The Long Game 35: Alzheimer's and Glucose Metabolism, Quality Time, Amp It Up, Open-Mindedness

📚 Self-Help Books, Ponzi Schemes in VC, the Dark Data Economy, Never Split the Difference and Much More!

Hi there, it’s Mehdi Yacoubi, co-founder at lifetizr, and this is The Long Game Newsletter!

Greetings from Paris 🇫🇷

If you missed the past episodes, you could catch up here.

In this episode, we explore:

  • Alzheimer’s & Glucose Metabolism

  • Quality Time

  • Active Open-Mindedness

  • Amping it up

  • Self-Help Books

Let’s dive in!

The city I’d want to live in in a few decades.


🥑 Health

🏥 A New Approach for Alzheimer’s?

Of the major diseases causing death, Alzheimer’s is undoubtedly the one we made the least progress on curing. As a reminder, here are the top causes of mortality in 2017:

  • Cardiovascular diseases (17.79 million)

  • Cancers (9.56 million)

  • Respiratory diseases (3.91 million)

  • Lower respiratory infections (2.56 million)

  • Dementia (2.51 million)

  • Digestive diseases (2.38 million)

Anyone interested in longevity has only one choice, for now. Living a long and healthy life is equivalent to delaying the onset of chronic diseases. That’s why Alzheimer’s is so important to study and eventually cure.

As we already covered here, David Sinclair explains in his book Lifespan that even if we cured all the major diseases causing death, we would only increase the average lifespan by a few years:

If we could stop all cardiovascular disease—every single case, all at one—we wouldn’t add many years to the average lifespan; the gain would be just 1.5 years. The same is true for cancer; stopping all forms of that scourge would give us just 2.1 years of life on average, because all other causes of death still increase exponentially. We’re still aging, after all.

Regarding Alzheimer’s, Vijay Pande from a16z argued that the cure for aging might be the cure for Alzheimer’s:

Aging doesn’t kill people—diseases kill people. Right? In today’s world, and in a country like the United States, most people die of diseases such as heart attack and stroke, cancer, and Alzheimer’s. These diseases tend to be complex, challenging, difficult, and extremely ugly to experience. And they are by nature chronic, caused by multifactorial triggers and predispositions and lifestyle choices.

What we are only now beginning to understand is that the diseases that ultimately kill us are inseparable from the aging process itself. Aging is the root cause.

He explains that “looking at aging will be our compass to the medicines of the future.”

Even if the ideal situation would be for Alzheimer’s researchers to join forces with aging researchers, right now, the Alzheimer’s field has one priority: trying different hypotheses and overcoming the ‘cabal’ that thwarted progress toward a cure for decades.

A few days ago, this paper: In Alzheimer Research, Glucose Metabolism Moves to Center Stage was published. Here’s the abstract:

Areas or patterns of reduced glucose metabolism are often seen in brain scans of patients with Alzheimer disease and other dementias. Now, a growing body of evidence suggests that glucose hypometabolism may be more than just a biomarker on brain scans: it may be a key player in dementia pathology.

At the Society for Neuroscience’s recent annual meeting, several research teams presented data on mechanisms that may hamper brain energy metabolism in Alzheimer disease—and potentially contribute to cognitive decline. At the same time, clinical researchers are exploring ways to slow or prevent dementia using drugs and lifestyle modifications typically prescribed for metabolic disorders like diabetes or obesity. These lines of inquiry have taken on new urgency as several amyloid-targeting therapies for Alzheimer disease have failed in clinical trials, leading to questions about whether the so-called amyloid hypothesis may be flawed.

Metabolism seems to be at the center of the new hypothesis regarding the cause of Alzheimer’s. The term “Type 3 Diabetes” comes back often to describe how Alzheimer’s is related to poorly controlled blood sugar.

Preventing chronic diseases was one of our main motivations to start lifetizr. A perfectly optimized metabolism is the pillar of great health and longevity, and taking a proactive approach here is always a great idea.

If you want to make sure you keep optimal metabolic health, you can request early access to lifetizr.

Get early access


🌱 Wellness

⏳ There’s No Such Thing as Quality Time

I keep coming back to this article from Ryan Holiday. People often see their life as on one side the “garbage time,” and on the other side, the “quality time.” This approach will leave you always waiting for the future or nostalgic for the past.

“I’m a believer in the ordinary and the mundane. These guys that talk about ‘quality time’ — I always find that a little sad when they say, ‘We have quality time.’ I don’t want quality time. I want the garbage time. That’s what I like. You just see them in their room reading a comic book and you get to kind of watch that for a minute, or [having] a bowl of Cheerios at 11 o’clock at night when they’re not even supposed to be up. The garbage, that’s what I love.”

It’s my necessary reminder to live in the present:

There’s a Tolstoy quote I love: “There is no past and no future; no one has ever entered those two imaginary kingdoms. There is only the present.”


If you enjoy this newsletter, make sure to subscribe if you haven't!


🧠 Better Thinking

👐 Active Open-Mindedness

I was reading Range: Why Generalists Triumph in a Specialized World, by David Epstein a few days ago, I found the idea of active open-mindedness fascinating.

During 20 years of the Cold War, forecasting expert Philip Tetlock collected and assessed the predictions of 284 experts. He concluded that experts are absolutely terrible at making predictions about anything.

Tetlock found that an expert’s years of experience, academic degree, and even the ability to access classified information made no difference. When experts said that some potential event was impossible, it happened in 15 percent of the cases. Events declared to be an absolute sure thing failed to occur in 25 percent of the time.

Even more worrying, Tetlock found that the more an expert appeared in the news, the more likely they were to be wrong (particularly timely in this pandemic time), or as Tetlock put it, “roughly as accurate as a dart-throwing chimpanzee.”

One of the problems was that many of the experts’ focus was too narrow. Having spent entire careers studying a single issue, they tended to have explicit theories about how it worked (unfortunately, we see a lot of this in nutritional epidemiology, where diets become religions, as covered in this excellent episode.) So what makes a better forecaster of future events? Researchers like psychologist Jonathan Baron point to active open-mindedness—a willingness to question your own beliefs. Most of us fail at this and can’t override our strong instinct to cherry-pick evidence that confirms our existing beliefs.

One way I found to do this is to retrain myself to enjoy being wrong and quickly update my beliefs once proven wrong.

For more on Philip Tetlock’s work on forecasting, here’s a great episode with Tyler Cowen:

"We want a lot of things from our forecasters, and accuracy is often not the first thing...we look to forecasters for ideological reassurance, we look to forecasters for entertainment, and we look to forecasters for minimizing regret functions"


⚡️ Startup Stuff

🚂 Amp it Up!

I really enjoyed this article from Frank Slootman, Chairman & CEO at Snowflake. He described the approach they adopted, the “secret sauce” that led them to massive success. In a few words: “Amp it Up!”

Bottom line: There is room up in organizations to boost performance by amping up the pace and intensity. Considerable slack naturally exists in organizations to perform at much higher levels. The role of leadership is to convert that lingering potential into superlative results.

Of course, amping it up is not an easy task and not every hire will be happy with this pace.

It is not easy because you will drive people out of their comfort zones. There will be resistance. Change is hard. Some will vote with their feet. If you want to be popular as a leader, this may not be for you.

Another part I found interesting is clarifying what you’re doing and how you’re doing it.

Our companies were built and run for performance, full stop. We were singleminded in our pursuit of goals, and drove our people to become the best version of themselves. For the best people, it was an incredibly liberating experience.

The last thing I loved from the article is the idea of changing people’s sense of urgency. It’s something I also experienced. Personally, a task can take you a week or a few hours, depending on your sense of urgency. Let that compound over 10 years, and imagine how different the results will be.

Somebody would ask me if he could get back to me about something next week, and I would reply ‘how about tomorrow morning? Might be completely unreasonable, did not matter. The point was to change people’s sense of urgency. 


📚 What I Read

📕 On the Self-Help Books Debate

I find the debate around self-help books very interesting, especially from my French perspective. In France, self-help books, and more generally, non-fiction is almost non-existent. You would very rarely hear French people talking about non-fiction, and most of the discussions around books revolve around the classics, the “Prix Goncourt,” and literature at large.

Why is that? I’m not sure I have the answer, but one thing is certain, some ideas and concepts just don’t sound good in French! A lot of the American way of thinking around self-improvement, developing new skills, mindset, and so on sounds bad in French. Honestly, I could never read a self-help book in French. It just doesn’t work.

So why aren’t French people reading non-fiction and self-help in English? Because as weird as it may seem from English-speaking countries, people aren’t fluent in English in most of the world.

Now, back to the debate around self-help books. I’ve read only classics for the first part of my life—Proust, Céline, Baudelaire, Balzac, Stendhal, Camus, etc.—and these books are fantastic and truly expand your horizons. Around five years ago, I completely switched my media consumption from France-oriented to US/International-oriented. I started reading only in English, and at that time, I discovered self-help books.

Right now, I feel that I understand both perspectives, and from each perspective, the other one doesn’t really make sense. When you’re reading for culture and for the beauty of it (and for signaling!), you don’t understand people reading self-help books. On the opposite side, when you read to learn, let’s say you’re building a company, you need to learn how to manage, how to hire, how to master your emotions, and so on; at that point, you don’t get why people only read fiction.

As often, I think the truth lies somewhere in the middle. Of course, the middle will look different depending on your media consumption right now, but I find a lot of value in doing a bit less of what I’m used to doing. For example, my father—who, up to recently, was reading only French literature—started to see the value of reading self-help books like Breath.

The last part of this debate is around signaling. It would be deluded to forget an essential part of human nature—signaling—and a big part of reading is done to be able to talk about these books and thus signal that you’re “that type of person.” I believe a lot of the hate that self-help gets is from people who want to appear so cultured that they can’t imagine reading something different than a Proust. It’s always funny to be confronted with a person like that, and I can’t help but think: if you never read self-help books, how are you learning new skills?

⚖️ Never Split the Difference

Talking about self-help, I read Never Split the Difference by Chris Voss this week, and I loved it! It’s a detailed guide to learn the essential skill of negotiation.

If you read and want to remember the important ideas, here’s the cheat sheet.


🎙 Podcast Episode of the Week

On The Long Game Podcast:

Vedica is a historian of South Asia and the Middle East, and she is the author of India and the First World War. Vedica is also the co-creator of the excellent newsletter Keeping Up With India about the Indian Tech ecosystem. Currently, she is a consultant at the Boston Consulting Group.

We start the conversation by talking about why Vedica started her newsletter about India. Then we talk about the specificities of the Indian tech ecosystem. We cover her series on Reliance and Jio, and Vedica explains why Reliance has become so powerful lately. We also discuss what are the most promising sectors right now in India.

My favorite part of the conversation was when Vedica explains why it's so important to read fiction.

On other shows:


🍭 Brain Food

🏴 Inside India’s Booming Dark Data Economy

This is an excellent article about what the data economy may lie ahead of us.

The black market for data, as it exists online in India, resembles those for wholesale vegetables or smuggled goods. Customers are encouraged to buy in bulk, and the variety of what’s on offer is mind-boggling: There are databases about parents, cable customers, pregnant women, pizza eaters, mutual funds investors, and almost any niche group one can imagine.


🎥 What I’m Watching

🤑 Venture Capital - Silicon Valley Ponzi Scheme - Chamath Palihapitiya

This is a thought-provoking video on the world of venture capital, startups, and growth at all costs. Chamath is just so good at dropping truth bombs!


🔧 The tool of the Week

✔️ Todoist

It’s a new year, and everyone has many resolutions and goals. I find it easier to stick to good habits when I use a task manager. Todoist is great, and it will hopefully help you stick to your good habits in 2021!


🪐 Quote I'm Pondering

Those who do not move, do not notice their chains.

— Rosa Luxemburg


If you enjoyed this newsletter, make sure to subscribe if you haven’t 👇


👋 EndNote

Thanks for reading!

I will see you next week. As always, if you're finding this newsletter interesting, give me your feedback; you can respond to this email or tweet at me!

If you’re an existing reader, I would deeply appreciate it if you share this with people who would find it a valuable resource. You can also “like” this newsletter by clicking the heart just below this, which helps me get visibility on Substack.

Share The Long Game by Mehdi Yacoubi

Have a great day,

Mehdi

Leave a comment