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.

Prolonging Life with Fecal Transplants

A game-changing result this week from the laboratory of Dario Valenzano (Max Planck Inst).  A single treatment of antibiotics in middle-aged fish followed by transplant of gut bacteria from young fish resulted in extension of mean lifespan by 41%, max lifespan by 30%.  Treated fish remained active at ages where untreated fish were slowing down.  I say “game-changing” because up until now the gut microbiome has been a fascinating but peripheral discipline in the study of health.  This single study raises the possibility that understanding the microbiome as a system could be a powerful new avenue toward health and longevity.  [Preprint of Journal Article]  [News Article in Nature]


There have been intriguing hints that the ecosystem of bacteria in the intestine have major effects on mood, on wellbeing and on disease.  But there has been no way to get a handle on the causal variables involved.  The mix of gut bacteria varies widely from person to person, depending on diet, genetics, social contacts and environment.  Thousands of species of commensal bacteria form a constantly-shifting ecosystem.  

Who is working for whom?  Do we think of the microbiome as a parasitic colony that manipulates the host’s biochemistry for its own ends?  or as as managed by the host (that’s your body)?

I’ve seen articles about the former proposition, but I’m skeptical because I can’t imagine an evolutionary mechanism.  It seems that these thousands of bacterial species don’t stay together from one individual to another.  They are not readily transmitted (in nature) as a group, except perhaps from mother to infant.  And if there is natural selection on the microbiome ecosystem as a whole, it must be for something that maximmizes opportunities for transmission.  It’s easier to imagine individual species, specialized to living in the human gut, that learn to gain an advantage over other species by manipulating the human metabolism in ways that favor that particular species over its rivals.

The latter possibility — that our immune systems have a handle on who may live and who may die in our intestines — is both easier to conceptualize and more promising.  It raises the possibility that part of the way the body regulates its own metabolism is indirectly, via bacterial secretions.  I have advocated the position that aging, like development, unfolds on under central regulation.  The medium for instructing the body in age-appropriate behavior is likely to be signal molecules in the blood.  Could it be that some of those signal molecules originate not in our brains or our endocrine systems, but in the bacterial reservoirs of our guts?

Background: Fish

Eleven years ago, Valenzano introduced African Killifish (Nothobranchius furzeri) as a new lab model for study of aging.  Evolved for a life cycle in short-lived African ponds that dry up after a brief rainy season, they have one of the shortest life cycles of any vertebrate.  As a grad student, Valenzano demonstrated substantial lifespan increases adding resveratrol to the fish’s water.

Loss of diversity is one of the ways that the gut microbiome is known to change with age, both in humans and in fish.

 

Background: Humans

There has been a great deal of study and writing over the last decade, but so far only one clinical intervention, plus this guidance for the general public: a high fiber diet encourages beneficial bacteria.

Four years ago, Michael Pollan wrote about microbiomes for the NYTimes magazine. Mark Lyte has connected the microbiome to psychology: depression, anxiety, maybe autism (popular article in the NYTimes two years ago).  Turns out that gut bacteria produce some powerful hormonal signals that go right into our bloodstreams and are decoded by our brains.  

Gut microbiomes vary widely from one individual to the next, but, strikingly, different sets of bacteria are able to perform similar services.  The bacterial gene profiles in healthy individuals don’t vary nearly so much as the specific component bacterial do [ref].  

In hospitals and in people treated with antibiotics, a new disease has arisen in recent years characterized by intestinal infection with a bacterium called Clostridium difficile.  Symptoms include chronic diarrhea, stomach cramps ad nausea.  The most effective treatment developed to date (90% cure) is a transplant of fecal matter from a healthy individual.  This can be accomplished with enema, but there is some indication that it is more effective if the fecal matter is introduced from the other end, into the stomach, and this has inspired freezing and encapsulation technologies to get around the disgust factor.

Beyond this one clinical application, there is speculation about treating other intestinal disorders with fecal transplants, including ulcerative colitis, inflammatory bowel, and Crohn’s disease, extending to Type 2 diabetes, obesity, and even flatulence.  Having the right mix of microbes is important for triglycerides, glucose regulation, and the insulin metabolism [ref].  There have been multiple studies in rodents and one (successful!) study in humans of fecal transplant to treat diabetes.  

Many of the diseases of old age, (arthritis in particular), are connected to autoimmunity.  Intriguing, if speculative, work has been done connecting gut microbiomes to autoimmunity [review].  Maybe the ubiquity of antibiotics in the developed world has led to a hyper-sensitivity, connected to increases in asthma, lupus, type 1 diabetes, possibly autism.  Maybe the mechanism by which this has hit us is through our gut microbiomes.

Nearly two decades ago, scientists put forth a concept called the ‘hygiene hypothesis’. According to this hypothesis, an improvement in personal hygiene as observed in the developed countries has led to an increase in the risk of allergic and autoimmune disease [ref]. Increase in incidences of various inflammatory and autoimmune diseases like inflammatory bowel disease (IBD), asthma, type 1 diabetes (T1D), and rheumatoid arthritis in the developed countries support this concept.

It is suggested that gut microbiomes are connected to immune function more generally.  Both in mice and in humans, resistance to sinus and bronchial, including pneumonia, has been demonstrated with the right kind of gut microbiota.

Gut microbiomes in supercentennarians have been analyzed, and differences from average people have been distinguished as specific bacterial familes that seem to be associated with longevity [ref].

 

Summary of the Killifish Results

Turquoise Killifish normally live 16 weeks (black line).  At 9½  weeks, fish were treated with antibiotics to kill their gut microbiota.  Those that received no transplant at all lived a little longer (purple line), and those that received gut biota from same-age fish (9 weeks) lived insignificantly longer (red line).  But those that received transplants from younger fish lived 22 weeks (green).

Fish that received young transplants were more active and showed more exploratory behavior later in life.  The authors performed proteome analysis on the microbiome as a whole, and found gene expression that suggested a stronger resistance to infections in the young-transplanted fish.  

Young fish transplanted with the microbiota of old fish quickly recovered their youthful biodiversity and their lifespans were unaffected.

Authors note that

  • Microbiomes of killifish are comparable in complexity to mammals, including humans.
  • Although short-lived, killifish suffer many of the same declines as humans in old age, including neurodegeneration, muscle loss, and increased risk of cancer, heart disease, and diabetes.
  • The four most abundant phyla of gut bacteria in the killifish are the same four that predominate in human intestines.
  • Like humans, fish lose diversity of their gut microbiomes with age.  The bacteria lost with age in fish and in humans include those that digest complex carbohydrates.
  • Fish in the lab have comparable lifetimes and comparable gut microbiomes to fish in the wild.
  • Microbiomes transplanted at 9 weeks persisted, and were mostly intact at the end of the fishes’ lives 10-15 weeks later.

The authors were able to characterize explicitly the network of bacteria associated with youth (and also with enhanced longevity), naming the specific species that seemed most important.  Some of the most important species were able to digest carbohydrates and ferment them into short-chained fatty acids, which are known to be anti-inflammatory.

In their “discussion” section, the authors suggest that the gut microbiome may be managed by the host (fish)’s immune system, and that management becomes lax in old age, allowing some commensal bacteria to disappear and more pathogenic types to predominate.  They go on to speculate that perhaps there is a feedback loop between the immune system and the gut microbiome that is activated with age: poorer management of the gut ecosystem by the host immune system results in takeover by bacteria that further weaken the host immune system, leading to a vicious circle.

Caveats

Remember that life extension percentages in short-lived species are always diluted when applied to long-lived species.  Sometimes they disappear altogether.  Resveratrol extends life of killifish by 60%, but failed to extend lifespan in most mice.

The microbiome transfer in killifish was done at 9 weeks of age, and it lasted the rest of their lives, which was another 8-15 weeks.  People live much longer, and the microbiome transplants would probably have to be repeated and maintained to have an effect.

Implications

Just in the last decade, the importance of the microbiome for many aspects of health has been uncovered.  But the microbial ecosystem has been considered too diverse, too irregular, too complex for study with the reductionist paradigms that Western science is so good at.  Transplanting entire microbiomes has proved to be quite feasible, however, if not to everyone’s taste.

If these results hold up (it looks to me like a very careful experiment, and Valenzano has an impeccable reputation), there is now strong motivation for studying microbiome transplants en masse, and this will certainly be accompanied by proteomic analysis.  It’s hard for me to imagine that life extension in humans will prove to be so simple as in killifish, but I wouldn’t be surprised if a host of benefits appear from youthifying our intestinal flora.

The intriguing possibility is that in addition to metabolic self-regulation by the rich network of hormones, RNAs and signal molecules, the body is also managing its metabolism by managing the bacterial mix in the intestine (and the chemicals they produce, many of which are bio-active).  A more disturbing possibility is that the gut’s microbial ecosystem manipulates the body for its own benefit; but I’d bet against this because it seems implausible from an evolutionary perspective.

Is fasting senolytic?

I am finishing a four-day fast today.  In the hope of synergizing senolytic modalities, I took 2.5 g of quercetin last night and another 2.5 g this morning.  I don’t take quercetin regularly, because studies in mice show that daily administration doesn’t lengthen lifespan, and may shorten it.  But for the present, quercetin is the most readily-available senolytic agent we have.  

It’s my speculation that fasting might prime senescent cells for elimination, in the same way that fasting has been shown to prime cancer cells for elimination by chemotherapy or radiation.  Valter Longo has been at the center of the latter research, and he tells me that he is testing the senolytic hypothesis now, with no results yet.

Quercetin is a flavonol found in many vegetables and fruits, especially capers, radishes, cilantro and onions.

Quercetin by itself has been found to be only a weak senolytic in mice, and it has not yet been tested in humans.  It is somewhat better when combined with dasatinib, but dasatinib is highly toxic and not something I would experiment with based on current knowledge.

People have asked about my fasting discipline.  I answer that different people have vastly different experiences, and you won’t know until you try for yourself.  I fast regularly one day a week, and when I take on a longer fast there is often a hump to get over on the second day, sometimes headaches and malaise.  I use enema to clear the colon on the second day, and often this seems to help.  I take caffeine daily while fasting, which is more than in my regular life.

The chief complaint I have after the second day is that I am too mellow, content to lie in bed.  No restlessness during sitting meditation.  Time slips by, and I feel no urgency about accomplishing anything.  I read things I might not otherwise find time for.  I go for long walks and entertain wide-ranging thoughts.

Senolytics against Aging: Snapshot of a Fast-Moving Field

Aging at the cellular level is called “cell senescence”, and it contributes profoundly to whole-body aging.  The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells.  Programs in universities and pharmaceutical labs around the world are racing to develop “senolytic” drugs, defined as agents that can kill senescent cells with minimal harm to normal cells.

Apoptosis is cell suicide, and (from the perspective of the full organism) it’s the best thing that can happen to senescent cells.  The authors of this newest Dutch study ask how it is that senescent cells escape apoptosis.  

FOXO is a protein that controls gene expression, a master transcription factor associated with aging and development.  (It is the homolog in mammals of the pivotal life extension protein first identified in worms as DAF16 in the 1990s.)  FOXO4 activiation in a cell can block apoptosis.  P53 is the most common trigger of apoptosis, the first protein biochemists usually think of in connection with apoptosis.  P53 has multiple functions in the cell nucleus, but as a trigger for apoptosis, it works through the mitochondria.  FOXO4 binds to p53 and blocks its induction of apoptosis.

The treatment studied in this paper is an artificially modified FOXO4, a dummy that binds to p53 in place of regular FOXO4, but doesn’t block senescence.  It has been named FOXO4-DRI, and it works by crowding out the native FOXO4.

The authors note, with caution, that mice with no FOXO4 at all appear normal; but apoptosis is an important cell function throughout the lifespan.  A cell must have “good judgment” about when to eliminate itself, and that works in both directions; in older animals and people, we not only see failure of apoptosis to eliminate senescent cells, but we also see healthy muscle and nerve cells undergoing apoptosis prematurely, and we lose muscle and brain mass as a result.  Other functions of FOXO4 include DNA repair, and mice that lack FOXO4 are subject to a high burden of DNA damage.

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for “selectivity index – 50%”) is defined by analogy to LD50 = the “lethal dose” of a toxin, the dose at which half of all cells die.  SI50 is defined as the ratio of LD50’s for normal and senescent cells.  It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die.  Authors of the current paper report SI50 about 12.  My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy.  After a standard dose is injected in humans, the cellular concentrations vary from person to person and from tissue to tissue. 

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection:

In other words, the vertical distance between the black and red curves is encouraging, but the horizontal distance is cause for concern.  Senolytic agent studied previously, including dasatinib, quercetin and ATTAC, did not include measurements of SI50 that we might use for comparison.

 

How does FOXO4-DRI perform in live mice?

Authors of this study were excited in a rush to publish.  They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves.  The indicatators of rejuvenation that they do report look positive:  increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.

 

Comparison to Last Year’s Senolytic

Here’s how authors of the current study characterize FOXO-DRI compared to two previously reported senolytic agents:

Two classes of anti-senescence compounds have been reported so far: Quercetin/Dasatinib, either alone or in combination [ref], and the pan-BCL inhibitors ABT-263/737 [ref, ref]. Quercetin and Dasatinib have been reported to be non-specific. We found no selectivity toward senescent IMR90 and therefore this cocktail was not explored further. ABT-263 and ABT-737 target the BCL-2/W/ XL family of anti-apoptotic guardians. Indeed, ABT-737 showed selectivity for senescent IMR90. However, already at low doses, it appeared to influence control cells as well. Also in a treatment regimen where both compounds were added in consecutive rounds of lower concentrations, FOXO4-DRI proved to be selective against senescence yet safe to normal cells.

I reviewed the Quercetin/Dasanatib paper two years ago.  It was an early proof-of-principle, using medications that are already known (and FDA approved).  But the 1-2 punch is not sufficiently selective–it is toxic to normal cells.

I missed the two papers about ABT-263  [ref] and ABT-737  [ref].  BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis.  Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2.  These two studies published in Nature last year, one from University of Arkansas, the other from the Weizmann Institute, both use radiation exposure to create a large population of senescent cells, and then show that the senescent cells are selectively eliminted by ABT.  The ABT-263 paper included some in vivo results, indicating enhanced growth of blood stem cells after senescent cells have been removed.  In vivo testing of ABT-737 was limited.  Neither group reports the selectivity index (SI50) as calculated by Keizer in the latest study; but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as FOXO-DRI.

DIS and OIS are the senescent cells; G and V are the control (normal) cells.  ABT 737 (the middle bar in each of the 4 sets) kills more than half the senescent cells, but at the cost of taking out ~20% of the healthy cells.

ABT-263 appears to be more selective than ABT-737.  Normal cells (left) are not noticeably affected at a concentration where ~70% of the senescent cells are eliminated (right).

The original marker used to identify and target senescent cells by the Mayo Clinic’s 2011 study was p16Ink4a.  The selective elimination technique they used (in 2011) was limited to genetically modified mice, but a year ago, a new paper from Mayo Clinic demonstrated a similar procedure for ordinary, non-GMO mice.  Twice weekly injections of an antibody that induced apoptosis in cells that expressed p16Ink4a extended lifespan of the mice by 25% – 30% compared to controls, comparable to the results in the 2011 paper.  Caveat: the control mice received sham injections that shortened their lifespans.

 

The Bottom Line

The idea of removing senescent cells has a lot of appeal.  Not only does it enjoy broad empirical support in mammals; it also pulls together several ideas about the origin of aging:

  • Parabiosis experiments and their follow-ons have convinced us that circulating chemical signals form the basis of an epigenetic clock.  Some of these circulating molecules are known to come from senescent cells.
  • Aging commonly accelerates exponentially with age, as though it were driven by a positive feedback loop.  Senescent cells secrete cytokines that make more senescent cells–there’s your feedback.
  • Short telomeres initiate senescent cells.  At any given time, there is a bell-shaped curve of telomere length among the body’s cells.  The tail of the telomere distribution contains a few cells that are driven to senescenceby having very short telomeres.

There is now a world-wide effort, making rapid progress toward specifity in senolytic treatments.  In other words, FOXO-DRI is the newest agent, and it shows the best ratio yet for killing senescent cells while avoiding collateral damage to healthy cells.  (It cannot be taken orally and must be injected, but perhaps this is not such a great drawback for a treatment that is needed only intermittently, every few years.)

How will such promising mouse results translate into human health and life extension?  We have as yet no data, not even anecdotes.  But perhaps we are near the point where hope and courage will motivate the first self-experimenting volunteers.  Caloric restriction and its mimetics produce much greater percent increases in lifespan in mice (2 year lifespan) compared to dogs (10 yrs) or monkeys or humans.  Senolytics work via a completely independent pathway; we can hope that percent benefits in humans will be closer to the mice.  Since this is about upregulating elimination of cells via apoptosis, the strongest benefits are likely to be against cancer, and mice are more vulnerable to cancer than humans.

This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up.  Sharing of information and resources could push this research over the top and give us the first full decade of human life extension.

Anti-aging breakthrough? This one looks authentic

Yes, there are too many reports the last few years of people announcing the end of aging.  But this, I feel, is the first time a drug has been discovered that has the potential to extend our lives by decades, with a few injections.

Background: As we get older, some of our cells become ‘senescent’.  They don’t just fall down on the job; they send signals out to the body which make us old and (especially) promote inflammation, leading to higher rates of cancer, heart disease and AD.  There are very few senescent cells—perhaps one in 10,000.  But they do enormous damage.

A few years ago, Jan van Deursen of Mayo Clinic showed that by killing off the senescent cells in mice, he could make them live 25% longer.  This was done with a drug, but the catch was that the mice were genetically modified.  Each senescent cell had a bomb in it, and all it took was delivering a trigger.  The treatment only worked if the mice were specially prepared (before birth) with this genetic modification.

This was 2011.  University labs  and drug companies around the world took appropriate notice, and they started working on ways to kill senescent cells without harming normal cells that would work in animals (including you and me) who have not been prepared ahead of time with bombs in their senescent cells.

Yesterday, scientists from the Netherlands announced successful deployment of a magic bullet that would kill senescent cells only.  It works in cell cultures, and it works as an injection in mice that have short lifespans.  (They haven’t had time yet to test it in fully normal mice, but in theory, it should.)

It’s a large molecule that you can’t take in a pill, because your digestive system would dismember it.  But it can be injected, and one dose ought to be rejuvenating.  I expect that people will be lining up to try this within a year, and that the injections will turn out to be needed only once in every few years.

My previous article on the subject
Link to Science News article by Mitch Leslie
Research Article