
Amish Mutation Protects Against Diabetes and May Extend Life - MrJagil
https://www.nytimes.com/2017/11/15/well/live/amish-mutation-protects-against-diabetes-and-may-extend-life.html?ribbon-ad-idx=20&rref=health&module=Ribbon&version=context&region=Header&action=click&contentCollection=Health&pgtype=article
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gwern
This is a candidate-gene study: a single gene in a single population without
replication. Previous candidate-gene studies on other traits have replication
rates as low or lower than 1% despite apparently dramatic effect sizes -
GWASes they definitely are not! I'll believe this mutation when I see it
replicated somewhere else.

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zach
Wow. We thought the Amish were just getting lots of healthy exercise, but it
turns out they’re the genetic Knights Templar, guarding a secret source of
life for hundreds of years. Of course, their lifestyle probably maintains the
healthiest gut flora around as well.

~~~
hueving
>Of course, their lifestyle probably maintains the healthiest gut flora around
as well.

Is there any science behind that statement or is it just a sort of
naturalistic fallacy?

~~~
freeflight
There is a study on Amish gut flora and it's relation to the metabolic
syndrome [0]. Old Order Amish are ideal for studies like that due to them
having such a genetically homogenous population. From a quick scan it seems
like that even among the Old Order Amish there are variations between
individuals gut flora, so I'm not sure they all have that "healthy gut flora"
like the parent suggested.

[0]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419686/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419686/)

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Dowwie
I can't imagine the Amish buy or make sugar-enriched foods, so a diet without
those would also contribute to their health

~~~
dsr_
The Amish love sugar as much as the next group along. Jams, jellies,
preserves; pies, cakes, and cookies are all part of their diet.

They are probably less likely to consume large amounts of prepackaged
desserts, sodas and snack foods than their "English" neighbors, but that
varies from community to community.

~~~
agumonkey
the culture you live in has enormous impact on how much you will attach to the
sensory pleasure of sugar bloated products. With time I started to develop new
taste, and I can recognize when something has too much sugar in it. Before
that I would be blind. If you live in a place with more subtle food, you
probably get years of advance at that game and you can find pleasure in other
nutrients. Also lifestyle change your diet, amish are said to be often working
outside in groups, that makes you hungry and not seeking for greedy/gourmet.

~~~
dsr_
I agree with your first point -- when I drastically reduced my sugar
consumption, it was only a few months before I felt that everything I had
liked before was horrendously over-sweetened.

However, your second point is not applicable. The Amish have a culinary
tradition of their own that stems from 18th C German cooking adapted to
American ingredients. Because they strictly limit their exposure to technology
changes, they do more manual labor than is common for their neighbors, but
this isn't correlated with a lack of desire for good (tasty, appetizing,
visually appealing) food. If you tour Pennsylvania, Ohio and Indiana, you'll
discover Amish foods and handmade goods being sold everywhere.

~~~
agumonkey
I don't know what amish eat, but I'd bet a dollar or two that it's not crude
industrial premade recipes, nor hamburger or pizzas and soda. If it is.. then
I am wrong, but I'd be surprised considering the conservatism mentioned in
articles about them; they seem to only accept things that have clear benefits
and not cheap ideas that look shiny (like any new technology).

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sanxiyn
If you like these kinds of story, you will enjoy this story about PCSK9:
[https://www.nature.com/news/genetics-a-gene-of-rare-
effect-1...](https://www.nature.com/news/genetics-a-gene-of-rare-
effect-1.12773)

~~~
reasonattlm
Also:

ANGPTL4: [http://www.tum.de/en/about-tum/news/press-
releases/short/art...](http://www.tum.de/en/about-tum/news/press-
releases/short/article/32985/)

ASGR1: [http://healthsciences.ku.dk/news/new-2016/mutation-
protects-...](http://healthsciences.ku.dk/news/new-2016/mutation-protects-
against-heart-disease/)

Growth hormone receptor: [http://www.nbcnews.com/health/aging/little-people-
ecuador-la...](http://www.nbcnews.com/health/aging/little-people-ecuador-
laron-syndrome-may-unlock-cancer-diabetes-cure-n511266)

And of course there are human loss of function myostatin mutants, but I can
never find the articles I recall reading years back on some of the few known
individuals.

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chiefalchemist
From what I understand the Amish diet and lifestyle doesn't map well to
mainstream America. To attribute their success (so to speak) to genes strikes
me as flawed.

If nothing else, this is a case for epigenetics. But to promote that you are
your genes, nothing more and nothing less, feels irresponsible, at best.

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tryingagainbro
Find a diabetes cure and be a the world's first trillionaire and probably go
directly to heaven when time comes :) ?

 _> >The total cost of diabetes and prediabetes in the U.S. is $322 billion.
\- The average price of insulin increased nearly 3 times between 2002 and
2013. \- People with diabetes have health care costs 2.3 times greater than
those without diabetes_ [http://www.diabetes.org/diabetes-
basics/statistics/infograph...](http://www.diabetes.org/diabetes-
basics/statistics/infographics/adv-staggering-cost-of-diabetes.html)

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reasonattlm
Publicity materials (which, for a change, are actually useful and helpful):
[https://news.northwestern.edu/stories/2017/november/amish-
li...](https://news.northwestern.edu/stories/2017/november/amish-live-longer-
healthier-internal-fountain-of-youth/)

Paper:
[https://doi.org/10.1126/sciadv.aao1617](https://doi.org/10.1126/sciadv.aao1617)

Researchers have found a noteworthy effect on longevity in a small study
population that includes the only known individuals with a loss of function
mutation in plasminogen activator inhibitor-1 (PAI-1). Individuals with the
mutation live seven years longer on average than near relatives without it.
Repeating the study with larger groups of people obviously isn't a practical
option in the case of rare mutations - we're stuck with the family trees that
the research community is fortunate enough to identify - but one nonetheless
has to wish for more individuals, in order to obtain a more reliable
confirmation, when an effect of this size is reported. It means taking a step
back to revisit questions we've asked ourselves about the odds of finding
significant longevity-enhancing mutations in our species, based upon the
absence of results for the past twenty years of searching.

This is also a finding that can and probably should be taken as support for
current work on elimination of senescent cells as a potential rejuvenation
therapy. PAI-1 isn't a gene pulled from thin air in this context. It is well
studied for its influence on aging, and appears to be one of the driving
regulators of the harmful effects of cellular senescence. Lingering senescent
cells accumulate with age, and secrete a mix of damaging signal molecules that
produce chronic inflammation, damage tissue structure, and alter the behavior
of nearby cells for the worse. This is known as the senescence-associated
secretory phenotype (SASP), and PAI-1 is involved in both the SASP and in some
of the processes by which cells become senescent. Studies show that inhibition
or loss of PAI-1 reduces some of the harms now known to be associated with
senescent cell presence, and in doing so slows measures of aging.

There is all sorts of past research into PAI-1 and senescent cells that we
might choose to draw lines between. To pick one example, PAI-1 inhibition can
slow atherosclerosis, just as can removal of senescent foam cells in
atherosclerotic plaque. There are no doubt overlapping mechanisms here, though
it seems clear that reducing PAI-1 levels has a variety of other effects as
well. Those effects can't be all that terrible given the existence of a
lineage of thriving human mutants lacking PAI-1, something that is always a
good demonstration to have in hand. There are a few other beneficial mutations
with a small human population to examine, such as those related to reduced
blood lipids or myostatin loss of function; we may see many of these lines of
research result in therapies in the years ahead.

And yet! While there will no doubt be an avalanche of funding into bringing
PAI-1 inhibitors to the clinic, ask yourself this: if tinkering with a
fraction of the harmful secretions of senescent cells is this beneficial, how
much better will it be to remove these damaging cells entirely via senolytic
therapies? All of those involved in this field should spend more time than
they do on work with a higher expectation value, I believe.

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microcolonel
One has to wonder: is PAI-1 a feature or a bug?

~~~
saalweachter
There are two things that make this question very difficult to answer.

The first is that our genetic code is spaghetti code beyond the dreams of the
most cowboy of the 70's cowboy assembly programmers. Our genes and proteins
are reused in different ways at different times in different cells in ways
that make it difficult to unequivocally call a gene "good" or "bad".

The second is that even evaluating along the simple "does it make things
survive and reproduce better?" evolutionary metric, you still need to consider
the exact, current environment a gene is being evaluated in; a gene can be
harmful today and beneficial yesterday, or vice versa. Maybe the gene confers
an immunity to a virulent, deadly, _extinct_ disease; maybe it was necessary
when another gene was present, a gene which has since changed.

Evolution isn't particularly fast, most of the time; any given organism will
be adapted to a smear of their environments as they existed over the last few
million years, and not perfectly adapted to any of them (unless their
environment has remained static).

~~~
Danihan
Excellently put. Good or bad all depends on _context_ and context (via ever-
changing environmental pressures) has changed about a billion times during our
long, winding path towards becoming modern homo-sapiens.

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wyclif
I believe it. Have you ever eaten a meal with the Amish? I have. They love
sugar and put it in _everything_. And they eat substantial meals because many
of the men are engaged in physical work. I got a distinct buzz, and that was
before dessert was served!

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blacksmith_tb
Does anyone have the SNP(s) in question handy? This one [1] seems likely, but
there appear to be several associated with PAI-1.

1:
[https://www.snpedia.com/index.php/Rs1799889](https://www.snpedia.com/index.php/Rs1799889)

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mamoswined
This is the first time I've read about a clotting disorder being beneficial
for heterozygotes besides sickle cell. I'm curious if other types of these
disorders show the same effect (I am a carrier of one myself).

