Reading Super Agers (3)

My first two notes both ended on the same question: supplements.

This is the third, covering the last part of the book.

In the first one I mentioned that I've taken NMN regularly for years. When I read the line "supplements probably can't help you live longer," I paused.

In this part, Topol unpacks that line.

The question is simple: with medical science this advanced, surely there must be some drug that helps with longevity? Could it be hiding among all those assorted supplements on the market?

Here goes — enjoy:

1. Fish Oil: 25,000 People, Five Years, No Effect

Let's start with the oldest name in the game — fish oil.

In 2019, a huge clinical trial called VITAL published its results. 25,871 healthy adults were followed for more than five years.

The researchers wanted to know just one thing: does a standard daily dose of one gram of omega-3 fish oil — the kind you can buy in any supermarket, with a mix of EPA and DHA — really keep heart disease and cancer at bay, as the legend goes?

The result: no effect.

Whether for cardiovascular events overall or for cancer incidence, there was no significant difference between people taking fish oil and people taking a placebo.

Topol's analogy is not exactly gentle: you think that daily gram of fish oil is giving your blood vessels a deep clean, but in reality it's more like your house is on fire and you're throwing a mouthful of water at it from a shot glass.

Worse still, taking too much DHA over the long term can also weaken immune function and affect platelet aggregation.

A piece of common sense people have lived by for decades, quietly set down by data from 25,000 people.

2. Blood Swapping: Youth at US$10,000 a Litre

Fish oil is an old-school supplement. So what about Silicon Valley's more sci-fi-sounding "black tech"?

Take blood-swapping therapy.

You may have heard the story of Silicon Valley multimillionaire Bryan Johnson — he once swapped blood with his young son, hoping that an infusion of young blood would reverse ageing.

Later, Johnson himself admitted it hadn't worked as hoped.

Topol says there are indeed companies offering young plasma infusions and plasma exchange, at prices as high as US$10,000 a litre. But there's very little human research on blood swapping, and the few studies that exist found essentially no benefit — for example, a small randomised trial in 9 Alzheimer's patients treated with plasma donated by young people showed no effect.

He stresses one point in particular: besides being expensive and lacking evidence, plasma infusion and exchange carry a serious risk of disease transmission.

Paying for a hope with no evidence behind it, while accepting a risk that definitely exists.

That's less like medicine and more like a ritual.

3. NAD+: The Part Where I Paused

And then we get to my part.

NAD+ is a metabolite produced by mitochondria that plays a central role in energy metabolism — promoting gene repair and slowing cellular ageing. As we age, NAD+ levels in the body decline.

So many companies started selling products claiming to restore NAD+, most commonly NR and NMN. One is a form of vitamin B3, the other a small organic molecule; both are converted to NAD+ once in the body — a high-tech version of "you are what you eat."

Topol's verdict: these products were never validated by human clinical trials before being sold widely.

For NAD+ to work in the body, it depends on the cooperation of many other substances the body produces itself. Simply taking synthetic analogues from outside may well be futile.

More worrying still, some research institutions and biopharma companies have deliberately downplayed its possible side effects — such as an increased risk of cancer.

For someone who's taken NMN for years, this section wasn't comfortable to read.

But discomfort is often the moment a book is doing its work.

I'm not going to jump to a conclusion. I've just moved it from "routine" back to "to be verified" — until there are large human randomised controlled trials, it shouldn't hold a settled place.

Much of what we do to our bodies is, at heart, paying for a story that hasn't been proven yet.

4. So, Is There Anything?

Topol sums up "biohacking" methods in a single sentence: they either lack evidence of clinical benefit from large human randomised controlled trials, or come with huge risks.

So is there anything that actually works?

He gives an answer, and one many people wouldn't expect: GLP-1 drugs — semaglutide and tirzepatide.

These drugs were originally used to treat diabetes and obesity.

How could drugs for diabetes and obesity have anything to do with longevity?

To answer that, you first need to accept one of the most subversive ideas in Topol's book.

Heart disease, cancer, dementia — three life-shortening diseases that seem to have nothing to do with one another share a common underlying mechanism: chronic inflammation and immune system dysfunction.

Start with heart disease. The conventional view is that atherosclerosis is simply blood vessels "clogged" with fat, like limescale in a water pipe. But at its core it is inflammation of the vessel wall — and all inflammation, ultimately, is triggered by the immune system.

Topol cites a piece of evidence. In a large clinical trial called CANTOS, scientists injected heart patients with a powerful targeted anti-inflammatory drug (canakinumab) designed specifically to suppress immune-driven vascular inflammation.

The result: patients' heart attack rates fell significantly.

Unexpectedly, the incidence of fatal lung cancer also dropped sharply.

Two birds with one stone. Cardiovascular disease and cancer share the same inflammatory switch.

Next, cancer. Cancer itself usually isn't fatal; what kills is metastasis. For cancer cells to roam the body and seed themselves, they first have to evolve extremely good camouflage to escape the immune system's pursuit — and an ageing immune system is precisely the easiest to fool.

Topol says that as long as the immune system stays strong, in the vast majority of cases cancer cells will stay locked in where they started.

Finally, neurodegenerative disease. Medicine long believed that the brain, protected by the blood-brain barrier, was an island largely untouched by the immune system. Now we know the brain is home to macrophages called "microglia" — the brain's sentinels, and its rubbish collectors too.

As we age, these sentinels become exhausted and fall into a state of "end-stage inflammation": instead of clearing metabolic waste, they start releasing pro-inflammatory factors, damaging synapses and causing brain cells to die.

Topol says it plainly: without this "inflammatory riot" inside the brain, Alzheimer's and Parkinson's would struggle to truly destroy the brain.

Three diseases, one source.

6. A Twenty-Year Window

If all these diseases share a root — traceable to an immune system out of control and chronic inflammation — then there's a way to break through.

Topol says these three big chronic killers usually take twenty years or more to lie dormant and develop. That gives us an extremely wide "early interception window."

GLP-1 drugs are currently the best-evidenced tool within that window.

A large randomised trial of 17,600 obese patients with a history of heart disease showed that after three years on semaglutide, the treatment group's risk of heart attack, stroke and cardiovascular death fell by 20%.

What's more interesting is the order in which things happened.

In these patients, inflammation levels and cardiovascular risk fell first — and only then did weight.

What does that tell us? That the underlying logic by which GLP-1 saves lives isn't just "losing weight makes you healthier." It first, and independently, lowers chronic inflammation throughout the body, thereby lowering cardiovascular risk.

Weight is the result we can see. Inflammation is the cause we've never been able to see.

7. The Key Is Hidden in the Gut

GLP-1 drugs have also shown surprising potential in neurodegenerative disease.

In a clinical trial of patients with early Parkinson's, GLP-1 drugs successfully stopped motor symptoms from getting worse — and this protective effect persisted even after the drug was stopped.

Biologically, this is a mystery. Many large-molecule GLP-1 drugs simply can't cross the blood-brain barrier directly in any significant amount.

Scientists speculate that these "gut hormones" use a kind of "remote control" mechanism: via the "gut-brain axis," they send signals directly to the cerebral cortex and hypothalamus, shutting down the inflammatory riot that drives neurodegeneration inside the brain without breaching the physical barrier.

In other words — the key to treating the brain's incurable diseases may be hidden in the gut.

In the second note we said that what determines your blood sugar response isn't the food, it's your gut microbiome. In this one, the gut shows up in the answer once again.

The body isn't a collection of organs each going its own way; it's a web we still haven't fully learned to read.

I should be clear: GLP-1s are prescription drugs, with their own indications and side effects. What Topol writes about is the possibility they open up in medicine, not a shopping list. The same goes for me.

Final Words

And with that, my three notes are done.

At the end of the book Topol keeps returning to one idea: what our generation can do — and the only thing we should do — is not try to reverse the underlying biology of ageing, but use existing technology to precisely intercept the specific chronic diseases quietly brewing inside us.

Looking back, these three notes are really one sentence unfolded three times:

Longevity doesn't mainly depend on genes — genes explain only 25–30%; the rest is in our hands;
There's no universal perfect diet, no universal exercise prescription, no universal screening age — only the set that's right for you;
Nor is there a universal longevity pill — fish oil, blood swapping, NAD+ are mostly hopes without evidence; what actually has evidence comes, of all things, from a drug originally meant for diabetes, and the insight behind it that "all diseases share one root."

Topol says the truth about longevity is actually simple: it isn't a war against ageing, but a revolution of choices. Choosing the diet and way of eating that suits you better, choosing more personalised testing and medicine, choosing more exercise, choosing closer social connections, and a more meaningful purpose in life.

In On the Shortness of Life, Seneca wrote: it is not that we have too little time, but that we waste a great deal of it.

Two thousand years later, a cardiologist used a whole book's worth of clinical data to say much the same thing —

The question has never been the length of life, but how long the healthy part lasts.

True longevity isn't living longer but living better: a body full of vitality, a clear mind, a rich emotional life, a life with meaning.

The book is finished.

The practice has only just begun.