A New Way to Live to 150?

Many years ago (40 years?), I began seeing articles in popular media about extending your life simply by eating less -- "caloric restriction" they called it.  It was noted that mice, yeast, and monkeys all lived longer if they consumed less calories -- sometimes what seemed like starvation level caloric restriction.  What was attracting attention were people doing extraordinary things to reduce their caloric intake (starving themselves) in the hope that they'd live to (as I read one man say) 150.  This phenomenon has been studied, and there is peer reviewed research (like this) about how that might work.

This suggests that anorexic people should live longer, but I wouldn't call that a good plan.  It may, however, relate to why intermittent fasting has such a positive effect on the chronic diseases (like Alzheimer's) that too often characterize old age.

I very often read about and hear from people wondering if there might not be a pill you can take that would do the same thing that fasting, dieting, and exercise do for the brain.  Well, there's a new candidate for something that might do that.  And not just the brain, perhaps every aspect of aging.  There's a "bile acid" called lithocholic acid (LCA) that might do it.  That's according to a research team at Xiamen University in China.  The acid apparently works by activating the metabolic master regulator AMP-activated protein kinase (AMPK).  Makes sense, right?  (If you figure that out, please let me know.) 

According to the researchers, significant caloric restriction  in people appears to improve metabolic health and markers of aging, even when people are not overweight to start with.  Tests with mice on Alzheimer’s disease suggest caloric restriction suppresses production of amyloid and tau and speeds removal of amyliod from the brain.  In us older folks, caloric restriction benefits working memory and processing speed but perhaps at the expense of our ability to conduct tasks that rely on good hand-eye coordination and cognitive flexibility.  But this means starving all the time and losing muscle mass, so it's not a good idea for most of us. 

According to this research, bacteria produce LCA in the small intestine when they break down primary bile acids.  LCA emulsifies fats to render them digestible.  But LCA can also be absorbed into the blood like other fatty acids produced by the microbiome, some of which improve the health of the brain.  

Remember the gut-brain axis?  Some really weird stuff goes on between the bacteria in your gut and your brain.  So take care of those bacteria.  (Eating beans and fermented foods, like kimchi, can help with this.  Some would add yogurt.  But aspartame and sucralose can be hard on the gut biome.)  

The scientists added LCA to the drinking water of some well-fed mice, and it activated AMPK in their skeletal muscles to the same degree seen in calorie-restricted mice.  While it didn’t extend their lifespans, it did boost their vigor: Old mice that ingested LCA ran farther on a treadmill and gripped a pressure-sensing bar harder. Their insulin sensitivity and glucose tolerance were better, and their muscles recovered faster after damage.  My reaction to this that, despite the promises, feeding people LCA may not actually extend your life.  But it's still improving important markers of Alzheimer's disease, notably insulin sensitivity and glucose tolerance.

So it seems like there's something here.  But all of these breakthroughs we keep seeing are frustratingly far from becoming reliable treatments.

How Bad Are Ultraprocessed Foods?

How bad are ultraprocessed foods?  Well, it depends on who you ask.

But first, what are we even talking about?  Back in August 2022, we discussed a relationship between a lifestyle of consuming ultraprocessed foods and Alzheimer's disease.  One thing we did in that article was explain what ultraprocessed foods are and give examples.  We also cited specific research associating things we eat that may qualify more as industrial products than food with the development of dementia.  For our purposes, in the Dementia Toolkit, we focused on the correlation of refined sugar and refined flour with inflammation and oxidation in the brain.  That's bad for Alzheimer's disease.  But the thought is that, beyond that, more bad stuff is going on with carbonated soft drinks, sweetened breakfast cereals, candy, packaged snacks, powdered instant soup, reconstituted meat products, etc.  These may (or may not) be causing the worldwide obesity epidemic, and obesity is associated with the development of Alzheimer's disease.

I came across a fascinating article in The New Yorker magazine that first looked at some interesting research conducted at the National Institute of Health but then interviewed some of the critics of the research.  The outcome was a sort of survey of diverse thinking on this subject.  And it is diverse.  

The concept of ultraprocessed foods was proposed by the Brazilian researcher we discussed in the 2022 article, but research aimed at confirming the hypothesis that anything meeting the definition of ultraprocessed food will put you in memory care has been mixed.  The research was published in the journal Cell Metabolism.  They weren't concerned with Alzheimer's disease, but rather obesity.  Does consuming ultraprocessed foods really cause obesity, or is that a myth?  And if so, why?  (Anything causing obesity will lead to Alzheimer's.)  

The answer is yes, it does.  But calorie for calorie, the influence on body mass is the same between ultraprocessed foods and real food.  It seems that, more than anything, people just like the soda and salami a lot more than real food, and so they eat a lot more of it.

The article did discuss the spectrum of foods that can be classified as ultraprocessed, noting that they're not all bad for you.  It kind of depends.  Yogurt without cane sugar can be considered ultraprocessed, but the article says that doesn't mean that it's bad for you.  (Exceptions: people with lactose intolerance and those concerned that dairy in general has a downside.)  Organic whole grain bread can also be considered ultraprocessed, but it's part of the MIND diet.  So some critics don't think there's been adequate discernment between the types of ultraprocessed foods that are or are not a problem.

How the research was conducted was quite interesting.  They took 10 men and 10 women and locked them away for a couple of weeks.  They were watched closely enough to make sure that no one ate anything that wasn't provided to them in the study protocol.  They were given as much food as they wanted to eat during 60 minute meal times, rotating between unprocessed and ultraprocessed foods at the end of each week.  Steps were taken to obscure what class of food people were being given.  Test participants were weighed at the end of each rotation of foods.

Participants gained an average of nearly 0.9 pounds after a week on ultraprocessed foods, but lost an average of about 0.7 pounds after a week on real food.  The authors concluded, "Our data suggest that eliminating ultra-processed foods from the diet decreases energy intake and results in weight loss, whereas a diet with a large proportion of ultra-processed food increases energy intake and leads to weight gain."

I try to stick with the MIND diet, avoiding ultraprocessed foods.  I do eat plain yogurt that I sweeten with allulose and monk fruit sweeteners (mixing in walnuts and blueberries), which might qualify as ultraprocessed.  And I eat a couple of slices of whole grain bread, as called for by the MIND diet.  But, even when I combine this diet with regular fasting, I still struggle to keep my weight where I want it.

Another day, another cognitive test

My care team began testing my memory and cognition annually in 2015.  I didn't get the 10 minute Mini-Mental Status Exam (the MMSE) or the minimally more sophisticated Montreal Cognitive Assessment (the MoCA).  No, it was the whole three-hour suite that probes every nook and cranny of your brain.  (Dr. Phatak discussed these tests in Beating the Dementia Monster.)  But in 2019, I was doing so well, they decided to relax it to every 2 years, and now I haven't had a test in almost three years.  They want to continue testing me triennially, but I'm able to get a sense for what's going on just in my daily activities.  For example, in a little while I'll have one of my practice sessions in Spanish with a friend in Ecuador.  How well will I be able to keep up the conversation?  I've been feeling pretty good about these activities for some time.  Nevertheless, my care team plans to test me diagnostically again this summer.

At the same time, I have been enrolled in a number of studies, mostly from the Alzheimer's Disease Research Center in Seattle.  One such study is referred to as vCog, and they want to see if these tests are just as valid if administered via Zoom as when they are administered in person.  So they have us take the test over Zoom, and then they test us a couple of months later in person.  And they repeat the whole process a year later.  Do the test results match?  Or do they show that tests administered via Zoom on your computer are less reliable than those administered in person?  We'll find out when they're done.  

But today, I had my last Zoom test.  And we should make the journey across the mountains to Seattle at the end of February for the last in-person test.  Since it's for research and not diagnostic, they're not allowed to tell me the results.  But I didn't have any trouble seeing that I did pretty well -- I feel very well about it all.  Of course, they will be able to share with me the results of the diagnostic tests I take this summer.

I've said this before, and I'll say it again.  Every morning when I wake up, I can hardly believe it.  I think back to how things were in 2015 -- when I was in free-fall -- to today, and I'm just amazed.  Of course, the first thing on the agenda every morning is a trip to the gym for an hour and a half.  That, along with the other members of the Dementia Toolkit, are the reason I can live the way I do.  Life is good.

Is Alzheimer's one disease ... or five?

We've said before that there seems to be more than one variation of the disease we call Alzheimer's.  Alzheimer's itself is characterized by the amyloid plaques around brain cells and tangles of collapsed microtubules inside dead cells.  We discussed in Beating the Dementia Monster how amyloid plaques and defective proteins in microtubules apparently kill brain cells.  In the form of the disease we call "young onset" or "familial" Alzheimer's disease, we see certain specific genes in play, and the symptoms appear when someone is in their 40s or 50s.  This differs from the form of the disease we call "old onset" or "sporadic" Alzheimer's, where symptoms don't generally appear before the age of 65.  Sporadic Alzheimer's (like mine) seems to be less influenced by genetic factors and more by lifestyle and environmental factors.  And genetic influence appears to be from different genes than those involved with young onset Alzheimer's, perhaps more than 30 different ones.

By the way, many researchers and doctors try to avoid the term "early onset Alzheimer's," because it confuses the age of the person with the stage of the disease.  Is it early in the persons life (like with young onset disease), or is it an early stage of the sporadic form of the disease but occurring when the person is, say, 80?

So we see here two varieties of Alzheimer's disease.  But can the disease be divided more finely?  Or is it possible that we really have more than one disease that we're dealing with?  In my opinion, we don't understand the disease well enough to say if there is more than one disease, but there is new evidence that we can discern at least five subtypes.  That's important, because it may be that experimental therapies that seemed to fail only failed because they were tried on one or two specific subtypes of the disease -- without realizing the therapy might be more suitable for another subtype.  Also, the varieties may progress differently, confusing expectations and treatments.

Research on different subtypes was published in the journal Nature Aging, "Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles."  Researchers, primarily from the Alzheimer's disease research center in Amsterdam, studied the cerebrospinal fluid of 609 people, examining the proteins they found.  Some study participants had normal cognition and no evidence of disease (the control group), while others had been diagnosed with varying stages of the disease.  Based on this evidence, the researchers believe they discerned five different subtypes of the disease. 

One thing that struck me right off the bat about these varieties was that subjects with one subtype went from the onset of dementia to death in an average of 5.6 years, while another subtype had an average survival time of 8.9 years.  That's a distinction.  Alzheimer's disease is the third leading cause of death in my state of Washington, and the sixth leading cause of death in the United States.  And, as we said in Beating the Dementia Monster, when I was 66, a researcher told me I was on track to be dead by the time I was 75.  That made sense, because at the time I was still in the mild cognitive impairment stage and so was still a few years out from actual dementia.  He also indicated that if I would just keep up my recent lifestyle changes, I could extend that 85.  And that seems to be what is happening, since I am now 75.  And I'm not dead.

But what are these five subtypes?  Well, if you're not a doctor or physiologist, they can be a bit hard to understand.  Or maybe a lot hard to understand, so we won't try to break them all down here.

But one subtype significantly weakens the blood-brain barrier (BBB), allowing trash to enter the brain from the blood.  As we discussed in Beating the Dementia Monster and in other posts on this blog, the BBB prevents larger molecules (including pathogens) from passing from blood into the brain.  This isolates the brain from the body's general immune system, so the brain must have its own immune system.  This system uses cells we call microglia.  Apparently, with this subtype, the BBB is weakened, and a variety of unwanted proteins enter the brain and begin to cause damage. 

In Beating the Dementia Monster, we said that problems with microglia could play a central role in the development of the disease.  Well, in another of these subtypes, the ability of microglia to protect the brain is impaired.  One thing the microglia are supposed to do is glom onto amyloid plaques and stop them from damaging cells.  But, in the variety here, the microglia are weakened, and their protective function is seriously reduced.

As we always hear, the authors of the study say more research is required.  And it's clear that a better understanding of these subtypes is important.  That will better inform research into treatments, since one treatment might better address subtype A than subtype B.  Also, some trials may have mistakenly found a treatment ineffective simply because it was tested on the wrong subtype.

I have always believed that there were more varieties of Alzheimer's disease than we recognized.  This research confirms my suspicions.

The Top Alzheimer's Discoveries of 2024 and my Cognitive Testing

For our blog, I try to be alert to what's going on in the world of Alzheimer's research, always looking for the next big thing.  When I find something that I think will interest you, I try to post about it here.  Of course, we have an array of readers with an array of interests.  Some say they get a lot out of posts about advances in research, while others tell me they're just interested in what's going on with me and my personal progress.

The twelve days of the Christmas season are in progress as are the eight days of Chanukah.  And so, New Years is only a few days away.  Every year in the media, this period is filled with reviews of the big events of the past year.  And something caught my eye -- an article in the New York Post, "Alzheimer's Discoveries Scientists Made in 2024."  I read it eagerly looking for something new, only to find that we have already covered pretty much all of their finds.  But here they are:

1.  A third new Alzheimer's drug was approved.  That was Kisunla, or, generically, donanemab.  We wrote about that back in July. 

2.  Blood tests could improve speed and accuracy of diagnosis.  We've been writing periodically on the progress of developing blood tests since 2018.  Here's an example.  My concern remains that a bad test result could prevent many from getting long term care insurance.

3.  Wildfire smoke raises risk of dementia.  We wrote about that in July.

4.  Alzheimer's causes physical changes in the brain.  This research "news" focused on the fact that things are going on the brain as much as 20 years before the first symptoms.  We explained that in the original Beating the Dementia Monster book several years ago, but popular media is just picking up on this now.  We wrote about this breaking news a bit cynically back in October.

My cognition hasn't been tested by my doctors for several years, partly because I don't see the point in it for now.  I'm clearly stable, and my memory and cognition are now consistent with normal aging.  That doesn't mean I'm cured; they tell me I've put the disease on hold for maybe 10 years.  Which is OK with me.

That being said, I am in several research studies that do some level of testing.  One of those is a project to validate cognitive testing done over Zoom.  They test me over Zoom, and then have me come to Seattle to test me the same way in person.  They do this annually for a couple of years.  Are the Zoom test results consistent with the in-person tests?  Once they've done enough tests with enough people they'll know.  

I have a number of things I watch in my own behavior as my personal, informal measure of how I'm doing.  Can I remember to lock my car door when I go to the store?  Am I driving well?  Can I speak or read in Spanish consistent with my history (something I do daily)?   My next Zoom test is in a week or two, and I'll have a more "official" read.  They won't tell me the results, but I've taken enough of these tests and seen how I was scored, that I can get a definite intuitive sense for where I'm at.  I don't anticipate anything disappointing.

An audiobook for Beating the Dementia Monster

So Dr. Phatak and I will be signing a contract with Echo Point Books to produce an audiobook of Beating the Dementia Monster.  Publication is still out by a few months, but it will be available on Audible (Amazon), Apple Books, Spotify, and some other platforms.  I had shied away from an audiobook, thinking it would confuse paper book sales, especially with respect to advertising.  But they tell me that people who buy audiobooks don't buy paper books and people who buy paper books don't buy audiobooks.  So this shouldn't cause confusion.

They will be using a professional voice actor to do the reading, so quality should be good.

I'm continuing to make videos for our YouTube channel.  YouTube tells me we've had over 1,000 views, but I'm still thinking of this as an experiment.  Production quality may be improving slowly, but it's still a lot of work to make one short video.  And they are short compared to others.  If you haven't been following a long, you're invited to come over to the channel and take a look.

A new virus linked to Alzheimer's disease - this one in your gut

We've written before about the herpes zoster virus as a potential culprit in the development of Alzheimer's disease -- the virus that causes chickenpox and shingles.  So we quoted some authorities who concluded from their research that the shingles vaccine may provide some protection from Alzheimer's disease originating from that source.  But now there's another virus under the Alzheimer's microscope, another member of the herpes family.  But, while herpes zoster inhabits the nervous system, this one lives in your gut.

The virus is called cytomegalovirus, or HCMV.  You may acquire it as a child and experience an apparently innocuous chronic infection in your gut.  Based on autopsy results, about 80% of us show evidence of having had an HCMV infection by age 80.  So it's pretty common. 

But the trouble starts when the virus either escapes the gut into the blood stream or follows the vagus nerve to the brain.  There it comes into contact with the brain's immune cells -- microglia.  In Beating the Dementia Monster we discussed the role that microglia may play in the development of the disease, notably by way of inflammation.  This somehow triggers the syndrome of amyloid plaques and clumps of microtubules with a defective form of tau protein that we associate with Alzheimer's disease. 

I choose my words carefully here.  It's increasingly clear that what we call Alzheimer's disease comes in different flavors which have different causes.  For example (as we explained in Beating the Dementia Monster), "young onset Alzheimer's disease" or "familial Alzheimer's disease" (which often strikes in someone's 40s or 50s) occurs in a different genetic environment from "sporadic Alzheimer's disease."  The latter is the common version, where symptoms begin to appear after the age of 65.  Are familial and sporadic Alzheimer's diseases exactly the same disease but with different causes, or are they distinct but slightly different diseases?  How many forms of the disease are there?  Or how many different disease are there that we label "Alzheimer's disease?"  Opinions vary.

There was a new study conducted by researchers from Arizona State University and Banner Alzheimer’s Institute on the possible role of HCMV in the development of Alzheimer's disease.  The findings were just published (December 2024) in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, with the title, "Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain."  The researchers concluded "[HCMV-microglia biochemistry] is consistent with an active HCMV infection, which may indicate an opportunity for the administration of antiviral therapy in subjects with AD."  Translation: "Stopping or preventing HCMV infections may be a way preventing or treating Alzheimer's disease."  But ... more research is required. 

Click here for more of a deep-dive on this topic.

We said here that there may be different varieties of Alzheimer's disease or even different diseases all labeled "Alzheimer's."  But, from everything I've read, they all respond to the lifestyle tools of the Dementia Toolkit.