9 ms·

Amish Mutation Protects Against Diabetes and May Extend Life

138 points by MrJagil 9y ago

chiefalchemist 9y ago
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.
reasonattlm 9y ago
Publicity materials (which, for a change, are actually useful and helpful): https://news.northwestern.edu/stories/2017/november/amish-live-longer-healthier-internal-fountain-of-youth/ https://news.northwestern.edu/stories/2017/november/amish-li... 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.
microcolonel 9y ago
One has to wonder: is PAI-1 a feature or a bug?
- saalweachter 9y ago
  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 9y ago
    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.
- twobyfour 9y ago
  It may depend on what era you live in and how liable you are to encounter starvation.
Dowwie 9y ago
I can't imagine the Amish buy or make sugar-enriched foods, so a diet without those would also contribute to their health
- pbnjay 9y ago
  Addressed in the article - with the same diet, 7% T2D incidence rate in non-affected population, 0% rate for those with the mutation.
  - rando444 9y ago
    "similar diet" .. All of the Amish communities I know produce all of their own food. I never see them as customers in restaurants or buying anything other than basic ingredients in stores. I'm sure it happens, but it would be extremely difficult to find people who have similar diets as the Amish, as you'd have to grow your own food and butcher your own animals to achieve a similar level of diet.
    - snewman 9y ago
      I think this is comparing Amish people with the mutation vs. Amish people without the mutation. Both groups are Amish eating Amish food in Amish communities with other Amish.
      - jermaustin1 9y ago
        I'm pretty sure you could have fit just one more "Amish" in that sentence.
    - zaroth 9y ago
      It's not similar diet to the outside world. But the two Amish groups with and without the mutation have similar diets so the Amish without the mutation act as the control group and have 7% incidence of T2D while the Amish group with the mutation have 0%. Presumable the p-value for normal Amish 7% vs. rest-of-US 8% is not significant in the numbers they studied, but the 7% vs. 0% was.
sanxiyn 9y ago
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-1.12773 https://www.nature.com/news/genetics-a-gene-of-rare-effect-1...
- reasonattlm 9y ago
  Also: ANGPTL4: http://www.tum.de/en/about-tum/news/press-releases/short/article/32985/ http://www.tum.de/en/about-tum/news/press-releases/short/art... ASGR1: http://healthsciences.ku.dk/news/new-2016/mutation-protects-against-heart-disease/ http://healthsciences.ku.dk/news/new-2016/mutation-protects-... Growth hormone receptor: http://www.nbcnews.com/health/aging/little-people-ecuador-laron-syndrome-may-unlock-cancer-diabetes-cure-n511266 http://www.nbcnews.com/health/aging/little-people-ecuador-la... 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.
squAmishCells 9y ago
Pros: You can eat more donuts. Cons: You are amish for a longer amount of time.
mamoswined 9y ago
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).
deleted 9y ago
[deleted]
zach 9y ago
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 9y ago
  >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 9y ago
    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/
  - chiefalchemist 9y ago
    There's more and more science about gut bacteria and general health - both body and brain. The gut...it matters ;)
  - zach 9y ago
    Just going off of an NYT article from last year about how Amish communities, and especially those who live among farm animals (what I, at least, think of as the "most Amish" lifestyle), have really healthy gut microbiomes: https://www.nytimes.com/2016/08/04/opinion/health-secrets-of-the-amish.html https://www.nytimes.com/2016/08/04/opinion/health-secrets-of...
- dialtones 9y ago
  Given the amount of inbreeding, “Knights Templar” probably isn’t the phrase I’d use.
tryingagainbro 9y ago
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/infographics/adv-staggering-cost-of-diabetes.html http://www.diabetes.org/diabetes-basics/statistics/infograph...
gwern 9y ago
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.
blacksmith_tb 9y ago
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
wyclif 9y ago
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!

138 points by MrJagil 9y ago

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.

reasonattlm 9y ago

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

microcolonel 9y ago

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

saalweachter 9y ago
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 9y ago
  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.
twobyfour 9y ago
It may depend on what era you live in and how liable you are to encounter starvation.

Dowwie 9y ago

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

pbnjay 9y ago
Addressed in the article - with the same diet, 7% T2D incidence rate in non-affected population, 0% rate for those with the mutation.
- rando444 9y ago
  "similar diet" .. All of the Amish communities I know produce all of their own food. I never see them as customers in restaurants or buying anything other than basic ingredients in stores. I'm sure it happens, but it would be extremely difficult to find people who have similar diets as the Amish, as you'd have to grow your own food and butcher your own animals to achieve a similar level of diet.
  - snewman 9y ago
    I think this is comparing Amish people with the mutation vs. Amish people without the mutation. Both groups are Amish eating Amish food in Amish communities with other Amish.
    - jermaustin1 9y ago
      I'm pretty sure you could have fit just one more "Amish" in that sentence.
  - zaroth 9y ago
    It's not similar diet to the outside world. But the two Amish groups with and without the mutation have similar diets so the Amish without the mutation act as the control group and have 7% incidence of T2D while the Amish group with the mutation have 0%. Presumable the p-value for normal Amish 7% vs. rest-of-US 8% is not significant in the numbers they studied, but the 7% vs. 0% was.

sanxiyn 9y ago

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-1.12773 https://www.nature.com/news/genetics-a-gene-of-rare-effect-1...

reasonattlm 9y ago
Also: ANGPTL4: http://www.tum.de/en/about-tum/news/press-releases/short/article/32985/ http://www.tum.de/en/about-tum/news/press-releases/short/art... ASGR1: http://healthsciences.ku.dk/news/new-2016/mutation-protects-against-heart-disease/ http://healthsciences.ku.dk/news/new-2016/mutation-protects-... Growth hormone receptor: http://www.nbcnews.com/health/aging/little-people-ecuador-laron-syndrome-may-unlock-cancer-diabetes-cure-n511266 http://www.nbcnews.com/health/aging/little-people-ecuador-la... 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.

squAmishCells 9y ago

Pros: You can eat more donuts. Cons: You are amish for a longer amount of time.

mamoswined 9y ago

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).

deleted 9y ago

[deleted]

zach 9y ago

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 9y ago
>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 9y ago
  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/
- chiefalchemist 9y ago
  There's more and more science about gut bacteria and general health - both body and brain. The gut...it matters ;)
- zach 9y ago
  Just going off of an NYT article from last year about how Amish communities, and especially those who live among farm animals (what I, at least, think of as the "most Amish" lifestyle), have really healthy gut microbiomes: https://www.nytimes.com/2016/08/04/opinion/health-secrets-of-the-amish.html https://www.nytimes.com/2016/08/04/opinion/health-secrets-of...
dialtones 9y ago
Given the amount of inbreeding, “Knights Templar” probably isn’t the phrase I’d use.

tryingagainbro 9y ago

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/infographics/adv-staggering-cost-of-diabetes.html http://www.diabetes.org/diabetes-basics/statistics/infograph...

gwern 9y ago

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.

blacksmith_tb 9y ago

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

wyclif 9y ago

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!