Bayesian Investor Blog

Book review: True Age: Cutting-Edge Research to Help Turn Back the Clock, by Morgan Levine.

Another year, another book on aging. This one comes close to saying important things about how to slow down aging, then chickens out just before reaching the finish line.

This review will focus on complaints, because there were a handful of problems which bothered me enough to write about. That feels a bit unfair, since my complaints focus on relatively small parts of the book. Much of the book is fairly good. The good parts just didn’t impress me enough to want to write much about them.

Epigenetic Clocks

Levine is best known for developing an improved epigenetic clock, PhenoAge. Where previous clocks tried to identify the methylation locations that are most strongly connected to aging, Levine used a larger set of methylation locations. Instead of just selecting locations that correlated with chronological age, Levine looked for locations that correlated with age as estimated by blood test results.

Early in the book, Levine writes:

I hope by now I have conveyed to you the importance of knowing your biological age.

My intuition does hint that it’s important, but the book does little to confirm that intuition, and didn’t even look like Levine was trying to do so until much later in the book.

Epigenetic clocks correlate with age-related deaths, more so than does chronological age.

Adopting a healthier lifestyle causes epigenetic clocks to report a lower biological age.

Does that imply that we should use epigenetic clocks to evaluate changes in our lifestyle? It’s certainly suggestive.

But there’s plenty of room for doubt. Most biomarkers turn out to be less valuable than they originally look. E.g. amyloid beta is somewhat helpful at identifying Alzheimer’s, yet a focus on reducing it has led researchers down a dead-end path.

Epigenetic clocks seem more promising than amyloid beta, but I don’t have an easy way to compare their value to those of better-known age-related biomarkers. E.g. a1c results give me more actionable advice, since they tell me more about which set of lifestyle mistakes I’m making, and which dietary changes will fix them.

Epigenetic clocks show some hope of providing more complete feedback about rates of aging than other biomarkers. They might even be measuring the root causes of aging. But I haven’t quite been convinced to replace my standard blood tests with epigenetic tests.

Programmed Aging?

Like many books about aging, True Age comments on the polarizing issue of whether aging comes from accumulated damage, versus being actively programmed.

Levine finds a middle-ground position which feels unsatisfying: aging is the default, and there’s some programming to counter it. Evolution selects for as much programmed maintenance as is justified by the benefits.

I’m left wondering whether the key parts of that reasoning are tautological truths, or whether Levine is hinting at substantive claims that I suspect are false.

There’s evidence that aging contributes to a large fraction of wild animal deaths. The energy costs of delaying aging don’t look large enough to offset the obvious costs of those deaths. So I’m pretty sure there are effects that Levine glosses over.

Levine also mentions that individual cells can be rejuvenated using Yamanaka factors. This evidence seems more likely in a world where a program actively creates aging, than in a world where programming is simply repairing damage.

I wonder whether Levine is hinting at a stronger version of programmed aging than she feels it’s safe to advocate? Maybe it’s better not to take a strong stand here, as it seems to only have weak effects on research strategies.

Growth Hormone

I’m concerned by Levine’s somewhat cryptic claim that “growth hormone … and IGF-1 have been shown time and again to also promote aging and, specifically, cancer”.

This seems to be a misleading exaggeration.

I’m paying close attention to this because I just finished being treated with growth hormone in the TRIIM-X trial, and because I’ve invested in Intervene Immune (the company running the trial).

Intervene Immune’s phase 1 trial based on growth hormone showed signs of reversing aging, including a reduction in age as measured by Levine’s PhenoAge test.

That trial was inspired by rat studies which showed evidence that growth hormone reverses aging.

What could Levine mean about “promoting aging”? What evidence conflicts with this PhenoAge result? The only answers I can see involve diabetes and cancer. Did I miss some other evidence?

Diabetes is certainly influenced by aging, but the evidence from cultures that don’t get diabetes suggests that it’s mostly a lifestyle problem that deserves to be classified as somewhat separate from aging.

The main issue seems to be cancer.

From Risk of cancer in patients treated with recombinant human growth hormone in childhood:

Whilst the strength of evidence for a relationship between GH/IGF-I axis and cancer risk is high in both cellular and animal models, data in humans are scarce and conflicting.

It looks like the only human study showing increased cancer risk from growth hormone treatment is Swerdlow 2002, reporting 2 cancer deaths out of 1848 young patients.

Levine cites a paper that she co-authored, Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population, which seems somewhat relevant here. It reports correlations which suggest that high growth hormone levels before age 65 cause cancer, but high growth hormone levels after age 65 reduce cancer rates. It seems like less direct evidence than Swerdlow 2002, since protein intake affects more than just growth hormone. I suspect the results are also confounded by other dietary differences. See also my comments on similar claims in Longo’s book.

In sum, there are decent reasons to be concerned about taking growth hormone before age 65, and the preponderance of the evidence weakly suggests that it reduces cancer risk after age 65. There’s likely harm from diabetes, especially in older patients, from naive use of growth hormone. A lot is known about how to avoid diabetes, but please don’t try growth hormone without expert advice about diabetes.

Practical Advice

Much of the book describes practical steps we can take today to slow aging. It’s mostly solid, but not novel, advice to lead a healthy lifestyle.

Her advice about food is quite similar to Longo’s Longevity Diet (Longo co-authored the protein paper I mentioned above).

Levine does a slightly better job than Longo about hinting that methionine might be a key part of why protein restriction sometimes improves health.

Levine has a mostly good section on calorie restriction, but I’m disturbed by this claim:

The other, and possibly most important, advantage of using nonhuman primates versus humans is that the scientists know exactly how much each animal is eating.

Barzilai’s Age Later reported that, for the key University of Wisconsin calorie restriction study on which Levine relies, a caretaker fed the monkeys extra, unrecorded, food that likely altered the study significantly. Why is Barzilai’s report being ignored?

The rest of Levine’s practical advice is about exercise, relaxation, and a little bit about Quantified Self approaches.

Conclusion

Levine has done good research, but seems not quite visionary enough to write a great book.

But imagine living to see one hundred or beyond in good health and then slowly declining over the remaining five to ten years. That is ideal, and that’s what our goal should be.

That comes just two pages after mentioning the ~300 year lifespan of Greenland sharks (which I previously mentioned as a food that I’m unlikely to try). Combine that with the evidence from the Yamanaka factors research, and I see a vision of postponing age-related decline forever.

When Levine writes about specifics of her research, I see small steps leading in the general direction of such a vision. Yet her more abstract descriptions seem to assume that aging research is poised for the kind of great stagnation that we see in many other parts of medicine.