from the two together is greater than each of the two treatments separately, but not as large as the sum of the two effects.  Whatever dinh lang and deprenyl do for the mouse’s physiology, there is some overlap in their effects, and some independendent action as well.

This twenty-year-old longevity study is the only one I’ve seen in which two treatments are combined to determine how the treatments work in tandem.  A lot more of this kind of work could be done.  Granted, mouse studies are expensive (in the neighborhood of a million dollars for a mouse lifetime, including controls).  But these studies of combined treatments will provide a vital bridge between theory and practical life extension in humans.

We now have evidence for life extension in mammals from many different treatments.  If we could add these effects together, we would have some stunning results!  But it is likely that some of them do essentially the same thing, acting through the same biochemical pathways with different agents.  Only some of the treatments are independent.

What we know about aging suggests that several independent processes are involved; so Practical life extension for humans will involve a combination of different measures. Experiments with combined treatments have the potential to tell us how these pathways may be interrelated, as well as providing practical guidelines for formulating the coming Youth Pill.

The best-known path to life extension works via calorie deprivation or hunger, or simulated hunger.  Calorie Restriction is a probable confounder in many lab studies of life span.  Last year, Stephen Spindler reviewed the literature on life extension studies in rodents, and found that many researchers had not made a clean separation between CR and the particular intervention they were studying.  The problem is that eating less has a strong and reliable benefit for life span, so any drug or herb that tends to suppress appetite may show a positive benefit for life span – a real but secondary effect.  Spindler complains that of the researchers doing life extension studies on mice and rats, very few of them report weight or food consumption, so it is impossible to know if the treatment they are studying has an independent benefit, or if it just induces the animals to eat less.

 

Spindler and Anisimov

The (UC Riverside) laboratory of Stephen Spindler has conducted mouse studies of longevity, reporting largely negative results.  But when Spindler assembled the review (cited above), his criterion was to include every substance that has been reported in a peer-reviewed publication to induce life extension in rodents.  These studies come from differently labs, and the quality is uneven.  Some are corroborated by more than one study from more than one lab, some have never been replicated, and some have been the subject of negative findings in Spindler’s own lab, but he lists them anyway.  Across the ocean, the Russian researcher who is Spindler’s opposite number is Vladimir Anisimov of the Petrov Institute in St Petersburg.  For decades, Anisimov has operated the largest laboratory in Russia devoted to aging medicine, and has reported many positive results, some of which have been replicated elsewhere.  Least known of Anisimov’s findings are the very promising results he has reported with short peptide chains.

I think of Spindler and Anisimov as bookends of the anti-aging literature.  Spindler’s criteria for inclusion are the strictest, and Anisimov’s the most liberal.

 

Categorizing the anti-aging molecules

Dozens of treatments that are reported to extend life span in rodents individually have never been tried in combination, and there are hundreds of potential combinations.  In order to make an educated guess as to which combinations are likely to work better together, it is helpful to categorize their modes of action, as far as they are known.  To this end, I have listed Spindler’s catalog, plus a few more, in nine groups according to their biochemical pathways.  There is considerable overlap in the mechanisms of action, so my criteria are somewhat subjective.  And I don’t claim that this list is exhaustive – it is Spindler’s list, supplemented by other interventions that I happen to know about.  Here are the nine groups, with treatments in each category listed in parentheses underneath:

  • CR mimetics / insulin  / IGF
    (metformin, MCP, dinitrophenol, resveratrol, pycnogenol)
  • Anti-inflammatory
    (aspirin, NDGA)
  • Neuroprotection  
    (ginkgo, deprenyl)
  • Mitochondria / ROS  
    (SkQ, CoQ10)
  • Anticancer
    (green tea, melatonin)
  • TOR = Target of Rapamycin  
    (rapamycin)
  • Increased autophagy  
    (spermidine)
  • Miscellaneous or unknown mechanisms
    (PBN, dinh lang, short peptides)

Metformin:  I wrote a full column on metformin last year.  It is available only by prescription, but it is out-of-patent and quite cheap.  There is robust evicence for anti-cancer and longevity benefits in diabetics, and I suspect that there are also benefits for non-diabetics, because we don’t yet have data on large numbers of non-diabetic people who have taken metformin.  Several studies find life extension in rodents from metformin [1, 2, 3] and some studies found no life extension.

MCP:  Marine Collagen Peptides  are derived from fish skins, and in one study demonstrated life extension and cancer suppression in mice.

DNP:  Dinitrophenol was found to extend life span modestly in one Brazilian study.  The authors claim the mechanism of action is as a CR mimetic.

Resveratrol is derived from red wine.  After attracting great excitement about ten years ago because of dramatic life extension in tests with yeast cells, flies, worms and fish, resveratrol was first studied in mice in 2007, with much more limited success.  All mice seemed healthier with resveratrol, but life span extension could only be demonstrated for mice on a diet that made them obese.

Pycnogenol is a proprietary extract of French maritime pine bark. It is reported to increase insulin sensitivity in diabetics.  One study showed modest life extension in non-diabetic mice that were genetically short-lived.

Aspirin, ibuprofen, other NSAIDs
Inflammation is associated with all the diseases of old age.  Anti-inflammation is once of the most promising avenues to life extension.  But tests with life span in rodents have shown mixed result.  Here is one positive report for both aspirin and NDGA from a well-respected and conservative research group at Jackson Labs in Bar Harbor.  (NDGA stands for nordihydroguaiaretic acid, a powerful antioxidant and anti-inflammatory derived from creosote.  NDGA is not sold as a human dietary supplement because of concerns about chronic toxicity from chronic use.)

Don’t forget fish oil and curcumin, potent anti-inflammatories from natural dietary sources.  But the only experiment testing for life extension (that I have been able to find) reported negative results.

Deprenyl

Dopamine is a neurotransmitter that decreases with age.  Low dopamine levels in the brain are the proximate cause of Parkinson’s disease, and in this sense, we are all pre-Parkinson’s patients as we age.  Deprenyl is an MAO-B inhibitor, which means that, via indirect action, it inhibits the uptake and disposal of dopamine.  Deprenyl makes dopamine hang around longer.

Another side of deprenyl is its action as a stimulant; it is a chemical cousin of methamphetamine, and it is metabolized to methamphetamine in part.  It can make you manic.

Since the pioneering studies of Joseph Knoll in the 1980s and 90s, there have been several replications, confirming life extension from deprenyl, but quantitatively smaller than Knoll had reported.  Perhaps we should not be surprised.  Science is done by human beings who are interested in the results, and their hopes and dreams find their way into the reported outcomes.  That’s why pharmaceutical companies should not be testing their own products for safety and efficacy, but don’t get me started…

Deprenyl-rat-study-summary

From Bickford et. al, 1997 http://www.sciencedirect.com/science/article/pii/S0197458097803132

Ginkgo biloba is a common tree from the orient, and its leaves have been used for thousands of years in Chinese medicine.  It has been found to improve cognitive function in animals and in humans.  In one study conducted at SUNY 15 years ago, it was associated with impressive life extension in rats.

Melatonin is a hormone secreted by our pineal glands, and it helps regulate sleep cycles.  We have less of it as we age.  Many studies have been done testing melatonin for life extension and other benefits in rodents.  Results are widely inconsistent.  Anisimov wrote the major review on the subject, and Spindler did not attempt an independent evaluation in his review.

 Green Tea extract

Many authors have claimed health benefits from green tea, and one Japanese study founda small benefit for life extension in mice.

Rapamycin is a powerful immune suppressant, prescribed for organ transplants, and probably not suitable for chronic human use.  Nevertheless, it has illuminated a whole new genetic pathway (TOR=”target of rapamycin”) and it has produced large benefits for life extension in mice, even when administered late in life.

Spermidine

Autophagy is the name of the cell’s main clean-up process, eliminating accumulated wastes.  Spermidine promotes autophagy, and is found in many foods.  As an anti-aging agent, it has been championed by Frank Madeo of University of Graz. He reports dramatic life extension in worms and flies, and smaller life increases in life span for rodents.

CoQ10 and SkQ
Coenzyme Q10, also called ubiquinone, plays a vital role in the body’s energy metabolism, which takes place in the mitochondria.  As we get older, we have fewer mitochondria, less CoQ10, and literally less capacity to turn sugar into energy.  CoQ10 supplement has benefits for heart health, and was considered a promising candidate for life extension.  But most experiments with rodents have not produced positive results. Here is one that has.

Vladimir Skulachev has devoted the latter part of his career to a molecule of his own invention, which combines a chelated, positively charged ion at one end of a carbon chain with a CoQ10 molecule at the other.  The positive ion acts like a tugboat, pulling the molecule through the mitochondrial membrane into the mitochondrion itself, where the CoQ10 can do the most good.  Skulachev’s molecule, nicknamed SkQ, concentrates itself a million-fold inside the mitochondria, where it is needed most.  In experiments with life span and health span, the SkQ molecule (administered eye drops) has reversed cataracts and macular degeneration, and (administered orally) has has extended life span in mice.

So far SkQ is only avaiable as eye drops, and can be purchased only in Western Russia.  Licensing is proceeding in Europe over the next few years, but in America it could easily be a decade away.

I know Skulachev and have great admiration and trust for him, but he has both an academic and a commercial interest in the success of SkQ.  I wish there were someone else working to corroborate his results.

 

Anisimov’s Short Peptide Experiments
A peptide chain is the same as a protein molecule.  All the body’s hormones and enzymes and most of its workhorse molecules are peptide chains, constructed of hundreds or thousands of amino acid molecules, linked together in a precise or, as dictated by the information in DNA. Anisimov’s magic bullets consist of just two or three or four amino acids linked together in a “short peptide chain”.

The Anisimov lab has been experimenting with these substances for decades, and he recently wrote a summary of findings.  Some of the peptide sequences were derived by extracting small molecules from the thymus and pineal glands, both organs that atrophy with age.  Anisimov documented life extension in rodent studies, up to 30%.  He also tested his short peptides on elderly human subjects – an experiment that probably could not have been done in the US – and found mortality rates suppressed by almost half (see table).

Anisimov-peptides-Lower-human-mortality

How can it be that there are major effects on life span from such small, simple molecules?  Anisimov theorizes that these peptides bind to DNA and act like transcription factors.  In other words, they are regulatory signals, triggering entire cascades of metabolic events.

This is promising work, crying out to be replicated at another lab.

PBN stands for N-tert-butyl-alpha-phenylnitrone, a “spin trap” antioxidant which is thought to act as a source of the signaling molecule NO (nitric oxide) in the body.  In 1998, a group at NIH in Washington, DC found substantial life extension from PBN in the drinking water of a short-lived mouse strain in their drinking water, yet no one has tried to repeat the experiment in 15 years.

Don’t forget telomeres
There are now many herbal extracts that are known to promote expression of telomerase, and (probably) work in vitro to increase telomere length.  Extracts of astragalus, milk thistle, horny goat weed, ashwagandha, tumeric root and fish oil have all shown promise in lab studies.  These substances are unlikely to extend life span in lab mice because, unlike humans, mice already express telomerase copiously through their lifetimes, and mouse telomeres are much longer than human telomeres.  But there are some rodents that don’t express telomerase, and they would make appropriate models for testing telomerase extenders alongside the above medications in life span studies.

 

Exercise, too

Exercise extends average life span in rodents as well as humans, and it should be included in combination tests with other treatments, because exercise and medications can interact constructively or destructively.  Exercise signals the body for life extension with peroxide, which looks a lot like oxidative damage.  There is a stunningly counter-intuitive finding from recent years that anti-oxidants can interfere with the life extension benefits of exercise.

A Social Perspective on Research

The time has come to test combinations, “Chinese menu style” – one from group A and one from group B.  We can look for combinations that do significantly better than either separately.  And as we close in on delaying the all most important pathways of aging, we should, theoretically, find synergy – that the life extension from all our interventions is greater than the sum of the individual benefits.

The million-dollar price tag for a rodent study has been a significant deterrent in the context of paltry and inconsistent support for research in anti-aging medicine.  But for individuals facing death from cancer, insurance companies are paying a million and more just to buy a few months or a year of tortured, debilitated life for a single individual.  A comparable investment in rodent studies will likely yield treatments that add years of healthy life for millions of individuals.  As a society, what are our priorities?  Where is our rationality?  The domination of American medicine by a capitalist model has produced grotesque distortions of medical economics.  The cost in dollars and human suffering are beyond comparison.

There is no longer any doubt that investment in the science of longevity will be vastly more effective than anything else we can do with our budget for medical care.

How we get old: 4 Processes of Active Self-Destruction

Link

Last week, I wrote that the new view frames aging as an active process in which the body attacks its own healthy tissues. Much of this damage appears avoidable, if only we kept churning out the same hormones we did when we were young, instead of changing to a less effective mix as we get older.  Some of these chemical signals that turn on in old age seem directly to trigger the destruction, as if “on purpose”. There are four processes that seem to be the main culprits: inflammation, immune derangement, cell suicide (or apoptosis) and telomere shortening. They make promising targets for new anti-aging research.

A challenge to evolutionary theory

It has been a surprise for evolutionary biologists, beginning in the 1990s, to discover that there are genes that regulate aging. More curious yet – some of the genes for aging have been around for at least half a billion years, from a time when one-celled eukaryotes (nucleated cells) ruled the earth. Usually, evolution is very good at holding on to what works, and getting rid of genes that are harmful. Aging ought to be in the second category – aging destroys fitness. Why would evolution preserve harmful genes and pass them on?

This sounds like a question for theorists, or even philosophers. But the question has taken on a practical importance now that biochemists know how to turn genes on and off. Should we turn off the aging genes? Would terrible things happen to us as a side-effect – sterility, or maybe cancer? Or would this be the shortcut we’ve all been waiting for – a new and more effective path to life extension?
Discovery of Genes for Aging

Nematode worms, fruit flies, and yeast cells are the most common lab organisms used to study aging because they can be grown in small containers and their life spans are conveniently short. Beginning in the 1990s, geneticists knew how to identify individual genes and remove them – mutate or snip them out from an egg cell, which contains a single copy of the genome that will be replicated into every cell of the adult. Here was a surprise that transformed aging science: for each of the three lab organisms, there were genes that could be removed, permitting the animal to live longer. What is more, these genes were closely related, underscoring the inference that they were no accident, but a surprising and paradoxical product of evolution. A common genetic basis also suggested that what we learned from simpler animals might also apply to humans.

Some of the earliest genes discovered to regulate aging were related to the insulin metabolism, and presumably mediate the mechanism by which aging is slowed by caloric restriction (or shall we say, “aging is accelerated by abundant food”?) In worms, DAF-2 was one of these genes.

It was natural to ask about the metabolic effects of DAF-2: what is its role in the metabolism? The Harvard laboratory of Gary Ruvkun was able to prepare “mosaic” worms that had different genes in different parts of their bodies. Before asking “how”, it would be interesting to know “where” DAF-2 was acting. Ruvkun and team tried mutating DAF-2 just in the muscles. No life extension. They repeated the experiment with DAF-2 mutated in just the digestive system. No life extension. But when DAF-2 was disabled in the nerve cells, that was sufficient to double the worms’ life span. [Ref] The nervous system suggested signaling and active, intelligent control. This finding helped to solidify the new paradigm: life span is actively regulated by the body.

 

Sharpening the evolutionary paradox

Here’s a detail that underscored the evolutionary paradox: The principle that “natural selection can only generate adaptations that are good for an individual’s fitness” is so fundamental to evolutionary theory, that theorists looked for an interpretation of the data that would support this axiom. The axiom might still be true if these preserved genes were selected for some powerful benefit, such that accelerated aging was a side-effect of genes whose primary effect was beneficial. This theory goes by the name antagonistic pleiotropy, and was first proposed by George Williams back in 1957.  (“Pleiotropy” is the word geneticists use to describe a single gene that acts in multiple ways.)

The gene DAF-2 did indeed have benefits, and the long-lived mutants appeared fat and lazy. But the benefits appeared when the gene was turned on in muscle cells, while the life-shortening effects came from the gene’s presence in nerve cells. It is normal for gene expression in different tissues to be separately regulated. Ruvkun emphasized that the costs and benefits were easily decoupled. If he could separate the two effects in a simple lab manipulation, why hadn’t nature learned to do the same over the aeons?

 

Implications for Anti-aging Medicine

The more we learn about the physiology of aging, the clearer it becomes that the standard evolutionary view doesn’t work. Three of the body’s systems that are highly evolved for self-protection morph, as we age, into means of self-destruction. These are inflammation, the immune system, and apoptosis. A fourth system – telomere loss, also called cellular senescence – seems to act like an aging clock, destroying our bodies on schedule. It is common to speak of this as “dysregulation”, as though it were just a mistake. But you have to wonder why natural selection would make such costly mistakes.

Each of these four makes an excellent target for anti-aging research, and when scientists learn to control all four, radical life extension of many decades will be the natural result.

 

Inflammation

Inflammation is the best-known and best-studied of the three, and research is well on its way. Inflammation is the body’s first line of defense against invading microbes, and it also plays an important role in eliminating diseased cells and damaged tissue in wounds and bruises. However, as we get older, inflammation turns against the body. Inflammation in cartilage is the proximate cause of arthritis , and in our arteries, inflammation creates the plaques which can lead to heart attacks and strokes. Inflammation damages DNA, and can turn healthy cells into cancers . Simple anti-inflammatory agents like aspirin and ibuprofen are the best-documented and best-accepted life extension pills we have right now – a cheap and simple way to add about 2-3 years to your life expectancy . They work because after age 50, inflammation is actually doing more harm than good, and generally dialing it down with a “dumb” drug has a substantial benefit. But to make further progress with inflammation, we will need “smart” drugs that can reduce the harmful effects of inflammation without hampering the action of inflammation where it is beneficial.

 

Immune derangement

Closely related is the problem of immune derangement. Our white blood cells fight invaders and destroy pre-cancerous cells before they can harm us. The smartest white blood cells are called T-cells, where the T stands for thymus. The thymus is a little gland above your breast bone where T-cells are trained to do their job. They are shown samples of all the body’s cell types, and they learn not to attack self, but anything else is assumed to be an invader.

But the thymus shrinks over our life time. It reaches its largest size when we are pre-teens, and by the time we are 50 it is half that size, and shrinking fast. In older people, the thymus is too small to do its job well. The T-cells are no longer learning their lessons, and they get confused. Sometimes they attack perfectly good tissue; and sometimes they miss a deadly invader, and let it pass. (Statisticians call these errors of Type 1 and Type 2.)

Other parts of the immune system are similarly deranged, making errors of both types. Our lives depend on having smart immune systems that can tell self from other. Since it is the immune system that directs inflammation, Type 1 errors might be the more damaging. In 2009, a study of mice made front page news, when it was announced that their life spans could be increased substantially, even starting in “middle age” with a drug called rapamycin . Rapamycin is a powerful immune suppressant, probably not suitable for long-term use in humans, but it points the way toward advances that might preserve immune specificity as we age. Simply maintaining our thymus glands will be a good start.

 

Apoptosis

Apoptosis is the biologists’ word for cell suicide. It is vitally important to be able to get rid of cells that are unneeded, or cells that have become diseased or cancerous. Under a signal from the mitochondria, our cells are programmed to dismember themselves in a safe and orderly fashion, to break up DNA into pieces, to cut proteins into individual amino acids that can be reused, then to dissolve the cell wall and allow the cell’s contents to spill into the bloodstream, where it is re-cycled. In the womb, apoptosis is deployed to kill nerves that are extraneously connected, and to dissolve the webs that grow between our embryonic fingers. When we are mature, apoptosis is triggered when a cell is invaded by a virus. One cell that sacrifices itself in this way can prevent the virus from multiplying, and thwart its attack on many other cells. Cells that are pre-cancerous may also detect that something is wrong, and they die via apoptosis before they can cause trouble.

We need apoptosis, and would be more vulnerable without it, but as we get older, apoptosis develops a “hair trigger”, and cells begin to commit suicide when they’re still healthy and useful. In an Italian study , life span of genetically-engineered mice was extended by removing a gene called p66 that promotes apoptosis. Overactive apoptosis is to blame for sarcopenia – the loss of muscle mass with age. Apoptosis is also implicated in the loss of brain cells that leads to Alzheimer’s Disease .

 

Cellular Senescence

This may be the most promising target of the four, because the other three require a better balance, with more discrimination between good and bad effects. But there is reason to think that longer telomeres will be an unqualified benefit to the body; in fact there are prominent scientists who think that telomere length might be the body’s primary aging clock.

Telomerase is the enzyme that our cells use to extend telomeres, restoring the lost ends. If we could get telomerase into the cell nucleus, it would do its job. But this is not so simple. Telomerase can’t be taken as a pill or even injected, because it is not transported to the cell nuclei where it is needed. However, every cell knows how to make telomerase, because the gene for telomerase is in every cell. The cell only expresses certain genes at certain times, and the telomerase gene remains locked up tight, except in human embryos.

Many of the experts in the field of telomere science believe that it should be possible to find promoters that turn on the telomerase gene. In fact there are herbal extracts available now that seem to work in a limited way to induce telomerase expression. Several companies are searching for better promoters.

There are other experts who fear that turning on the telomerase gene might be dangerous, that it will lead to higher risk of cancer. The fears are based on the fact that most cancers find ways to turn telomerase on. But while it is true that cancer causes telomerase, it is not true that telomerase causes cancer. People with longer telomeres have longer life expectancies and lower cancer rates. Both in animals and in people, telomerase therapies have not increased cancer risk .

 

The future

As a strategy for research, study of the body’s signaling holds the best promise for big strides in life extension. We can work at fixing what goes wrong, engineering solutions to the damage that appears at many levels, and in many tissues as we age. But if much of this damage is self-inflicted, it will be easier to prevent it than to fix it. The fact that aging is highly regulated suggests it should be possible to modulate aging from the top down by intervening in the regulatory chemistry.

Evolutionary theorists are still adamant that aging could not have been selected as an adaptation, but their theory is holding back progress. One of these days they will have to face the overwhelming evidence that aging has evolved as an active process of self-destruction. Both evolutionary theory and geriatric medicine will be profoundly affected.

———-

Follow-up on factors besides calories that affect weight 

Two weeks ago, I wrote that the efficiency in absorbing food calories is affected by many factors including gut microbiota.  In Science Magazine this week, an experiment is described in which transfer of bacteria from the intestine of a lean mouse to an obese mouse induced weight loss.  For the “lean bacteria” to take over required a change in diet.