# Book review: Age Later

Book review: Age Later, by Nir Barzilai.

Books by serious researchers on how to defeat aging are now coming out
almost as fast as I have time to read them.

This one mostly aims to enable us live in good health to 115, preferably
via a few simple pills.

Age Later is fairly similar to Sinclair\'s
[Lifespan](http://www.bayesianinvestor.com/blog/index.php/2020/07/10/lifespan/).
At least, the differences are small compared to how they differ from
Aubrey de Grey\'s [Ending
Aging](http://www.bayesianinvestor.com/blog/index.php/2008/07/31/ending-aging/).
I\'m a bit concerned by this, since anti-aging research has not yet
demonstrated enough results to justify converging on a single strategy.
Maybe that\'s just an artifact of who\'s writing books?

The book has only a little bit of theorizing about the causes of aging
and about why we should expect it to be curable. Barzilai endorses
Sinclair\'s unimpressive attempts at a theory.

Barzilai waits until the last page to mention an argument that aging
can, in principle, be fully reversed (as opposed to delayed). To wit,
that fetal cells start with an age of zero, even though the egg and
sperm show clear signs of being as old as the parents.

### Studies of Centenarians

A fair amount of the book is devoted to evidence from centenarians.

Barzilai provides plenty of examples which indicate that they have far
from perfect genes and lifestyles. It\'s unlikely that we can get much
in the way of useful advice from this. E.g. exercise clearly helps some
people live longer, while others get can away without it. Since I can\'t
tell which category I\'m in, I treat exercise as necessary.

One questionable example:

> Most striking, two of the centenarians had variants that are a major
> risk factor for Alzheimer\'s (APOE4) - the textbooks say they should
> have been suffering from dementia at age seventy and dead at eighty

I suggest that Barzilai look for a better textbook. Experts who study
pre-agricultural tribes say that people there don\'t get dementia. I\'m
pretty sure that\'s due to lifestyles, not a shortage of APOE4. Also,
[APOE ε4 Is Not Associated with Alzheimer's Disease in Elderly
Nigerians](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855121/). APOE4
seems well adapted for the lifestyles of many of our distant ancestors,
but not so well adapted to the lifestyles of the most developed
countries. Presumably, the APOE4 centenarians had enough features of
ancestral lifestyles to meet their particular needs.

Centenarian biomarkers seem to be a more interesting topic. High
[humanin](https://en.wikipedia.org/wiki/Humanin) and HDL levels in
centenarians might hint at some promising interventions.

### Calorie Restriction

Age Later contains a disturbing claim about the semi-famous University
of Wisconsin calorie restriction study ([Caloric Restriction Delays
Disease Onset and Mortality in Rhesus
Monkeys](https://science.sciencemag.org/content/325/5937/201)).
Barzilai, one of the reviewers of the study, noticed that the monkeys
weighed more than was plausible for calorie restricted animals, and got
the researchers to admit that a caretaker had given the calorie
restricted monkeys almost as much food as the controls.

This apparently means that the study\'s report of 30% calorie
restriction was bogus. Yet my attempts to find discussion of this
accusation on the web have turned up nothing. I\'m very confused. How
can Science just ignore this? Did everyone involved just decide that the
deviation didn\'t last long enough to matter?

Does it mean we should dismiss the whole study? Or conclude that a
smaller than reported degree of calorie restriction produced the
reported benefits (i.e. that the study understates the benefits)?
Barzilai seems uninterested in pursuing this issue. He thinks calorie
restriction \"works\", at least for some humans, but that the costs
outweigh the longevity benefits (he prefers a form of intermittent
fasting).

### Metformin

Barzilai\'s favorite near term hope for treating aging is metformin. It
has been shown to extend life in a number of species, and there\'s some
weak evidence of large benefits in healthy humans. Barzilai makes the
human evidence sound stronger than it actually is - the [most
interesting study
showed](https://www.sciencedirect.com/science/article/pii/S1568163717301472)
that diabetics getting metformin outlive non-diabetic controls. However,
metformin is only given to relatively healthy diabetics. It\'s not hard
to imagine that patients who were selected to get metformin were
unusually healthy except for their diabetes.

See [here](https://nintil.com/longevity/#metformin) and
[here](https://www.gwern.net/Longevity#metformin) for balanced summaries
of metformin. My guess is that metformin is valuable for the large
number of people who are developing [insulin
resistance](https://www.apoe4.info/wiki/Insulin_Resistance), although
it\'s healthier, and usually possible, to avoid insulin resistance in
the first place.

Barzilai does note that he considers metformin just a first step in
handling aging, and he hopes it will pave the way for more ambitious
research.

### Funding

There\'s a good deal of money for research into patented treatments for
aging that would likely be expensive, but not much funding for cheap
treatments such as Metformin.

Barzilai sees it as critical that the FDA now recognizes aging as a
disease. I see that as only having moderate effects on the cost of
getting a treatment for aging approved (e.g. any aging treatment ought
to qualify as a cancer treatment, but trials might need twice as many
patients if only the cancer benefits count). Barzilai recounts evidence
that progress is being held back much more by the reluctance of funding
agencies, such as the NIH, to consider aging a disease (or is their
reluctance due to a presumption that it\'s untreatable?), yet somehow he
doesn\'t say that it\'s important for the NIH to classify aging as a
disease.

Barzilai has done a great job of [convincing the
FDA](https://www.fightaging.org/archives/2019/10/aubrey-de-grey-on-the-tame-metformin-trial/)
to more or less agree to a definition of aging that recognizes it as a
disease which is worth curing.

The definition seems mostly appropriate. Barzilai complains that the FDA
rejected the use of diabetes as evidence of age-related loss of health.
Barzilai is mostly right here. The FDA seems to be demanding that aging
be defined in terms of outcomes that are clearly quite harmful (stroke,
dementia, death). Diabetes doesn\'t guarantee a big decline in quality
of life. Cancer is a more complicated story, and is likely the most
critical aspect of aging to fix - how did the FDA decide to include it
but not diabetes?

The definition is pretty likely to exclude just about any treatment that
doesn\'t help with aging. But I have some concerns that it might end up
locking in criteria that are overly expensive to meet. E.g. if
[epigenetic clocks](https://nintil.com/epigenetic-clocks) prove to be
reliable measures of age-related health, trials which use those clocks
as the primary outcome might be an order of magnitude cheaper.

Barzilai expresses doubts about epigenetic clocks, because \"methylation
may not be such a reversible process.\" That\'s odd, since there was a
[study](https://www.nature.com/articles/d41586-019-02638-w) showing
reversal in humans which was published in time that it could have been
squeezed into the book, and [an RCT showing
reversal](https://www.medrxiv.org/content/10.1101/2020.07.07.20148098v1)
published shortly after Age Later. It seems clear that our main doubts
about epigenetic clocks ought to be the risk that the clocks are just
symptoms, not causes, of aging.

### Conclusion

Age Later is a moderately good book, probably appropriate for
influencing funding agencies to shift a bit more money to aging
research. It\'s a bit more focused than I\'d like on small improvements.

It didn\'t quite convince me to buy stock in Barzilai\'s company,
CohBar.