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.

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.

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.

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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.