New Evidence that Long Telomeres cause Cancer, and Why I Think It’s Wrong

Since 2003, I’ve been saying that long telomeres are a path to long life.  The opposing view says that nature allows our telomeres to shorten to protect us against cancer.  Up until this spring, there has been little evidentiary support for the cancer theory.  Now, a major new study uses genetics to argue that longer telomeres increase risk of cancer as much as five-fold.  The study contains many statistical checks, but I’m going out on a limb to say I think the experts have made a conceptual error.

Up until now, epidemiological studies in humans and lab studies in animals have shown consistently that shorter telomeres increase risks for all the diseases of old age.  People’s telomere length tends to decline with age, but among people of the same age, those with shorter telomeres tend to die sooner.

The new study finds a very different conclusion: that shorter telomere length leads to much lower risk of cancer, while longer telomere length leads to slightly lower risk of heart disease.  Put these two together, and you predict pretty much the same life expectancy for people with long telomeres and short telomeres.

The new studies are based on genetics and account for telomere length only indirectly.  Nevertheless, it is claimed, they are more reliable than the old studies (based on direct observation) because they are able to eliminate a statistical anomaly that (they claim) is super-important.  

I believe the new study is actually less reliable, and that we should believe the more direct studies like the ones I have reported here in the past.  My reasons are that

  • The previous studies are straightforward, direct correlations.  Methodology in the new study relies on very small differences in telomere length, tiny differences that are lost in the noise and very difficult to detect.
  • The new studies require very large implicit extrapolation that is not necessary in the old studies.  The 50 to 1 extrapolation is very speculative, and it magnifies the noise along with the signal.
  • It is likely what these new studies are seeing are actually direct effects of genetics on cancer risk.  Even very small (direct) effects of genotype on cancer would appear in their methodology as though they were huge (indirect) effects of telomere length.  This is what I believe is happening, and why I don’t trust their results.

I may be wrong about this.  I’m questioning seasoned experts in the field based on my general knowledge of statistics.


Two years ago, I reported on a Danish study linking short telomeres to higher mortality, especially heart disease (CV).  I took this as clear proof that telomere length was not just a marker of aging but a cause.  The implication is that you can live longer by adopting lifestyles and taking supplements that extend your telomeres.

The core of my argument, based on the the Danish study, was this:

  • Impact of telomere length on mortality, raw data:   3.38 (meaning that the 10% of people with the shortest telomeres were dying at a rate 3.38 as high as the 10% with the longest telomeres)
  • Same calculation, corrected for age:  1.54
  • Same calculation, corrected for age and all other hazard variables:  1.40

Conclusion: This demonstrates that age is the biggest factor in mortality, and telomere length is second, with a strong effect, independent of age.  All the health variables together have only minor effect compared to age and telomere length.

The Danish study did a multivariate analysis, also called ANOVA.  This is a statistical technique designed to separate out the factors that contribute to an outcome (in this case, mortality) and assign percentages of causality.  What their analysis revealed was that the strongest cause of increased mortality is age itself, and that telomere length comes second.  Everything else, from smoking to depression to a history of infections, is much less important than age and telomere length.  I interpret this to say that short telomeres are probably a direct cause of increased disease risk.

A popular theory is that the association of short telomeres with higher mortality is only incidental.  Stresses, infections, smoking, etc. cause both shorter telomeres and higher mortality.  But these are separate pathways.  It is not the shorter telomeres that are causing higher mortality, but short telomeres happen to be associated with higher mortality because both are caused by various stressors in a person’s past.  If this is true, you can’t improve your odds of living longer just by extending your telomeres.

But I believe that the Danish study disproves this theory.  If the stressor theory were correct, then the Danish analysis would have found that the relationship between stressors and mortality was stronger than the relationship between telomere length and mortality.  In fact, they found the opposite.

 

The New Genetic Study

The result reported by the new study is that longer telomeres creates a very much higher risk of several common cancers.  On the other hand, longer LTL (=leucocyte telomere length) protects against heart disease.  The protective effect for heart disease is much smaller, but many more people die of heart disease than of these particular cancers.  The result is a wash.  Longer LTL is neither a net benefit to health nor is it a net risk.  People with longer and shorter LTLs have similar overall mortality risk, about the same life expectancy.

 

Disease Odds Ratio
Glioma 5.27
Ovarian cancer 4.35
Lung cancer 3.19
Neuroblastoma 2.98
Bladder 2.19
melanoma 1.87
Testicular 1.76
Kidney 1.55
Endometrial 1.31
Basal cell skin 1.22
Breast Cancer 1.06
Heart disease 0.78

“Odds ratio” refers to a person’s probability of contracting the corresponding disease.  For example, the first line means that people whose telomere length is one standard deviation (1 sigma) longer than average have a risk of glioma 5 times greater than people who have average telomere length.

This result gains credibility because it is exactly what the theory would predict.  Nature has optimized LTL by compromising between two risks.  If the average LTL for our species were longer, then we’d get more cancer.  If it were shorter, we’d get more heart disease.  The reason there is so much variation among the population, people with much longer and much shorter telomere length, is that it doesn’t matter very much.

So here is agreement between experiment and theory, a tidy situation that scientists like to see.  What is more, there is a widely-held belief that the methodology of the new study is more reliable than studies in the past that are more direct and simpler.  Nevertheless, I’m about to offer my opinion that the previous studies were right, the theory is wrong, and, in fact the design of the new study is seriously flawed.

This was the latest and far the largest in a series of GWAS studies going back four years [ref, ref, ref].  GWAS stands for Genome-Wide Association Study.  The idea is to work around life experience variables that might create a correlation without a causal connection.  In the present case, the target is to detect any causal relationship between leucocyte telomere length (LTL) and various diseases, while filtering out associations between LTL and disease risk that might be incidental, as described above.  The researchers looked for small genetic differences (called SNPs) that are linked to telomere length.  These vary from one individual to the next, and they persist through a lifetime.  The next step is to compare numbers of people with a particular SNP variant among those who have the disease and those who don’t have the disease.  Are people who have the SNP associated with longer telomeres more or less likely to develop the disease?  From the answer to this question, they infer a causal relationship, not between SNP and the disease but between telomere length and the disease.

Observational studies look for a direct relationship between LTL and disease.  GWAS studies look for an indirect relationship between SNP and LTL, SNP and disease.  The indirect study is widely considered to be a more reliable indicator of causal connection than the direct study.  Why?

“Mendelian randomization studies are less susceptible to confounding in comparison to observational studies…Given the random distribution of genotypes in the general population with respect to lifestyle and other environmental factors, as well as the fixed nature of germline genotypes, these results should be less susceptible to confounding and reverse causation than those generated by observational studies.”

The reasoning is that people have their genomes for their entire lives, independent of how they live, what they do, what they are exposed to.  By working with the genome, the statisticians can be sure to eliminate the standard objection that (for example):

  • Stress directly decreases LTL
  • Stress directly increases risk of disease
  • Therefore, short LTL will appear to be linked with disease, even though short LTL doesn’t cause disease.

 

Problems with GWAS studies

But the GWAS methodology also introduces new problems of its own.  The main problem is that the statistical sensitivity of the study is seriously reduced.  This is because the relationship between SNP and LTL is very weak.  All ten SNPs together constitute a very small factor among many larger ones that create difference in LTL between one person and the next.

“The selected SNPs correspond to 10 independent genomic regions that collectively account for 2% to 3% of the variance in leukocyte telomere length”

And of course, very few people have all 10 SNPs going in the same direction.  The study is forced to work with people who have, for example 10 positive SNPs out of 16 compared to others who may have 5 positive SNPs out of 16.

Their LTL is really quite close together.  To compensate for this, the statisticians divide by a small number to extrapolate outwards.  For example, the difference between typical people in the study is about 1/20 sigma*.  And the difference between risk of glioma (brain cancer) for these people is only about 0.08** .  But the difference is reported as “what would have been the risk of brain cancer if the difference had been not 1/20th but one full sigma.  They extrapolate exponentially, so the conclusion comes out quite startling: They claim that people with 1 sigma of extra LTL have 5 times greater chance of getting brain cancer.

What they find: people with 0.05 sigma extra LTL have 1.08 times the risk of getting brain cancer.

What they report: people with 1 sigma extra LTL would have (by extrapolation) 5 times the risk of getting brain cancer.

They conclude that there is a large effect of telomere length on cancer, but they do this by the following reasoning:

  • There is a small effect of these genetic variations on telomere length.
  • There is a small effect of these genetic variations on cancer risk.
  • Dividing the small by the small, they conclude: if the mechanism for these genetic variations affecting cancer is mediated by their effect on telomere length, then the effect of telomere length on cancer must be quite large.

I’m sorry to belabor this, but it’s important, and it’s hidden in the methodology.  People who do these studies know that an odds ratio (OR) of 1.08 means nothing.  The state of the art in epidemiology is rarely able to attach meaning to odds ratio that is close to 1.  It is lost in the nosie.  But an OR of 5 is something easy to see.  It stands out from the noise and is easy to detect.

The description of the methodology in this study hides the fact that they are working with ORs less than 1.08 and extrapolating exponentially outward to make the ORs look very large and significant.

 

What I think is really going on

The study finds a large and consistent result that demands some explanation.  I’m claiming that the explanation they offer (in terms of telomere length) is wrong.  So why do I think they get the results that they did?

A few of the sixteen SNPs that are considered in the study correspond to slight variations on the form of the telomerase molecule.  I’m guessing that these mutated forms of telomerase cause an increased risk of cancer.  The increased risk doesn’t have to be large.  As in my example above, the increased risk for brain cancer would have to be just 8%, and the increased risk for lung cancer (more important because it is more common) only 6%.  Because of the extrapolation by an exponent of 20 that is implicit in their methodology, these small effects would be reported as though they were odds ratios of 5 (for brain cancer) and 3 (for lung cancer).

Another possibility is that one or more of the SNPs happen to be more common in a segment of the population that is prone to cancer, for whatever reason.  It may be that a particular SNP is more common in an ethnic group that has high smoking rates, or that is prone to melanoma because of lighter skin, or has a diet and lifestyle that leads to a slightly greater risk of cancer.  For example, it is known that people of African extraction have SNPs associated with longer telomere length, and they also have higher risks for many cancers, including lung and [ref].  (Africans have lower risk of glioma, so the correlation goes in the wrong direction for this particular example.)  At the risk of beating a dead horse, I emphasize again that even a small increased risk would be magnified by the extrapolation that is implicit in the methodology of the GWAS, and appear very large and scary when misinterpreted as an effect of telomere length.

GWAS is also referred to as “Mendelian randomization studies” because they depend very much on the assumption that different SNPs are randomly distributed in the population.  Of course, this assumption is not literally satisfied.  How significant is the deviation from random distribution?  I will be investigating this question, and I’ll let you know what I find.

 

The Bottom Line

There is a sharp conflict between the new GWAS results [Haycock, 2017] and the observational results [Rode, 2015] reported two years ago.  They can’t both be right.  If the GWAS results are as Haycock claims, there would have been glaring increases in cancer risk that Rode could not have missed.  If Rode is correct, then the methodology of Haycock must be flawed.

The reasoning in GWAS studies depends on a huge extrapolation.  I am saying it is more likely that the effect of genetic variations on cancer risk is direct, not (as per Haycock’s assumption) mediated by telomere length.  It could be that a very small direct effect of one of these SNPs is reported as though it were a large indirect effect, working via telomere length.

For now, I’m sticking with my previous counsel: Lengthening telomeres is a viable strategy for improving health and longevity.  If you take supplements that promote telomerase, you are not adding to your cancer risk.  Because of the large net benefit, lengthening of telomeres should be a major target for medical research.

But as I said at the outset, I am criticizing the new study from the outside, and it is quite possible that I have misunderstood the methodology.  I have sided with the direct observational studies and I have been skeptical of the GWAS studies, but it may be that the consensus in the field is correct, and that GWAS studies really are more reliable indicators of causality.

I intend to get to the bottom of this, and will report my findings in future columns.

__________

* Sigma is a standard deviation of telomere length in the population at large. If you know what that means, that’s great; if you don’t it doesn’t matter to the logic of what I’m saying.

** Disease risk is typically reported as an odds ratio.  In this case, 0.08 would mean that, in their raw data, people in the study with the longer LTLs had a risk of 1.08 times as great as people with shorter LTLs.  You get to 1.08 not by adding 1 but by raising e to the power 0.08.

Building the Case that Aging is Controlled from the Brain

Last week, a new study came out fingering the hypothalamus as locus of a clock that modulates aging.  This encourages those of us who entertain the most optimistic scenarios for anti-aging medicine.  Could it be that altering the biochemistry of one tiny control center might effect global rejuvenation?  

First some background….

I have staked my career on the interpretation that aging unfolds under the body’s full control.  Even those aspects of aging that look like random damage are actually damage that is permitted to accumulate as the body pulls back its defense mechanisms late in life and dials up some biochemical processes that look an awful lot like deliberate self-destruction

I believe that aging is governed by an internal biological clock, or several semi-independent and redundant clocks.  There are

  • A telomere clock, counting cell divisions on a flexible schedule, eventually producing cells with short-telomeres that poison us.
  • The thymus, crucial training ground for our white blood cells, shrinks through a lifetime.
  • An epigenetic clock alters gene expression over time in directions that give rise to self-destruction.
  • A neuroendocrine clock in the hypothalamus
  • Perhaps other clocks, yet to be identified.

 

A dream is to be able to reset the hands of the clock.  If we’re lucky, then changing the state of some metabolic subsystem will not just temper the rate at which we age, but actually restore the body to a younger state.  Most of the research in anti-aging medicine is still devoted to ways to engineer fixes for damage the body has allowed to accumulate; but I belong to a wild-eyed contingent that thinks the body can do its own fixing if we understand the signaling language well enough to speak the word “youth” in the body’s native biochemical tongue.

Some of these clocks are more accessible and easier to manipulate than others.  The epigenetic clock is most daunting, because it presents the spectre of a global network of signal molecules circulating in the blood, transcription factors that mutually support one another in a state of slowly-shifting homeostasis.  This system could be so complex that it might take decades to understand, and then hundreds of different signal molecules in the blood would need to be re-balanced in order to recreate homeostasis in a younger condition.  (For several years, the Mike and Irina Conboy have been looking for a small subset of molecules that might control the rest, but in a private conversation they recently told me they are less optimistic that a small number of factors controls all the rest.)

At the other end of the spectrum, the hypothalamic clock presents the most optimistic scenario.  It is tightly localized in a tiny region of the brain, and might be relatively easy to manipulate, with consequences that rejuvenate the entire body.  The hypothalamic clock hypothesis is an attractive target for research because, if correct, it will offer direct and straightforward control over the body’s metabolic age.

That aging unfolds according to an internal clock remains a controversial claim, but what everyone agrees is that the body has some way to know how old it is.  There has to be a clock for development that determines when growth surges and stops, when sex hormones turn on and, if it’s not too great a stretch, when fertility ends and menopause unfolds.

The clock that governs growth and development has yet to be elucidated—a major metabolic mystery by my lights.  The clock that we know about and (sort of) understand is the circadian day-night clock that governs sleep and waking, giving us energy at some times of the day but not others.

Is the life history clock linked to the circadian clock?  Maybe the body just counts days to tell how old it is?  This possibility was eliminated, at least for flies, using experiments with cycles of light and dark that were consistently longer or shorter than 24 hours.  Flies living with fast day-night cycles (less than 24 hours) lived shorter, as predicted; but flies living with long day-night cycles failed to have longer lifetimes,  In fact, deviation from 24 hours in either direction shorten the fly’s lifespan [2005].  

But this study suggests the short-term clock and the long-term clock may be linked in a way that is less straightforward.  Melatonin may be another reason to expect a connection.  Melatonin is the body’s cue for sleep, and Russian studies have documented a role for melatonin in aging.  A third motivation comes from the fact that aging disrupts sleep cycles, and (in a downward spiral) disrupted sleep cycles are also a risk factor for mortality and diseases of old age.

Cells seem to have their own, built-in daily rhythms.  I want to say “transcriptional rhythms”, adding the idea that gene transcription is the locus of control; however, red blood cells are the counterexample—they exhibit daily cycles, even though they have no DNA to transcribe [2011].  Individual cycles are designed to be 24 hours, but they would soon drift out of phase with day and night if they weren’t centrally coordinated.  The reference clock that keeps the others in line is in the SCN, the suprachiasmatic nucleus, a handful of nerve cells in a neuroendocrine part of the brain called the hypothalamus.

Think of a million pendulums that are all tuned to swing with a period of 24 hours.  All that it takes is a tiny nudge to all these pendulums each day to keep them in phase with one another, so they are all swinging together.  The SCN provides this nudge in a smart way, based on information from the eyes (light and dark) and endocrine signals that indicate activity and sleep.  The SCN is upstream of the pineal gland, and supplies the signal that tells the pineal gland when it’s time to make melatonthematic index of scarsonatas.  The natural resonances of individual cells become entrained in a body-wide response.

 

What does all this have to do with aging?

Experiments in the 1980s and 90s showed that the SCN is related to annual cycles, but the relationship seems to be not as strong or as simple or as direct.  For example, squirrels in which the SCN was removed had no daily sleep-wake cycles at all, but their annual cycles of fertility and oscillations of weight were affected inconsistently, more in some animals than others.  Transplanting a SCN from young hamsters into old hamsters cut their mortality rate by more than half, and extended their life expectancies by 4 months [1998].

I have written in this column [one, two] about research from the laboratory of Claudia Cavadas (U of Coimbra, near Lisbon) indicating that inflammation and inflammatory cytokines in the hypothalamus are at the headwaters of a cascade of signals that lead to whole-body aging.  They have emphasized the role of TGFß binding to ALK5 and of the neurotransmitter NPY.  We usually think of inflammation as a source of damage throughout the body, but in the hypothalamus, inflammation seems to have a role that is more insidious than this, with full-body repercussions.  Blocking inflammation in the hypothalamus is a promising anti-aging strategy.

New Paper on micro RNAs from the Hypothalamus

Along with Cavadas, Dongshen Cai (Einstein College of Medicine) has been a leader in exploring neuroendocrine control of aging that originates in the hypothalamus.  Several years ago, Cai’s group demonstrated that aging could be slowed in mice by inhibiting the inflammatory cytokine NF-kB and the related cytokine IKK-ß just in one tiny area of the brain, the hypothalamus.  “In conclusion, the hypothalamus has a programmatic role in ageing development via immune–neuroendocrine integration…”  They summarized findings from their own lab, suggesting that metabolic syndrome, glucose intolerance, weight gain and hypertension could all be exacerbated by signals from the inflamed hypothalamus.  In agreement with Cacadas, they identified GnRH (gonadotropin-releasing hormone) as one downstream target, and were able to delay aging simply by treatment with this one hormone.  IKK-ß is produced by microglial cells in the hypothalamus of old mice but not young mice.  Genetically modified IKK-ß knock-out mice developed normally but lived longer and retained youthful brain performance later in life.

In the new paper, Cai’s group identified micro-RNAs, secreted by the aging hypothalamus and circulating through the spinal fluid, that contribute to aging.  A small number of stem cells in the hypothalamus were found to keep the mouse young, in part by secreting these micro-RNAs.  Mice in which these stem cells were ablated had foreshortened life spans; old mice that were treated with implants of hypothalamic stem cells from younger mice were rejuvenated and lived longer.  A class of neuroendocrine stem cells from the third ventricle wall of the hypothalamus (nt-NSC’s) was identified as having a powerful programmatic effect on aging.  These cells are normally lost with age, and restoring these cells alone in old mice extended their life spans.

Exosomes are little packets of signal chemicals. Micro-RNAs from stem cells in the hypothalamus are collected into exosomes and shipped down through the spinal fluid.  These exosomes seem to constitute a feedback loop.  On the one hand, they are generated by the hypothalamic stem cells.  On the other hand, they play a role in keeping these same cells young, and producing more exosomes.

Life extension of about 12% was impressive given that there was just one intervention when the mice were more than 1½ years old, but of course it’s not what we would hope for if the master aging clock were reset.  For really large increases in lifespan, we will probably need to reset two or even three of the clocks at once.

 

The Bottom Line

The reason the body has multiple, redundant aging clocks is to assure that natural selection can’t defeat aging by throwing a single switch.  That means the clocks must be at least somewhat independent.  Nevertheless, I judge it is likely that there is some crosstalk among clocks, because that’s how biology usually works.  To effect rejuvenation, we will have to address all aging clocks, but we see some benefit from resetting even one, and expect more significant benefit from resetting two or more.

The most challenging target is the epigenetic clock,built on a homeostasis of transcription and signaling among hundreds of hormones that each affect levels of the others.  Reverse engineering this tangle will be a bear.

The idea of a centralized aging clock in the hypothalamus seems far more accessible, and is promising for the medium term.  Still, it does not suggest immediate application to remedies.  The hypothalamus is deep in the brain, and you and I might be reluctant to accept a treatment that required drilling through the skull.  A treatment based on circulating proteins and RNAs from the hypothalamus would be less invasive, but even that might have to be intravenous, and include some chemistry for penetrating the blood-brain barrier.  RNA exosomes seem to be our best opportunity

As Cavadas’s group has already pointed out, it is inflammation in the hypothalamus that is amplified by signaling to become most damaging to the entire body.  This raises the interesting question: could it be that the modest anti-aging power of NSAIDs is entirely due to their action within the brain?  In other words, maybe “inflammaging” is largely localized to the hypothalamus.

Mitochondria in Aging, II: Remedies

The once-popular mitochondrial free radical theory of aging proved to be too glib. Aging isn’t fundamentally about dispersed damage; rather, dispersed damage is a result when the body’s defenses stand down in old age.  Nevertheless, the mitochondria do play a role in aging, largely through signaling and apoptosis.  Antioxidants targeted to mitochondria may be an exception to the rule that antioxidants don’t prolong lifespan.  And other supplements and strategies that either promote production of new mitochondria or enhance their efficiency of operation show promise for modest lifespan extension.


Growing new mitochondria

A ketogenic diet leads to generation of new mitochondria, as do caloric restriction and exercise.  Exercise when the body is starved for sugar (low glycogen) is the most potent stimulator of new mitochondrial growth.  Exercise while fasting, or continue to exercise after you “hit your wall”.

Hormones that promote mitochondrial proliferation include thyroxin, estrogens, and glucocorticoids.  Promoting new mitochondria has a tendency simultaneously to suppress apoptosis, programmed cell death [ref].  At later ages, apoptosis of cells that are still functional tends to be a larger problem than the failure of cancerous cells to eliminate themselves by apoptosis.  In other words, suppressing apoptosis is (on balance) a good thing for anti-aging, but the downside is it can also increase risk of cancer.

 

Ubiquinone=CoQ10

Coenzyme Q-10 (aka ubiquinone) is an essential part of mitochondrial chemistry, shuttling electrons along their way to the ATP molecules that mitochondria generate as their primary energy export to the cell.  It’s often called an antioxidant, but that’s not the primary role of CoQ10.

As a supplement, it is well-established with a good reputation.  There is lots of evidence for benefits to health markers, especially athletic endurance, several aspects of heart health, and erectile dysfunction.  If you have fibromyalgia or if you are taking statins, CoQ10 is strongly indicated.  For chronic fatigue syndrome, it’s definitely worth trying.  

But there’s no reason to expect it will increase your life expectancy.  Supplementing with ubiquinone increases the lifespan of worms but not mice or rats [ref, ref].

Worms that cannot make unbiquinone live 10 times as long.  Just saying…

A few years ago, ubiquinol was introduced as a more bioavailable form of ubiquinone.  It’s more expensive, but there is not clear evidence that it is more bioavailable.

 

PQQ

Pyrroloquinoline quinone is helpful but not necessary part of mitochondrial chemistry.  Bacteria make a lot of it; plants less; mammals only tiny quantities.  Mice completely deprived of PQQ show growth deficiency, but the amount that they need is tiny compared to the quantities in PQQ supplements.

PQQ is a growth factor for bacteria, and the principal health claim for PQQ is that it can stimulate growth of new mitochondria.  The evidence is based on biochemistry and cell cultures.  In live mice, it has been shown that PQQ deficiency results in a mitochondria deficiency, but not that large quantities of PQQ lead to more mitochondria.

Bill Faloon (LEF) and Joseph Cohen (selfhacked) are big fans of PQQ, and you can read a list of benefits here.  Cohen claims PQQ helps with sleep quality and nerve growth, leading to better cognitive function.  

Small quantities of PQQ can be absorbed from many plant foods, but not animal foods.  Much larger quantities come in supplement form. 100 g of tofu has just 2µg (micrograms).  Supplements are usually 5-20 mg, hundreds of times as much as you’re likely to get from a vegetarian diet.  Here is a table of PQQ concentrations in foods:

 

SkQ and MitoQ

These are two closely related molecules, originally synthesized in Russia in the 1970s, but it wasn’t until the 1990s that their therapeutic value was documented by two New Zealand scientists.  One end of the molecule is CoQ10 (or a version found in plants, claimed to be even more powerful as an antioxidant).  The other end of the molecule is an electric tugboat that pulls the molecule into mitochondria.  

I’ve written a  detailed report three years ago.  At the time, I noted that the Russians claimed to extend lifespan of mice modestly with SkQ, and SkQ was found (also in Russian labs) to be a powerful rejuvenant for aging eyes.  The Russians sell SkQ as eye drops.  The Kiwis sell MitoQ as skin cream and also as pills.

Earlier this year, the Russian labs announced that SkQ had substantially extended lifespan of a mouse strain that was short-lived because of a mitochondrial defect.  None of the Russian claims have been reproduced in Western labs.  Three years ago, I was inclined to give the Russians the benefit of the doubt, but now I’m starting to wonder, since the New Zealand company has a laboratory arm, and they haven’t announced anything nearly so impressive.

 

Humanin and her sisters

Mitochondria have ringlets of their own DNA, encoding just 37 genes.  (That doesn’t mean that the mitochondria only need 37 proteins; the great majority of proteins needed by mitochondria are coded in chromosomes of the cell nucleus, and transported to the mitochondria as needed.)  Just 16 years ago, the first mitochondrial-coded protein to be discovered was named Humanin, because it was found to improve cognitive function to dementia patients, restoring some of their “humanity”.  In addition to being neuroprotective, humanin promotes insulin sensitivity.  Humannin’s action is not confined to the mitochondrion in which it was produced, but in fact it  circulates in the blood as a signal molecule.  Blood levels of humanin decline with age.

Humanin

In experiments with mice, humanin injections have been shown to protect against disease.  Lifespan assays with humanin are not yet available.

To date, HN and its analogs have been demonstrated to play a role in multiple diseases including type 2 diabetes (25, 43), cardiovascular disease (CVD) (2, 3, 47), memory loss (48), amyotrophic lateral sclerosis (ALS) (49), stroke (50), and inflammation (22, 51). The mechanisms that are common to many of these age-related diseases are oxidative stress (52) and mitochondrial dysfunction (53). Mitochondria are major source of ROS, excess of which can cause oxidative damage of cellular lipids, proteins, and DNA. The accumulation of oxidative damage will result in decline of mitochondrial function, which in turn leads to enhanced ROS production (53). This vicious cycle can play a role in cellular damage, apoptosis, and cellular senescence – contributing to aging and age-related diseases. Indeed, oxidative stress is tightly linked to multiple human diseases such as Parkinson’s disease (PD) (54), AD (55), atherosclerosis (56), heart failure (57), myocardial infarction (58), chronic inflammation (59), kidney disease (60), stroke (61), cancers (62, 63), and many types of metabolic disorders (64, 65). We and others have shown that HN plays critical roles in reducing oxidative stress (6668). [2014 review]

Pinchas Cohen, MD (Dean, School of Gerontology, University of Southern California Davis, Los Angeles, California) is an expert in humanin, a protein (peptide) produced in mitochondria. Mitochondria are energy-generating organelles in cells, which have their own DNA separate from the DNA in the nucleus. The amount of DNA found in the mitochondria is much less than that found in the nucleus. As such, mitochondrial DNA contains codes for only a few proteins, humanin being one of them. Humanin was discovered by a search for factors helping to keep neurons alive in undiseased portions of the brains of Alzheimer’s disease patients. Humanin protects neurons against cell death in Alzheimer’s disease, as well as protecting against toxic chemicals and prions (toxic proteins)[ref].  Dr. Cohen’s team has shown that humanin also protects cells lining blood vessel walls, preventing atherosclerosis. In particular, they have shown that low levels of humanin in the bloodstream are associated with endothelial dysfunction of the coronary arteries (arteries of the heart).[ref] Humanin has also been shown to promote insulin sensitivity, the responsiveness of tissues to insulin. Because humanin levels decline with age, it is believed that reduced humanin contributes to the development of aging-associated diseases, including Alzheimer’s disease and type II diabetes. [Ben Best]

Personal notes: This lab near where I am visiting in Beijing is taking leadership in characterizing a group of short peptides similar in origin to humanin, and this company across the street from us is selling mitochondrial peptides.

If humanin were a patentable drug, there would be much excitement and multiple clinical trials for AD, probably leading to expansion into general anti-aging effects.

 

MOTS-c

This is another short peptide of mitochondrial origin, only recently discovered and characterized.  I was alerted to its existence by a study from a USC lab that was written up here in ScienceBlog just this month (reprinted from a USC press release).  Results are new but impressive.  Mice injected with MOTS-c had more muscle mass, less fat, more strength and endurance.  MOTS-c protected their insulin sensitivity when mice were fed a high fat diet [ref].  Lifespan studies haven’t been done yet.

Like humanin, MOTS-c is manufactured inside mitochondria from a template in mitochondrial DNA, but it is exported from the cell and appears in the bloodstream as a signal molecule.  Blood levels of MOTS-c decline with age.  It is a mini protein molecule with 16 amino acids, too big to survive digestion so it can’t be taken orally.  

MOTS-c holds much potential as a target to treat metabolic syndromes by regulating muscle and fat physiology, and perhaps even extend our healthy lifespan.”[ref]

Let’s keep your eyes on this one over the next year or two.

 

Gutathione / NAC

I’ve never heard anyone say a bad word about glutathione.  It’s the antioxidant with no downside.  Genetic modifications that upregulate glutathione have increased lifespan in worms, flies and mice.  

For a long while, it has been assumed that you can’t eat glutathione, because it doesn’t survive digestion.  Some researchers at Penn State disagree, finding impressive increases in tissue and blood levels when people were supplemented with up to 1 g per day raw glutathione.  Liposomal glutathione is an oral delivery form that gets around the digestion problem, especially when taken with methyl donors like SAMe.

The herb Sylimarin=milk thistle may increase glutathione.  For now, the precursor molecule N-Acetyl Cysteine (NAC) is the best-established supplement we have to promote glutathione.  In the one available study, supplementing with NAC greatly increased lifespan in male but not female mice.  NAC also increases lifespan in worms and flies.

N-Acetyl Cysteine

Glutathione

 

For the future, we might hope to do better.  Less than 20% of the cell’s glutathione actually makes its way to the mitochondria, where it is most needed.  There are esters of glutathione that, in theory, ought to be attracted into the mitochondria.  They have been tested in cell culture only, but are more than ripe for animal testing [ref].

 

Nicotinamide Riboside (NR) and other NAD+ enhancers

The chemicals NAD+ and NADH are alternative, cycled forms of an intermediate in the process by which mitochondria make energy.  Levels of NAD+/NADH decline with age.  NR is a precursor to NAD+, and it has been demonstrated (preliminary results in humans) that NR supplementation increases blood levels of NAD+.

It may be awhile before we know for sure whether this leads to better health or longer lifespan.  Niagen and Basis are heavily promoted with credible scientifists behind their products, and many early adopters offer subjective reports of short-term benefits.  There is one mouse study claiming to pull a 3% extension of lifespan out of the noise, and perhaps I am less open to the finding because the article, published prominently in Science, seems so breathless in describing benefits.

 

Melatonin

The primary role of melatonin is to regulate the body’s sleep/wake cycle.  Melatonin declines with age and the timing of our daily melatonin surge gets fuzzier and less reliable with age.sleep quality deteriorates.  Sleep quality suffers.

Melatonin is well-established in mice as a modest longevity aid, although results have been inconsistent.  12 out of 20 studies showed a lifespan increase, and the remaining 8 showed no increase or decrease.  Whether nightly supplementation affects mortality rates in humans has never been determined.

Melatonin is concentrated in mitochondria as much as 100-fold, and it may even be created there [ref], independent of the circulating melatonin that is secreted from the pineal gland at night.  One of its actions is as a mitochondrial antioxidant and scavenger of ROS.

Twenty years ago, Walter Pierpaoli promoted melatonin as a sleep aid, cancer fighting hormone that would enhance your mood and your sex life while keeping you young.  Russian labs have also been optimistic.  My take is that melatonin is a legitimate anti-aging hormone, and is especially useful for those of us whose sleep is disrupted with age.  It is widely available, cheap and safe.  Unless you’re fighting jet lag, 1 to 2 mg at night is all you need.

Also worth mentioning

Magnesium is required for manufacture of glutathione.  Selenium works along with glutathione.  Omega-3 fatty acids can promote synthesis of glutathione.  Acetyl L-carnitine transports fat fuels through the mitochondrial membrane.  Alpha-lipoic acid is part of the mitochondrial energy metabolism.

The Bottom Line

Commercial interests can make some messages louder than others, and the health news we hear is affected by what is profitable as much as by what is healthy.  Exercise is primary, but has no sales value.  Of the supplements reviewed here, NAC is the best-established for mitochondrial health and a possible effect on lifespan.  It is cheap and available.  Liposomal glutathione is certainly more expensive and possibly more effective.  Melatonin is even cheaper, and has been found to increase lifespan in multiple rodent studies, with broad benefits apart from modification of mitochondrial function.  Humanin and MOTS-c, not yet close to commercial availability, seem to be promising substances to explore for health, though not for profits.

Mitochondria in Aging, I Mechanisms and Background

A popular theory a generation back sought to trace aging to oxidative damage originating in the mitochondria.  Every cell in the body has hundreds or thousands of mitochondria, the sites of the high-energy chemistry that produces ROS as toxic waste. The hope was that by quenching the ROS, aging might be turned off. The “Mitochondrial Free Radical Theory” is built on a flawed theoretical foundation, and anti-oxidants don’t extend lifespan. Nevertheless, the mitochondria play a role in aging.  Historically, mitochondria were mediators of the first organized mechanisms of programmed death over a billion years ago, and they retain a role in processing signals that regulate lifespan.  Curiously, though a quadrillion mitochondria are dispersed through the body, they act in some ways like a single organ, sending coordinated signals that regulate metabolism and affect aging.


Mitochondria are in the cells of all plants and animalshundreds or thousands of mini power plants in each cell.  They burn sugar to make electrochemical energy in a form the cell can use.  They are loyal and essential servants.  But it wasn’t always so.  More than a billion years ago, mitochondria came into the cell as invading bacteria.  Though they’ve long ago been domesticaed, they retain a bit of their autonomy as a relic of the past.  Mitochondria have their own DNA.  Like bacteria, mitochondrial DNA is in the form of loop, a plasmid rather than a chromosome.  Each mitochondrion keeps several copies of the plasmid.  

Mitochondria retain from their distant pathological past the capacity to kill the cell.  This is an orderly process known as apoptosis=programmed cell death.  Mitochondria are not the jurors that sentence the cell to death, but only the executioners acting on external signals.

Aging of the body as a whole is centrally coordinated, though the nature and location of the clock(s) remain a major unsolved problem.  Communication about the age state of the body is carried through signal molecules in the blood, and tissues respond accordingly.  Mitochondria not only pick up on these signals, they also contribute circulating signals of their own.  Apoptosis is dialed up in old age.  Along with inflammation, it is a primary, local mode of the self-destructive process that is aging.  We lose too many cells to apoptosis, cells that are still healthy and useful, and mitochondria are the proximate cause of this loss.

Portrait by scanning electron microscope, artistically colorized

 

Signaling, up, down and sideways

The big picture is that mitochondria take their orders from the cell nucleus, where the vast majority of the DNA is housed.  The transcription factors that determine what mitochondrial genes are expressed are housed in the nucleus.  In addition, there is feedback, retrograde signaling, by which mitochondria communicate to the nucleus the state of their own health and of the cell’s energy mtabolism in general.  The nucleus responds with changes in transcription based on communication from the mitochondria.

A great part of the diverse benefits of caloric restriction, and perhaps of exercise, too, are thought to originate in signaling from the mitochondria.  

In addition to sending and receiving signals from the cell nucleus, mitochondria talk to each other.  They coordinate extensively within a cell, and they also generate hormones that are transmitted through the bloodstream, talking to distant cells and foreign mitochondria.

 

Mitochondria and Cancer

Cancer cells have impaired mitochondrial metabolism.  They don’t burn sugar through the usual, high-efficiency mode that combines with the maximal amount of oxygen; rather they use fermentation—anaerobic breakdown of sugar.  Cancer cells do this even when oxygen is plentiful, despite the fact that it generates much less energy per sugar molecule.  Cancer cells are starved for energy, and they gobble up sugar at a high rate.  (PET scans are able to visualize tumors on the basis of their sugar consumption.)  Eating a very-low-carb diet is a cancer therapy.  

90 years ago, a Nobelist and Big Thinker in biomedicine named Otto Warburg gave us the hypothsis that mitochondria with impaired glucose metabolism are the root cause of cancer.  We usually think of cancer as starting with mutations that lead to uncontrolled growth and proliferation, but in the Metabolic Theory of Cancer, mutations and proliferation are secondary to this change in mitochondrial chemistry.  Today, proponents of the Warburg Hypothesis are a small but enthusiastic minority, armed with facts and arguments that I have not yet found time to assess.  But I am struck by the fact that when the nucleus of a cancer cell is transplanted into a healthy cell, the healthy cell remains healthy; and when the nucleus of a healthy cell is transplanted into a cancer cell, the cell remains cancerous [ref, ref].  This seems to be prima facie evidence that the essence of cancer is not to be found in chromosomes of the nucleus.

 

Fewer, less efficient, and more toxic waste with age

We have fewer mitochondria as we age, and this is plausibly connected to lower muscle strength and endurance as well as energy in the organ that uses energy most intensively=the brain [ref].  The relationship is subtle enough that it is not completely nailed down, despite decades of work from true believers.  Since mitochondria mediate apoptosis, it is also plausible that loss of muscle cells and nerve cells with age (at least partially through apoptosis) is also mediated by mitochondria.

Cells that need a lot of energy have a lot of mitochondria. Heart muscle cells are packed with them.

Compounding the problem, the mitochondria that we do have become less efficient with age.  They are giving us less energy, and they are generating more reactive oxygen species (ROS).  Simultaneously, the cell is generating less of the native anti-oxidants that protect from ROS.  Glutathione, ubiquinone, and superoxide dismutase all decline with age.  This is one of the ways the body destroys itself.  Oxidative damage accumulates in old but not young people.  Oxidative damage may also contribute to telomere shortening.

Somehow, ROS generated by impaired mitochondria produce damage that accumulates, but ROS generated by exercise signal the body to ramp up the repair processes, and produce a net gain in health.  It is not clear how the two processes are distinguished.  The reason that anti-oxidants don’t work to extend lifespan is probably that they interfere with the signaling functions of ROS.

The best-documented way in which mitochondria deteriorate is that their DNA develops mutations.  I find this something of a conundrum—not that mitochondria should accumulate mutations over the course of a lifetime but that they don’t accumulate mutations from one generation to the next (in the germline).  Mitochondria proliferate clonally, without sex.  Sex shuffles genes in many combinations, so that the good genes can be separated from the mutated ones, and the latter eliminated before they get fixed into the genome.  Without sex, how do mitochondria avoid accumulating mutations over the aeons?  And since they largely do manage to avoid accumulating mutations over millions of years, why can’t they avoid accumulating mutations over the course of a few decades within a human body?

 

Are mutations in mitochondrial DNA a cause of aging?

Mitochondrial mutations accumulate with age.  Genetically modified mice with a defective gene for replication of mitochondrial (but not nuclear) DNA age faster and die earlier.  This has generally been taken as proof that mitochondrial mutations are a factor in aging, but it need not be so.  In fact, mitochondria function well with a high tolerance for genetic errors, and it is not clear whether levels of mitochondrial mutations in aging humans cause significant problems, or even whether mutations are related to the general decline in mitochondrial function with age.  An alternative explanation for the mito-mutator mice is that they have developmental problems already in utero, and these may lead to premature aging even without accumulation of mito mutations.

Mitochondrial mutator mice

Stem cells keep dividing and producing new functional (differentiated) cells through the life of the animal.  They seem smart enough to minimize the damage from mitochondrial mutations.  Stem cells have been observed to hold on to the best mitochondria, and pass the damaged ones off to the cells that have a limited lifetime. This helps keep the errors from proliferating, and is in the best interest of the organism as a whole.  It’s interesting that mother budding yeast cells do the opposite—they hold on to their damaged mitochondria and pass the cleanest and purest on to their daughter cells [ref].  Mammalian mothers also seem able to choose the best mitochondria to pass to their daughters, purifying the germline [ref].  In other words, though their behavior is the opposite of stem cells, both behaviors are adaptive for the long-term interest of the organism (and its progeny).

In summary, the age-related increases in oxidative damage and ROS production are relatively small and may not explain the rather severe physiological alterations occurring during aging. Consistent with this hypothesis, the absence of a clear correlation between oxidative stress and longevity [across species] also suggests that oxidative damage does not play an important role in age-related diseases (e.g., cardiovascular diseases, neurodegenerative diseases, diabetes mellitus) and aging. Experimental results from mtDNA mutator mice suggest that mtDNA mutations in somatic stem cells may drive progeroid phenotypes without increasing oxidative stress, thus indicating that mtDNA mutations that lead to a bioenergetic deficiency may drive the aging process [but this is not assured, since these mice seem to suffer substantial damage already in utero]. There is as yet no firm evidence that the overall low levels of mtDNA mutations found in mammals drive the normal aging process. One way to address this experimentally would be to generate anti-mutator animal models to determine whether decreased mtDNA mutation rates prolong their life span. [Bratic & Larsson review]

 

Mitochondrial evolutionary conundrum

Mitochondria reproduce clonally, like bacteria.  In fact, all the mitochondria in your body were inherited from one of your mother’s egg cells, and she got her mitochondria from your maternal grandmother, and so forth back in time—matrilineal all the way.  How is it that defects don’t accumulate in the mitochondrial genome?

As far as I know, the way in which the integrity of the mitochondrial genome is maintained remains an unsolved problem.  We do know that mutations in mitochondrial DNA increase with age in some tissues but not others [ref].  The reason you have to speak up when you talk to your grandmother is probably related to mitochondrial defects in neurons [ref].

Over the course of millions of years, mitochondria do not lose their genetic integrity, though the mitochondrial genome evolves more rapidly than the nuclear genome, and different species tend to have distinctive mitochondrial genomes.  The mystery is why detrimental mutations should accumulate over decades, but not over aeons.

To me, this is powerful evidence that there is a mechanism for managing the evolution of the mitochondrial genome.  It probably involves selection by the cell so that mitochondria that are functioning efficiently are encouraged to reproduce.  The cell acts like a human lab that is breeding tomatoes or Labrador retrievers for specific characteristics that the breeder or the cell finds most useful.  Probably there is also gene exchange among the different copies of the plasmid within a mitochondrion, and between mitochondria as they sometimes merge during the lifetime of a cell (my speculation).

 

What’s going on?

A theme in this blog (and in my thinking) has been that aging is not a dispersed process of locally-occurring damage, but is centrally orchestrated.  Well, mitochondria are about as far from “central” as you can get.  We have about a quadrillion of them, dispersed through every cell in the body (except red blood cells).

Mitochondria talk to each other within a single cell.  They merge and they reproduce, coordinating with one another and with the cell nucleus.  Now it appears they also send signals through the bloodstream (more next week).  Could they be acting like a single organ, dispersed through the body? Maybe.  Sensing the body’s state of energy usage and fuel sufficiency, they send signals that contribute to calculations about lifespan.

My guess is that aging is coordinated by a few biological clocks (centralized like the suprachiasmatic nucleus and the thymus or dispersed like telomeres and methylation patterns), and that mitochondria are not counted among the clocks.  But mitochondria are important intermediates.  The old story is that they generate energy and generate tissue-damaging ROS.  The new story is that they are also centers of signal transduction, probably based on their first-hand knowledge of the energy status of the body.

End of Part I.
Next week, I will discuss some supplements
and health strategies based on mitochondria.

Preventing Dementia

Abating Risk of AD

Dementia seems to appear out of nowhere.  People feel like helpless victims of their genes.  But this is a misconception.  How much does the dreaded ApoE4 gene increase your chance of getting dementia?  This is not a straightforward calculation precisely because the correlation must be controlled for many diet and lifestyle factors that are proving to be just as important as genetics.  For women with ApoE4 from one parent, risk of AD is doubled, but this factor is easily reclaimed with diet, exercise and supplements.  For men, the effect of one copy of ApoE4 is small enough to be lost in the noise.  For men and women with two copies of ApoE4, risk of AD is very high, but even here factors under your control offer hopeful remediation.

I confess that I love public attention.  For a long time, I thought of this as a personal failing, and consciously avoided pursuing publicity.  When I came up with radical notions about evolutionary biology and the direction of medical research, I counted on people to think for themselves and evaluate the evidence; if they looked only at the credentials of the theorist, I was seriously outgunned.

Reputation shouldn’t matter, but it does  Only in the last decade, I have come to realize that people are receptive to ideas from those they already trust, and skeptical of ideas that come from an unknown source. I’m learning to burnish my reputation…

So when I got an inquiry from a CBS news intern asking “What can we do to improve our odds of avoiding dementia?”, I set aside time to review the literature before I talked to him.  Here’s what I found.

 

Exercise is most important

Five areas that I investigated are:

  1. Physical exercise
  2. Mental stimulation and social factors
  3. Metabolic syndrome / insulin sensitivity
  4. Diet
  5. Brain-targeted drugs and supplements

As I set out on my quest, I was prepared to find that #2 was the most important.  For longevity, social connections are more important than anything else; and I reasoned that for keeping the brain healthy in late life, this should be even more true.  But I was surprised.  #2, mental stimulation and social factors are effective in some studies but not others.  The clear winner in the literature is #1.  There is robust evidence that physical exercise lowers your risk of dementia.  Here’s a meta-analysis from 2011 and a review from 2017.  Modest amounts of exercise are way better than being a couch potato.  There is some extra benefit from being a gym rat, but there are diminishing returns with intensity.

Social connection and intellectual stimulation

The most positive study connecting social factors with a slowing of cognitive decline was in 2001.  A team from UCLA followed 1200 men and women over 7.5 years, and concluded that, among social factors, “emotional support” was the most important factor.

But in subsequent studies, the importance of emotional support faded.  In a review in 2010, no social variables made the list of protective factors.  And this 2016 study found social connectivity to be connected to base levels of cognitive function at midlife but not to 20-year change in cognitive performance.

 

The MIND diet

Of several diets that have been tested for neuroprotective benefit, the MIND diet, developed by Martha Morris of Rush University in Chicago seems to be the best documented.  In the only test so far, Morris claims it can cut AD risk by 50%.  The M in MIND is for Mediterranean, of which the MIND diet is a variant.  Start with lots of leafy greens, berries and nuts, fruits and vegetables, olive oil, whole grains and fish for protein and omega 3s.  The MIND variant emphasizes blueberries and walnuts, which seem especially good for the brain. [Details at WebMD]

Habitual coffee drinking is associated with a modest decrease in risk [2016], but tea, especially green tea is better [2015].   This study [2006] found a factor of 2 benefit for the heaviest tea drinkers in Japan.  Caffeine seems to be moderately neuroprotective [2008], but the best benefit comes from catechins=polyphenols, for which decaf tea works as well.)  Green tea is part of the MIND diet.

 

Metabolic Syndrome

Beginning 20 years ago, a strong association was found between metabolic syndrome and AD [1997].  Insulin treatments seemed to worsen the risk [1999] — indeed, excessive insulin seems to be at the heart of the connection.  Some people started saying we should think of AD as type 3 diabetes.  Metformin is the standard treatment for diabetes, and this study [2011] found that taking metformin brought the risk of AD in diabetics back down to a rate comparable with age-matched non-diabetics.  But this study [2013] found that taking metformin actually increases risk of AD.  A strong hypothesis is that metformin uses up vitamin B12.  B12 is essential for functioning of neurons, and is concentrated in the brain.  Many people are deficient in B12 even without metformin, and anyone taking metformin should be supplementing with B12.  Whether there is residual risk of AD from metformin even with B12 remains to be seen, but probably it’s not just people on metformin who should be supplementing with B12 [2014, 2015].  Low protein diets are protective for many aspects of aging, and the MIND diet is mostly vegetarian.  B12 is one essential nutrient that can’t be derived from vegetable sources.

 

Drugs, Hormones and Supplements

The most common pharmaceutical approach is to enhance the neurotransmitter acetylcholine.  Acetylcholine is found wherever nerves are found, for cognition, sensation and motor control, and it seems especially imortant for memory.   Alpha GPC (glyceryl phosphoryl choline) is an acetylcholine precursor which can be taken orally.  In this study [2003], 132 AD patients taking Alpha-GPC tested better after 90 and 180 days than at the outset, compared to worsening in those taking placebo.  Whether A-GPC is nootropic or neuroprotective is less clear.  Here is a bibliography from Examine.com.

I’ve been slow to recognize the potential of angiotensin receptor blockers (ARBs), prescription drugs which seem to be a new class of age-slowing drugs which I have not discussed previously.  The best known is Losartan. This study [2010] found a 25% reduction in AD.  And in studies with rats, ARBs increase lifespan [2009].  They work by relaxing the arteries, lowering blood pressure, relieving in the process the risk of all cardiovascular diseases.  The trouble with ARBs is that people don’t like them.  Some people feel lethargic, weak and unmotivated.  Some people cough.  Telmisartan is supposed to be the drug in this class with the least side effects.

Both male and female sex hormones are protective against dementia [2017].  A modest way to get this benefit without taking sex hormones is by supplementing with DHEA.  DHEA levels decline with age, and serum DHEA is lower in AD patients, suggesting but not proving that DHEA might be protective.

Pregnenolone is another hormone precursor, and in fact the body makes DHEA from pregnenolone.  As with DHEA, we have less pregnenolone as we get older.  Studies with mice have found pregnenolone leads to increased memory retention in the here and now.  Evidence that it is neuroprotective is lacking.

Poor sleep quality, sleeping more than 8 or less than 7 hours per night, and sleep apnea are all risk factors for dementia [2016].  The effect is large, but the data is thin.  Sleep is commonly disrupted in AD, with melatonin levels that are low and not synched to the circadian cycle.  Melatonin supplementation is a natural thing to try, and there has been some limited success with melatonin as a treatment for AD [2010 review].  I found no data on whether it helps as a preventive, but sleep-inducing pharmaceutical alternatives are associated with increased risk.

 

Honorable mention

These supplements are reported to be neuroprotective or nootropic or both.  It’s interesting to me that there is an overlap.  We don’t have to choose “now or later”, but can have our cake and eat it, too.

Primarily nootropic Primarily neuroprotective
Bacopa
Ginkgo biloba
Ginseng
Gotu kola
Huperzine
Piracetam
Lion’s Mane Mushroom
Acetyl L-Carnitine
Ashwagandha
Nigella sativa (=kalonji=charnoucha)
Curcumin (turmeric)
Ginger
Omega 3 fatty acids
Alpha lipoic acid


Hope for the doubly unlucky

One person in 50 has two copies of the ApoE4 gene.  Age-adjusted risk of dementia is more than 10 times higher for both male and female.  For these folks, there is a theory [1989] that keeping blood cholesterol low can completely ameliorate the risk.  The theory comes from a mechanistic analysis and extrapolates from the odd fact that Nigeria has the highest prevalence of ApoE4 in the world, but there is no elevation of dementia.  More recent [2016] is speculation that ApoE4 carriers need much more omega 3 than the rest of us.

My favorite Alzheimer’s study comes from Dale Bredesen at Buck Institute [2014], who offered intensely personalized treatment protocols to ten Alzheimer’s patients, and dramatically improved cognitive performance for 9 of the 10.  This is a stunning example demonstrating what medical science is capable of when institutional barriers are removed and clinicians have time to work with patients individually.

Dale Bredesen

Bredesen’s work offers incidentally the hopeful possibility that the benefits of some of the measures I have described are cumulative, and that with carefully crafted individual programs they can be combined to push Alzheimer’s risk back many years.

Aging Gets Personal

Writing this blog has introduced me to a community (that’s you) with which I have shared a great deal of information, and from which I have learned more.  You have become dear to me.  Now I’ve been away for many weeks, away from my home (Philadelphia) and away from this blog.  I’ve been in California and Switzerland and (now) China.  Here are some snippets of what I’ve learned and what I’ve been thinking.


My mother was proud of me when I was a physicist, but since I took up the study of aging she only shakes her head and stops just short of calling my work immoral.  She has been a lifelong advocate for population control and family planning.  “There are already too many people in the world.  When people started living longer, the population started booming.”

She is 95, posts a living will on her refrigerator, in her purse and in her car.  She wears beaded jewelry that says, “Do Not Resuscitate”.  But when she had a stroke last month, a neighbor called 911, and the medics did what they are trained to do.  I spent several weeks by her bedside, and making arrangements for her rehabilitation and physical therapy.  Her mind and speech seem unaffected, but she sees it as a grave injustice that she is still alive.

This has been an opportunity for me to examine my attitudes toward death and the prejudices of my culture.  Still raw, I have only questions, not answers…

  • How can we reconcile Ecology’s iron law that there is no life without death with the foundational sentiment of all human morality that tells us every human life is sacred?
  • Is every experessed wish for death an expression of despair or depression?  Is it always a call for help, or is there ever a situation where we should honor a person’s wish to die?
  • If we honor and work toward fulfilling an individual’s wish for added years of life, should we equally honor another individual’s wish for a prompt and painless end?
  • If our culture embraces the legitimacy of a wish to die, how can we prevent the Vonnegut scenario: social pressure to commit suicide because someone is disabled or different or just because many people wish to get rid of him or because it is a burden to care for him?
  • What can we learn from the way death is regarded in other cultures?  When someone over 80 dies, the Chinese are prone to treat it as a rite of passage, rather than a cause for mourning.

My encounter with hospitals and insurance served to instantiate and reinforce my dim views of the American system.  Limitation of liability everywhere impedes effective care for individuals.  “What is covered” is more important than “what is best for the patient,” and coverage is maddeningly arbitrary and variable from one policy to the next. Doctors, by and large, are kindly with the best of intentions, but their brains are fried by quotas and schedules; they have no time to work with a patient, to listen to symptoms, to explore diagnostic possibilities and treatment options.  Most know less about diet, exercise and supplements than you do, dear reader.  Hospitals will do everything to keep the patient from dying on their watch, but nothing to put individuals under their care on a path to long-term health and wellbeing.

 

Back to Biology

While in California for my Mom, I had a chance to make three visits to colleagues in the biology of aging.

From Andy Mendelsohn, I learned that a stem cell can be made to differentiate into a particular kind of somatic cell by one or a few transcription factors. Furthermore, you don’t have to start with a stem cell; applying these same factors to a different kind of somatic cell re-directs it toward the target of the transcription factors.  For example, applying the nerve cell TFs to a skin cell can turn a skin cell into a nerve cell.  Andy raised the possibility that this re-programming process is rejuvenating.  What would happen if you applied the skin cell TFs to an old skin cell?  Would it become a young skin cell?  This is an area ripe for experiment!

Andy also reminded me of a topic I wrote about 4 years ago: the hypothalamus as an endocrine aging clock, and the role of inflammation in suppressing two anti-aging hormones, to wit, GnRH and NPY (gonadotropin-releasing hormone and neuropeptide Y).  If there is a centralized clock at the root of aging, the hypothalamus is currently our best candidate for its location [ref, ref].  Both these are small proteins.  NPY has a short residency time in the blood, and there is yet no practical way to increase its level, but GnRH is normally released in pulses, and might it might be easy to enhance these artificially; in fact, there are several synthetic variations of GnRH sold as drugs.  The fact that they suppress male sexuality is a deterrent to experimentation by most men.

I learned that Elissa Epel has begun a long-term project to collect and share data on lifestyle habits for health and longevity.  She plans to develop a cell phone app both to remind and encourage and also to record metabolic responses.  Users will be able to learn what is working for their own individual bodies, and to share information so that others can benefit from their experience.  For Epel as a researcher, the payoff is crowdsourced data from which to study correlates of good health and long life.  I signed up on the spot to be her statistician. TrackYourLyf.com is under development.

The third visit was with Mike and Irina Conboy – see below.

 

Geneva Symposium on Anti-aging Medicine

I was honored to be invited to a small symposium in Geneva last week, sponsored by the St Petersburg laboratory of Vladimir Anisimov and Vladimir Khavinson.  I spoke on my favorite topic these days: the potential value of quick-and-dirty screening for combinations of age treatments that might synergize to induce major increases in lifespan.  I proposed a medium-scale experiment with 1300 mice that would test all combinations of 3 treatments among a pre-selected universe of 15. This size of experiment seems to be a statistical sweet spot for combinatorics.

The most revealing talk from my vantage was Claudio Franceschi’s glimpse into broad effects of the gut microbiome, a topic which I’ve written about recently.  Diversity of our intestinal flora decreases with age.  Centenarians seem to have different microbiomes from the rest of us, with an enhanced role for allochtonous flora, which just means niche-adapted bacteria [ref].  We are used to thinking of allochtonous bacteria as associated with infections and pathology.  They prompt an inflammatory response in the host (that’s us) to a greater extent than other bacteria.  Why would there be more of these in centenarians?

There is a powerful interaction between the microbiome, the immune system, the endocrine system, and the central nervous system [ref].  Presently, high fiber diets are the only generally-agreed path toward healthy microbiomes.  Fecal transplants and probiotics are of uncertain value with respect to long-term health.  Here’s a paper from 6 years ago in which a particular strain of yoghurt bacteria (LKM512) was introduced into intestines of mice with dramatic effect on their mortality.  The field is developing rapidly now that people appreciate how important it is.

Given the sponsors of the one-day symposium, I was not surprised to see an emphasis on short peptides.  These are micro proteins, just 3 or 4 amino acids strung together, that have been studied in St Petersburg with remarkable results: extension of lifespan in mice, and halving the mortality rate among older experimental subjects who receive peptide supplements.  Why isn’t anyone trying to replicate these studies in the West?  Khavinson has leapt ahead to open a clinic in St Petersburg where various peptides are prescribed for various ailments, and one of the peptide docs has a satellite clinic in Italy.  I met an American doctor who runs a clinic in Alaska where you can buy oral versions of epitalon and other peptides from a British company.  But the British web site does not list chemical compositions of their brand-name peptides, and though Dr Lawrence is full of enthusiasm and anecdotes, there is no data nor plan to collect data on their effectiveness in humans.  To my mind, this is a case of commercialism leaving science behind.

Which brings me to one more topic…

 

Plasma Transfusions for Rejuvenation, Ready or Not

In the news this week is Ambrosia, Jesse Karmazin’s company which provides transfusions of blood plasma from young donors to old recipients, who pay about $8,000 for 1.5 liters of blood.  When I first spoke with Karmazin nearly two years ago, he told me he had analyzed Stanford Hospital data on hundreds of patients who had received transfusions for various reasons.  He made the remarkable claim that he was able to trace the source of the blood in these transfusions, and found that patients who had received transfusions from young donors had had lower mortality and significantly better outcomes than those who had been paired with older donors.  This is an impressive finding if true, but Karmazin refused to share his data with me, claiming “patient privacy”, even if all personal identifiers were redacted.  At the time, he said that his motivation was to boost research in the field, that plasma transfusions were already an approved procedure and needed no special FDA approval, and that he thought he could fund the project by charging costs to the experimental subjects.  When I exchanged emails with him this week, he said that the data generated by his company would be treated as “intellectual property” and not shared openly with the scientific community.

My opinion is that, based on mouse studies, plasma transfusions are a promising procedure, but we have yet to explore how much is needed, the frequency and severity of complications, what are the benefits and how long they last.  A medium-sized body has about 5 liters in circulation.  Is 1.5 enough to make a difference?  That these experiments will be done is a huge step forward, but the benefit depends on data that is made available to the scientific community.  If the result is dramatic age reversal, we will all know about it pronto.  But if (more likely) the result is nuanced, we might be starved for balanced information.

One other company experimenting with human subjects is Alkahest, founded by Tony Wyss-Coray of Stanford.  Alkahest has received approval to do a trial with early-stage Alzheimer’s patients, using 2 liters of blood from a young donor, spread over 4 weeks.  The endpoints they will be examining involve cognitive function.

Wyss-Coray has voiced scathing charges of irresponsibility against Ambrosia.  Meanwhile, Berkeley’s Irina Conboy (in a private conversation last month) has been highly critical of Alkahest.  It was Conboy who originally brought the idea of parabiosis experiments to a Stanford lab 15 years ago, where she and her husband Mike and Wyss-Coray and Amy Wagers (now at Harvard) were all students together.  She said that Alzheimer’s was the wrong target, that the amount of blood being provided would not be enough to make a difference, and that repeat transfusions exposed patients to the risk of anaphylactic shock if some patients’ immune response to the alien proteins got out of hand.

The Conboys have been working on isolating the active ingredients that make old blood harmful and young blood beneficial.  I asked how that work was progressing.  While they would not share details, they said that early hopes for a small, manageable number of active factors had not panned out.  They were hopeful, however, that all the necessary factors belong to a few major pathways, and that transcription factors could be identified that would selectively activate these pathways.  From a New Scientist article:

Older people who received transfusions of young blood plasma have shown improvements in biomarkers related to cancer, Alzheimer’s disease and heart disease. Since August 2016, Ambrosia has been transfusing people aged 35 and older with plasma – the liquid component of blood – taken from people aged between 16 and 25. So far, 70 people have been treated, all of whom paid Ambrosia to be included in the study. The first results come from blood tests conducted before and a month after plasma treatment, and imply young blood transfusions may reduce the risk of several major diseases associated with ageing.

None of the people in the study had cancer at the time of treatment, however the Ambrosia team looked at the levels of certain proteins called carcinoembryonic antigens. These chemicals are found in the blood of healthy people at low concentrations, but in larger amounts these antigens can be a sign of having cancer. The team detected that the levels of carcinoembryonic antigens fell by around 20 per cent in the blood of people who received the treatment. However, there was no control group or placebo treatment in the study, and it isn’t clear whether a 20 per cent reduction in these proteins is likely to affect someone’s chances of developing cancer.

The team also saw a 10 per cent fall in blood cholesterol levels. “That was a surprise.” This may help explain why a study by a different company last year found that heart health improved in old mice that were given blood from human teenagers. They also report a 20 per cent fall in the level of amyloids – a type of protein that forms sticky plaques in the brains of people with Alzheimer’s disease. One participant, a 55-year-old man with early onset Alzheimer’s, began to show improvements after one plasma treatment, and his doctors decided he could be allowed to drive a car again. An older woman with more advanced Alzheimer’s is reportedly showing slow improvements, but her results have not been as dramatic.

 

The Only Experimental Subject Who Matters

We have come to expect that clinical trials require thousands of participants, tracked over years or decades.  Even for measures of clear long-term value like exercise and vitamin D, the trends have to be wrenched from the scatter with statistical vicegrips.  The message in this situation is that individual responses to any intervention vary widely, and the individual variation is far larger than the average effect.  Does this suggest an individual strategy for your personal health?  One man’s food is another man’s poison.  You are not an average.  There’s enormous potential benefit if you can figure out which side of the curve you fall on.  Of the many supplements and diets and practices that are beneficial to some people but not others, which is most helpful to you?

Headline: Soon, Medication Will be Custom Tailored to Your Specific Genetics

Everyone agrees that individualized medicine is the wave of the future.  You don’t have to wait for a gene map that tells you exactly the right treatment for your personal gene combinations.  With a little patience and discipline (ok—maybe a lot of discipline), you can find out for yourself.  What you need is a system for trying many different ideas—the more diverse the better—and a notebook or spreadsheet for recording what you notice.

There are many conditions at which Western medicine excels.  Vaccines have wiped out polio, which left my father with a right leg 4 inches shorter than his left.  If you have appendicitis, don’t hesitate to get an appendectomy, and if you contract malaria, thank science for quinine.   

But there remain many conditions for which Western medicine has no answer, and standard practice is to mask symptoms with temporary expedients.  It means only that medical science has not identified a cure that works for everyone; there may well be something available that can cure you.

All of “evidence-based” medicine is derived from studies of many people, usually thousands of people, sometimes millions of people.  The usual situation is that individual responses vary all over the map, and what is reported is the average.  

If there’s an absolute cure, no side-effects, no recurrence, but it only works in 20% of the subjects, you won’t even hear about it.  If there’s a cure that requires discipline—for example, a rigorous exercise program or a severely restricted diet–you’ll never hear about it even if it works for everyone, because the study will be undermined by “compliance issues”.

Of course, let’s learn all we can learn from large-scale studies.  But don’t let’s stop there.  The one experimental subject you care about is the one over whom you have the most control.  You are not an average, but you are knowable—your tolerances and your limits, your preferences, your individual and highly specific response to a medication or a diet or a new rhythm of sleeping and waking, of discipline and free play, of working and working out.

The procedure is perfectly straightforward and common sensical, though few people are doing it.  It is the essence of the scientific method:

  • Choose one condition to focus on.  Prioritize what will have the greatest impact on your wellbeing, but also consider what has clear symptoms you can feel or measure.  Start with something about which you feel open-minded and optimistic—you can advance later to chronic conditions for which you may have abandoned hope.
  • Choose a treatment or change in life habits that you think has a chance of addressing that condition.  (Guidance for this step below.)
  • Decide how long is a fair test.  Naturally, an approach that offers results in with a few days is easier to test than something that you suspect will take a year.  (We’ll use “two weeks” as an example.)
  • Choose a time when you expect a routine that is typical for you.  Better not to start at a time when you’re traveling or beginning a new job or a new relationship.
  • Begin keeping records.  Every evening without fail, record a number that codes how well you’re doing with this condition.  Add a few words of description if you like.  Keep your record in a diary, a notebook, or (if you’re comfortable with them) in a spreadsheet.  Begin with a two week reference period, life as usual.
  • Then begin your first treatment period.  Keep records for another two weeks.
  • Only at the end of the first four weeks, look back at your daily records.  Can you see any difference between the reference period and the test period?  It may be clear at this point that this treatment isn’t working, and it’s time to try something else.  But unless you’re pretty sure, give it at least one more trial period: two weeks off and two weeks on.
  • At this point, you have a decision to make.  You have recorded your subjective judgments, and now you step into the role of objective scientist to make the decision based on your data.  Was there a clear difference between the test periods and the control periods?  (Secondarily, ask, “is this something that it is easy to continue doing?”) You’re not desperate—there are lots of other things you can try.  Make a decision to
    • Drop this idea for now and try something else.
    • Keep doing this, and add a new treatment.
    • Keep doing what you’re doing—it looks as though it solves the issue completely.
  • Repeat until you are where you want to be.

 

How do you know if it’s working?

Some kinds of feedback are easier than others.  The most difficult concern your long-term risk of getting cancer or heart disease, but even here you may be able to find surrogate measures that provide a good indication of what is helping.

  • The easiest case is objectively measurable.  If you are interested in losing weight or lowering blood sugar or increasing sprint speed or the number of pushups you can do, it’s obvious what to measure.  (There’s emerging technology for checking blood sugar frequently, without finger pricks, available from several sources [Dexcom, iHealth, Abbotts, review].)  
  • More subtle are subjective feelings, including chronic pain, congestion, stiffness, anxiety, wellbeing, engagement, enthusiasm, mental focus and physical energy.  Only you can judge; but it’s easy to fool yourself, and perceive patterns that don’t stand up to scrutiny.  Your best strategy is to keep meticulous daily records.  Rate your pain or your energy on a scale from 1 to 10.  How many hours were you able to work undistracted?  Record, too, brief, qualitative descriptions of your mood and energy level and your creative output.  Don’t review these until the experiment is complete, and then look back and evaluate your record as objectively as you can, comparing “on treatment” and “off treatment” times in the aggregate.  (For this stage, you may find it helpful to engage a friend to evaluate your written account more objectively.)
  • Yet more subtle are indications from our bodies that offer a clue to what is good or bad for us.  Many of us have been raised in a culture which tells us to pop an aspirin and show up at work no matter how miserable we feel.  Yoga and meditation practice can lead you back to an intuitive sensitivity to your body.  Mindfulness practice can re-sensitize you to subtle body signals that you have learned to ignore.

Blood tests are useful for longer-term experiments.  A1C is an indication of average blood sugar.  C-reactive Protein tracks with the body’s inflammation level and correlates with cardiovascular risk.

Many of us are interested in long-term benefits that are unlikely to show up in a two-week test.  These experiments are not more difficult, just slower.  Test at intervals of 6 months to a year.  There are commercial telomere tests available that can plot one indication of your biological age.  Horvath’s DNA methylation clock can be used to track a set of markers that is, collectively, a more robust, objective indicator.  For these long-term tests, we don’t have the luxury of trying one test at a time, (one year on – one year off?) but we can try a combination of lifestyle changes based on a hunch, then check our progress annually to see if we are on the right track.

 

What to try?

  • Do I sleep better if I do Qi Gong before bed?
  • Do I get more done at work if I bicycle than if I drive?
  • Does my blood sugar go down if I don’t eat wheat?
  • Is daily aspirin making my back less stiff?
  • Does bacopa improve my creative output?

A friend of mine, a PhD biochemist, jumped into action when his sister-in-law was diagnosed with glioblastoma.  This is a devastating form of brain cancer that is almost always fatal within a few months.  But, scouring PubMed, Greg located three unrelated, obscure studies from the past in which safe and available supplements led to complete cures in a minority of subjects. He found the three ingredients—one from an off-shore source—but he couldn’t get permission to administer them until his sister-in-law was in a hospice unit, deemed to be in her final hours.  But within weeks she was back on her feet, and now, two years later, she is still alive.

This is one model: look on the web for listserves with personal stories, or traditional medicines, or “failed” trials in the medical literature.  

I’ve mostly used Examine.com and LEF as fertile sources of ideas.  Suggestions from friends are perfectly legitimate.  Follow your intuition; hunches are the seed of many scientific discoveries.  (Don’t censor up front; the time for objectivity is in the evaluation phase.)

Keeping a Daily Spreadsheet Record (sample data – not real)

Develop your sensitivity
The controlled experiment is a powerful tool for learning about yourself.  But even more basic, paying attention to your inner life can be an important first step toward elevating your wellbeing.  We are all conditioned to keep mum about our inner state, men even more than women.  Simply paying attention to what is going on inside helps to avoid injuries and (in my unscientific opinion) helps to speed healing locally.  Notice your mood, your energy level, subliminal pains, productivity, ability to pay attention and connect to others.  It’s a habit that leads to more conscious choices and better alignment of your outer habits with your inner directions.