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There is an new study on the link between genetics and obesity reported on in this popular press article:

 


 

Study [1] is the (rather technical) abstract for the paper associated with the story. I'll do my best to summarize the background and the findings of this study, which I found really interesting.

 

First a little background. It has been known for a while that a particular gene on chromosome 16 named FTO has many (over 200) SNPs (single nucleotide polymorphisms - i.e. common variations in particular base pairs along this gene), several of which appear to be associated with obesity. Here are two older studies [2][3] that address this linkage. Study [2] focused on SNP rs9939609. It found that people who carry one (or especially two) copies of the 'obese' allele ('A') for this SNP were significantly more likely to be obese than those who carry the 'lean' variant ('T'). Study [3] found the same thing for three other FTO SNPs, rs1421085, rs17817449 and rs8043757. It found that people with the 'obese' variants for these three SNPs ('C', 'G' and 'T', respectively) were about 2.5 times more likely to be obese than those who had the lean variants for these three SNPs ('T', 'T', 'A', respectively).

 

The newest study [1], focused on the first of the three SNPs from [3], namely SNP rs1421085, and did something really cool and cutting edge. They took fat cells from mice and humans and used the recently-developed CRISPR gene editing technique to change this particular SNP from the 'obese' variant ('C') to the 'lean' variant ('T'), and then observed what happened to the cells. What they found was that the fat cells converted from being thermogenically active, 'beige' fat cells (i.e. like brown fat cells) to 'white' fat cells that are much more efficient at storing fat, rather than burning it. This can be spun as a nice mechanistic story to explain why at least this SNP is associated with obesity. People who have 'C' for rs1421085 produce more white fat cells, making them more efficient at storing fat - i.e. they have a more 'thrifty' genotype and will therefore (presumably) store more fat for a given calorie intake.

 

Now comes the interesting citizen science part. Data on all four of obesity-related SNPs mentioned above are available to subscribers of 23andMe. Simply log in, then go to this page:

 


 

to get a list of all 200+ SNPs from the FTO gene that 23andMe sequences, and search on the page for these four SNPs. Here are my results:

 

    rs9939609      TT    (lean variant = T)

    rs1421085      TT    (lean variant = T)

    rs17817449    TT    (lean variant = T)

    rs8043757      AA    (lean variant = A)

 

As you can see, I've inherited two copies (one from each of my parents) of the 'lean' allele for each of these four SNPs. So it is no wonder that unintended weight gain has never been an problem for me - at least according to these SNPs I have the antithesis of the 'thrifty genotype'.

 

I'm curious what other CRONies who are also subscribers to 23andMe have for these SNPs, and whether they consider themselves to have a 'thrifty genotype' (easily gain weight) or not. I also wonder whether long-term success on a CR lifestyle is in any way correlated with the values for these SNPs. There is some indication [4] that some of the FTO SNPs (including rs9939609) have an effect on energy intake and preference for energy dense (i.e. high fat) foods, and from [2] we saw that people with the 'obese' allele for rs9939609 and who eat a high-fat, low-carb diet have a higher BMI, which could discourage people trying to practice CR in order to lose weight. Conversely, having a 'thrifty genotype' might make it easier to maintain a low calorie intake without becoming terribly skinny, which can sometimes result in social pressure to eat more to avoid looking like a concentration camp victim.  :)

 

Anyway, I've probably grossly oversimplified the science, but I found it fascinating and would be interested to hear what other 23andMe subscribers have for these alleles.

 

--Dean

 

-------------------------------

[1] N Engl J Med. 2015 Aug 19. [Epub ahead of print]

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.

 

Claussnitzer M(1), Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V,

Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH,

Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M.

 

Background Genomewide association studies can be used to identify

disease-relevant genomic regions, but interpretation of the data is challenging. 

The FTO region harbors the strongest genetic association with obesity, yet the

mechanistic basis of this association remains elusive. Methods We examined

epigenomic data, allelic activity, motif conservation, regulator expression, and 

gene coexpression patterns, with the aim of dissecting the regulatory circuitry

and mechanistic basis of the association between the FTO region and obesity. We

validated our predictions with the use of directed perturbations in samples from 

patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples 

from patients. Results Our data indicate that the FTO allele associated with

obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a

tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts

a conserved motif for the ARID5B repressor, which leads to derepression of a

potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during

early adipocyte differentiation. This results in a cell-autonomous developmental 

shift from energy-dissipating beige (brite) adipocytes to energy-storing white

adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as 

well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in

mice reduced body weight and increased energy dissipation without a change in

physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes

from participants with the risk allele restored thermogenesis, increasing it by a

factor of 7, and overexpression of these genes had the opposite effect in

adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by

CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the

risk allele restored IRX3 and IRX5 repression, activated browning expression

programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions

Our results point to a pathway for adipocyte thermogenesis regulation involving

ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced

pro-obesity and anti-obesity effects. (Funded by the German Research Center for

Environmental Health and others.).

 

PMID: 26287746

 

---------------

[2] Br J Nutr. 2012 Nov 28;108(10):1859-65. doi: 10.1017/S0007114511007410. Epub 2012

Jan 23.

 

Association of the fat mass and obesity-associated (FTO) gene variant (rs9939609)

with dietary intake in the Finnish Diabetes Prevention Study.

 

Lappalainen T(1), Lindström J, Paananen J, Eriksson JG, Karhunen L, Tuomilehto J,

Uusitupa M.

 

A cluster of variants in the fat mass and obesity-associated (FTO) gene are

associated with the common form of obesity. Well-documented dietary data are

required for identifying how the genetic risk can be modified by dietary factors.

The objective of the present study was to investigate the associations between

the FTO risk allele (rs9939609) and dietary intake, and to evaluate how dietary

intake affects the association between FTO and BMI in the Finnish Diabetes

Prevention Study during a mean follow-up of 3·2 years. A total of 479 (BMI >25

kg/m2) men and women were genotyped for rs9939609. The participants completed a 3

d food record at baseline and before every annual study visit. The average

intakes at baseline and during the years 1, 2 and 3 were calculated. At baseline,

the FTO variant rs9939609 was not associated with the mean values of total energy

intake, macronutrients or fibre. At baseline, a higher BMI by the FTO risk

genotype was detected especially in those who reported a diet high in fat with

mean BMI of 30·6 (sd 4·1), 31·3 (sd 4·6) and 34·5 (sd 6·2) kg/m2 for TT, TA and

AA carriers, respectively (P =0·005). Higher BMI was also observed in those who

had a diet low in carbohydrates (P =0·028) and fibre (P =0·015). However, in the 

analyses adjusted for total energy intake, age and sex, significant interactions 

between FTO and dietary intakes were not found. These findings suggest that the

association between the FTO genotype and obesity is influenced by the components 

of dietary intake, and the current dietary recommendations are particularly

beneficial for those who are genetically susceptible for obesity.

 

PMID: 22265018

 

-----------------------


[3] Gene. 2015 Mar 1;558(1):75-81. doi: 10.1016/j.gene.2014.12.050. Epub 2014 Dec 24.

 

Common variations in the FTO gene and obesity in Thais: a family-based study.

 

Chuenta W(1), Phonrat B(2), Tungtrongchitr A(3), Limwongse C(4), Chongviriyaphan 

N(5), Santiprabhob J(6), Tungtrongchitr R(7).

 

Several studies have revealed the association between single nucleotide

polymorphisms (SNPs) in the first intron of fat mass and obesity-associated (FTO)

gene and obesity. To date, more than 100 SNPs in the FTO gene have been

identified in various populations. Nevertheless, this association has not yet

been confirmed in Thai populations. The aim of this study was to investigate

whether FTO variants are associated with obesity in Thais. We analyzed ten

variants in the FTO gene (rs9939609, rs9926289, rs8050136, rs9930501, rs9930506, 

rs9940646, rs9940128, rs1421085, rs17817449, and rs8043757) in 12 families (83

persons); composed of 12 proband cases and 71 associated family members. All

participants were genotyped using polymerase chain reaction (PCR) method and DNA 

sequencing assay. We found significant associations between three SNPs located in

the first intron of FTO gene (rs1421085, rs17817449, and rs8043757) and obesity. 

The odds ratios were 2.82 (95% CI, 1.16-6.90, p=0.02) for rs1421085 and

rs17817449, and 3.15 (95% CI, 1.28-7.76, p=0.01) for rs8043757. Strong linkage

disequilibrium among ten SNPs was observed (D'>0.8). Haplotype analysis

(combination of rs1421085 (T/C), rs17817449 (T/G), and rs8043757 (A/T)) showed

that the CGT haplotype is associated with an increased risk of obesity (OR, 2.42;

95% CI, 1.18-4.97; p=0.018) when compared to the reference haplotype (TTA). The

SNPs rs1421085, rs17817449 and rs8043757 in the first intron of the FTO gene are 

associated with increasing risk of obesity in Thais.

 

Copyright © 2014 Elsevier B.V. All rights reserved.

 

PMID: 25542809  [PubMed - indexed for MEDLINE]

 


------------------

[4] N Engl J Med. 2008 Dec 11;359(24):2558-66. doi: 10.1056/NEJMoa0803839.

 

An obesity-associated FTO gene variant and increased energy intake in children.

 

Cecil JE(1), Tavendale R, Watt P, Hetherington MM, Palmer CN.

 

Author information: 

(1)Bute Medical School, University of St Andrews, St Andrews, United Kingdom.

 

Comment in

    N Engl J Med. 2009 Apr 9;360(15):1571-2; author reply 1572.

    N Engl J Med. 2008 Dec 11;359(24):2603-4.

 

BACKGROUND: Variation in the fat mass and obesity-associated (FTO) gene has

provided the most robust associations with common obesity to date. However, the

role of FTO variants in modulating specific components of energy balance is

unknown.

METHODS: We studied 2726 Scottish children, 4 to 10 years of age, who underwent

genotyping for FTO variant rs9939609 and were measured for height and weight. A

subsample of 97 children was examined for possible association of the FTO variant

with adiposity, energy expenditure, and food intake.

RESULTS: In the total study group and the subsample, the A allele of rs9939609

was associated with increased weight (P=0.003 and P=0.049, respectively) and

body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped

subsample, the A allele was also associated with increased fat mass (P=0.01) but 

not with lean mass. Although total and resting energy expenditures were increased

in children with the A allele (P=0.009 and P=0.03, respectively), resting energy 

expenditure was identical to that predicted for the age and weight of the child, 

indicating that there is no defect in metabolic adaptation to obesity in persons 

bearing the risk-associated allele. The A allele was associated with increased

energy intake (P=0.006) independently of body weight. In contrast, the weight of 

food ingested by children who had the allele was similar to that in children who 

did not have the allele (P=0.82).

CONCLUSIONS: The FTO variant that confers a predisposition to obesity does not

appear to be involved in the regulation of energy expenditure but may have a role

in the control of food intake and food choice, suggesting a link to a hyperphagic

phenotype or a preference for energy-dense foods.

 

2008 Massachusetts Medical Society

 

PMID: 19073975

Edited by Dean Pomerleau

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Hi Dean!

 

I'm a bit confused.  My understanding is that brown fat promotes thermogenisis, while white fat simply stores the fat.  So, true, more white fat will store fat more efficiently -- and tend to make the individual fatter.  So an SNP that increased the ratio of white/brown fat, will tend to promote obesity.  You seem to reach the opposite conclusion.

 

???

 

  -- Saul

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Hi Dean!

 

I'm a bit confused.  My understanding is that brown fat promotes thermogenisis, while white fat simply stores the fat.  So, true, more white fat will store fat more efficiently -- and tend to make the individual fatter.  So an SNP that increased the ratio of white/brown fat, will tend to promote obesity.  You seem to reach the opposite conclusion.

 

???

 

  -- Saul

Everything you say here is in agreement with my understanding as well. What makes you think I've reached the opposite conclusion?

 

Dean

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Hat tip to PEzzell (Peter) over on the Living CR Way forums who found another interesting association between a SNP on the FTO gene, obesity and brain shrinkage. He points to this 2010 study [1] which found that nearly half of people of western European descent have the risk genotypes (GT or TT) for SNP rs3751812, and having either of these two genotypes was associated with higher BMI, waist circumference, and increased brain shrinkage in healthy elderly people. To quote the paper "FTO risk allele carriers versus noncarriers had an average brain volume difference of approximately [-]8% in the frontal lobes and [-]12% in the occipital lobes". I'm fortunate to be GG for this SNP.

 

The good news for those less fortunate is that diet and lifestyle can apparently mitigate the influence of FTO alleles on obesity, and therefore potentially brain shrinkage. Study [2] found that "high-fat diets and low physical activity levels may accentuate the susceptibility to obesity by the FTO variant."  So people with FTO gene variants that make them prone to obesity might want to consider going low-fat, and make sure to get plenty of exercise.

--Dean
 

-----------

[1] Proc Natl Acad Sci U S A. 2010 May 4;107(18):8404-9. doi:

10.1073/pnas.0910878107. Epub 2010 Apr 19.

A commonly carried allele of the obesity-related FTO gene is associated with
reduced brain volume in the healthy elderly.

Ho AJ(1), Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin
AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN,
Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR Jr, Weiner
MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM;

 

Alzheimer's Disease
Neuroimaging Initiative.


A recently identified variant within the fat mass and obesity-associated (FTO)
gene is carried by 46% of Western Europeans and is associated with an
approximately 1.2 kg higher weight, on average, in adults and an approximately 1
cm greater waist circumference. With >1 billion overweight and 300 million obese
persons worldwide, it is crucial to understand the implications of carrying this
very common allele for the health of our aging population. FTO is highly
expressed in the brain and elevated body mass index (BMI) is associated with
brain atrophy, but it is unknown how the obesity-associated risk allele affects
human brain structure. We therefore generated 3D maps of regional brain volume
differences in 206 healthy elderly subjects scanned with MRI and genotyped as
part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of
systematic brain volume deficits in carriers of the obesity-associated risk
allele versus noncarriers. Relative to structure volumes in the mean template,
FTO risk allele carriers versus noncarriers had an average brain volume
difference of approximately 8% in the frontal lobes and 12% in the occipital
lobes-these regions also showed significant volume deficits in subjects with
higher BMI. These brain differences were not attributable to differences in
cholesterol levels, hypertension, or the volume of white matter hyperintensities;
which were not detectably higher in FTO risk allele carriers versus noncarriers.
These brain maps reveal that a commonly carried susceptibility allele for obesity
is associated with structural brain atrophy, with implications for the health of
the elderly.

PMCID: PMC2889537

PMID: 20404173 

 

------------
[2] Am J Clin Nutr. 2009 Nov;90(5):1418-25. doi: 10.3945/ajcn.2009.27958. Epub 2009
Sep 2.

Fat and carbohydrate intake modify the association between genetic variation in
the FTO genotype and obesity.

Sonestedt E(1), Roos C, Gullberg B, Ericson U, Wirfält E, Orho-Melander M.

Author information: 
(1)Department of Clinical Sciences in Malmö, Nutrition Epidemiology, Lund
University, Malmö, Sweden. emily.sonestedt@med.lu.se

BACKGROUND: The fat mass and obesity-associated gene (FTO) has been shown to be
associated with obesity and to influence appetite regulation.
OBJECTIVE: The aim was to examine whether dietary factors (macronutrient and
fiber intakes) and leisure-time physical activity modify the association between 
genetic variation in FTO and body mass index (BMI; in kg/m(2)).
DESIGN: A cross-sectional study examined 4839 subjects in the population-based
Malmö Diet and Cancer study with dietary data (from a modified diet history
method) and information on the genetic variant FTO (rs9939609). Direct
anthropometric measures were made, and leisure-time physical activity was
determined from the duration participants spent on 18 different physical
activities.
RESULTS: Significant interactions between energy-adjusted fat intake and FTO
genotype (P = 0.04) and between carbohydrate intake and FTO genotype (P = 0.001) 
on BMI were observed. The observed increase in BMI across FTO genotypes was
restricted to those who reported a high-fat diet, with a mean BMI of 25.3 (95%
CI: 24.9, 25.6) among TT carriers and of 26.3 (95% CI: 25.8, 26.8) among AA
carriers (P = 0.0001). The FTO variant was not associated with a higher BMI among
subjects with lower fat intakes (BMI = 25.7 and 25.9 in TT carriers and AA
carriers, respectively; P = 0.42). Among individuals with a low-carbohydrate
intake, we observed a mean BMI of 25.4 for TT carriers and of 26.8 for AA
carriers. The increase in BMI across genotypes was mainly restricted to
individuals who reported low leisure-time physical activity (P for trend = 0.004,
P for interaction = 0.05).
CONCLUSION: Our results indicate that high-fat diets and low physical activity
levels may accentuate the susceptibility to obesity by the FTO variant.

PMID: 19726594

Edited by Dean Pomerleau

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    rs9939609      TT    (lean variant = T)
    rs1421085      TT    (lean variant = T)
    rs17817449    TT    (lean variant = T)
    rs8043757      AA    (lean variant = A)
 
As you can see, I've inherited two copies (one from each of my parents) of the 'lean' allele for each of these four SNPs. So it is no wonder that unintended weight gain has never been an problem for me - at least according to these SNPs I have the antithesis of the 'thrifty genotype'.
 
I'm curious what other CRONies who are also subscribers to 23andMe have for these SNPs, and whether they consider themselves to have a 'thrifty genotype' (easily gain weight) or not. I also wonder whether long-term success on a CR lifestyle is in any way correlated with the values for these SNPs. There is some indication [4] that some of the FTO SNPs (including rs9939609) have an effect on energy intake and preference for energy dense (i.e. high fat) foods, and from [2] we saw that people with the 'obese' allele for rs9939609 and who eat a high-fat, low-carb diet have a higher BMI, which could discourage people trying to practice CR in order to lose weight. Conversely, having a 'thrifty genotype' might make it easier to maintain a low calorie intake without becoming terribly skinny, which can sometimes result in social pressure to eat more to avoid looking like a concentration camp victim.  :)

 

Very interesting, Dean.

 

My results:

    rs9939609      AT    (lean variant = T)
    rs1421085      CT    (lean variant = T)
    rs17817449    GT    (lean variant = T)
    rs8043757      AT    (lean variant = A)
 
It seems I'm split on all of them. I definitely have a lean phenotype and have been very lean 7-11% my entire life, usually around 8-9%, regardless of weight gain or loss ranging from 135 to 250 and back down to 180 pounds, with lifestyles ranging from competitive runner, competitive powerlifter, rather sedentary, and just keeping in shape with more moderate activity, and while eating diets ranging from very-low-fat, very-low-carb, more processed, more whole-foods, omnivorous, and vegan. I've always been pretty active though, and if I overeat I get fidgety and restless, my exercise tends to be spontaneously greater volume or higher intensely, and I get very warm. I also have a quite pronounced converse effect if I under-eat, quickly and robustly becoming slothful, relatively weak, and cold.

 

My thoughts are that the FTO genes contribute but play a relatively small predictive role in most people, which is what is seen with most SNPs for body weight and composition.

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Thanks for posting your results James. Someone else with a very mixed set of alleles for this set of SNPs posted to the Living the CR Way forum post on the topic, and made the same observation as you about always being lean.

 

It looks like you are right that the FTO gene is probably just one of many that impacts one's tendency to be lean or obese.  I guess it isn't surprising. The determination of phenotype from genotype usually turns out to be more complicated than one would naively surmise. 

 

--Dean

Edited by Dean Pomerleau

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Hi Dean and Zeta!

 

I had the same thoughts as Zeta.

hey'

I don't have my genome sequenced -- I had an email from "Project Einstein" -- they want to sequence the genomes of a large number of Abstract Math and Theoretical Physics Profs, who they regard as "distinguished" -- I'm in the group.  (This is the same group that first sequenced the Neanderthal genome, from fossil DNA).  I sent them my sample over a year ago -- they haven't finished yet.  The advantage:  They'll include detailed interpretations of the significance of every known genetic detail relevant to my genome; and they're a lot more reliable, probably, than the commercial sequencers -- such as 23&me.

 

Anyway, to get back on topic:  Remember the "Ob/Ob mice"?  No special advantage to being thin (or not thin) when comparing Ob/Ob  and non-Ob/Ob mice.

 

So, I think that Zeta's right.  (And I personally don't know if I'm genetically "thin" or not).

 

<_<

 

  -- Saul

 

 

 

 

  --  Saul

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Hi again, Zeta!

 

I should have noted in my last post that, certain things are certainly relevant to successfully being on CR (whether your a "naturally thin human" or an "Ob/Ob human :)") :  Low IGF1, low testosterone (for males), lower body temperature, etc; the list is on the main CR Society website.

 

  -- Saul

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Hi Rodney,

 

Anectdotes you supply methinks.

 

pdf's availed.

Body Mass Index in Young Adulthood, Obesity Trajectory, and Premature Mortality.
Hirko KA, Kantor ED, Cohen SS, Blot WJ, Stampfer MJ, Signorello LB.
Am J Epidemiol. 2015 May 13. pii: kwv084. [Epub ahead of print]
PMID:25977515
http://arc.crsociety.org/read.php?2,224575,224575#msg-224575

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Rodney,

 

You bring up two good points about the propensity to be thin as it relates to the practice of CR.

 

First, its well known that too abrupt onset or too severe calorie restriction can be detrimental to health and longevity in rodents, and presumably in other mammals (including humans). Having more metabolic reserves (in the form of fat), and a tendency not to lose whatever reserves one has, may help one avoid the negative effects of the stress/shocks associated with CR. The late-life "obesity paradox", where elderly people who are overweight and even obese have better odds of surviving than very thin people can be attributed at least in part to having more metabolic reserves, allowing one to weather the wasting that often accompanies illness or injury during old age.

 

Your second observation is that excessive thinness may be an indicator of latent disease (e.g. a early sign of cancer) that could reduce one's life expectancy. Indeed, when studies of the association between weight and mortality are done well, they ignore the first 5-10 years after the baseline measurements are made, to weed out thinness and increased mortality resulting from metabolic wasting due to latent disease. In such studies, the so called "obesity paradox" is usually attenuated - i.e. thinness is not (greatly) associated with excess mortality.

 

Study [1] is an interesting recent example. It measured men's weight at two widely separated time points (mean age at study onset was 47, and a second measurement was made 26 years later, when subjects were, on average, 73). Following the second measurement, mortality rates were tracked over the subsequent 12 years.  They found that having constant normal weight, or gaining weight between the two measurement points 26 years apart were associated with about equal, and relatively low mortality. But either being overweight/obese at the time of both measurements, or (especially) losing weight between the two measurements, was associated with either 30% or 80% excess mortality, respectively. The excess mortality for weight loss wasn't significantly attenuated even when diagnosed diseases at the time of the second measurement were controlled for, but the weight loss could have been a sign of latent, undiagnosed disease that would kill they guy over the subsequent 12 years.

 

Another explanation sometimes given for the obesity paradox is that when (nearly) everyone is eating a crappy diet, eating more of it can sometimes be beneficial, allowing one to avoid nutritional deficits. Protein is one nutrient sometimes cited as having pro-longevity value when consumed in extra amounts in the elderly (e.g. [2]), because of the difficulty elderly people have in assimilating it.

 

If there are any takeaway messages from these, they would seem to me to be:

  • If possible, start CR in early or middle adulthood, when the body is more resilient.
  • Ease into CR, to avoid a big shock, especially if starting relatively later in adulthood.
  • Back off on the severity of one's CR practice (and perhaps add extra protein) when one's gets to be in the elderly range (65-70+), to avoid nutrient deficiencies and maintain some metabolic reserves so one can weather the 'slings and arrows' that will eventually come.

--Dean

 

-----------------

[1] Am J Epidemiol. 2013 Nov 1;178(9):1452-60. doi: 10.1093/aje/kwt157. Epub 2013 Sep 5.

The "obesity paradox," frailty, disability, and mortality in older men: a prospective, longitudinal cohort study.

Strandberg TE, Stenholm S, Strandberg AY, Salomaa VV, Pitkälä KH, Tilvis RS.

An inverse relationship between overweight and mortality (the "obesity paradox")
is well documented, but there are scarce data on how body weight during the life
course affects this relationship. In the Helsinki Businessmen Study, we examined
the effect of weight trajectories on incident disability, frailty, and mortality
by stratifying 1,114 men (mean age of 47 years in 1974) into the following 4
groups based on body mass index (weight (kg)/height (m)(2)) values measured
twice, in 1974 and 2000: 1) constantly normal weight (n = 340, reference group);
2) constantly overweight (n = 495); 3) weight gain (n = 136); and 4) weight loss
(n = 143). Twelve-year mortality rates (from 2000 to 2012) and frailty and
mobility-related disability in late life were determined. Compared with
constantly normal weight, weight loss was associated with disability (odds ratio
(OR) = 2.4, 95% confidence interval (CI): 1.1, 4.9) and frailty (OR = 3.7, 95%
CI: 1.3, 10.5) in late life. Constant overweight was associated with increased
disability (OR = 1.9, 95% CI: 1.1, 3.2). Men with constantly normal weight had
the fewest comorbidities in late life (P < 0.001). Higher 12-year mortality rates
were observed both with weight loss (hazard ratio = 1.8, 95% CI: 1.3, 2.3) and
with constant overweight (hazard ratio = 1.3, 95% CI: 1.03, 1.7). Those with
constantly normal weight or weight gain had similar outcomes. We observed no
obesity paradox in late life when earlier weight trajectories were taken into
account.

PMID: 24008903

 

-----------

[2] Cell Metab. 2014 Mar 4;19(3):407-17. doi: 10.1016/j.cmet.2014.02.006.

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.

Levine ME(1), Suarez JA(2), Brandhorst S(2), Balasubramanian P(2), Cheng CW(2),
Madia F(3), Fontana L(4), Mirisola MG(5), Guevara-Aguirre J(6), Wan J(2),
Passarino G(7), Kennedy BK(8), Wei M(2), Cohen P(2), Crimmins EM(1), Longo VD(9).

Mice and humans with growth hormone receptor/IGF-1 deficiencies display major
reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1
activity, we examined links between protein intake and mortality. Respondents
aged 50-65 reporting high protein intake had a 75% increase in overall mortality
and a 4-fold increase in cancer death risk during the following 18 years. These
associations were either abolished or attenuated if the proteins were plant
derived. Conversely, high protein intake was associated with reduced cancer and
overall mortality in respondents over 65, but a 5-fold increase in diabetes
mortality across all ages. Mouse studies confirmed the effect of high protein
intake and GHR-IGF-1 signaling on the incidence and progression of breast and
melanoma tumors, but also the detrimental effects of a low protein diet in the
very old. These results suggest that low protein intake during middle age
followed by moderate to high protein consumption in old adults may optimize
healthspan and longevity.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMCID: PMC3988204
PMID: 24606898

Edited by Dean Pomerleau

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Hi everyone,

Just came across the following:

PPARG genotype accounts for part of individual variation in body weight reduction in response to calorie restriction.

 

Lots of SNPs mentioned, but without full access to the paper I can't check them.

 

Al, anyone, have access to the full text?

 

One of the mentioned SNPs is discussed here:

 

 

(I'm CC at rs1801282.)

 

Zeta

 

Edited by Zeta

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Hi Al !

 

Welcome to the CR Forums. I hope we will see a lot more of you and your posts!

 

I dug through the paper [1] that you pointed to to that supposedly refutes Rodney's theory / observation that being naturally thin is bad news. Its major finding was that being overweight, and especially obese, (as self-reported) at 21 years of age was associated with a large increase in mortality (mostly from cardiovascular disease) 25-50 years later, at least among this population of mostly African American, largely poor people from the southern US.

 

Some of the interesting sound bites from the full study:

  • Being underweight when young is ok - Being underweight at 21 years of age was no worse (nor better) than being normal weight when it came to mortality (from all-cause, CVD or cancer) many years later.
  • In healthy non-smokers, young-adult obesity is even worse for mortality - Among the healthy never smokers, participants who were overweight or obese as young adults had a 27% (95% CI: 8, 48) or 80% (95% CI: 50, 117) higher mortality risk, respectively, than did participants with a young-adult BMI in the normal range

But:

  • In healthy non-smokers, gaining weight over wasn't bad - "[in healthy non-smokers] the association remained null for those who moved from a nonobese category in young adulthood to an obese category in middle adulthood".
  • Losing a lot of weight subsequent to young adult obesity was bad - Participants who were obese at 21 years of age but nonobese at cohort entry (approximately 20–45 years later) were found to have the highest relative mortality risk (2.39x mortality rate in healthy never-smokers who went from obese to non-obese compared with healthy never smokers who remained non-obese throughout the study). Losing weight to become non-obese was actually worse than staying obese among healthy never-smokers (2.39x mortality vs. 1.7x mortality, respectively, relative to never-obese).
  • "Our findings imply that becoming obese in middle adulthood carries few consequences in relation to all-cause mortality in this population, which suggests that the 
    most serious detrimental outcomes of obesity might be triggered in early adulthood."

The fact that being overweight/obese in young adulthood was associated with higher mortality, particularly from cardiovascular disease much later in life is perhaps not too surprising. CVD is a disease that develops over many years, so starting bad habits of diet/lifestyle when young results in more time for damage to accumulate and eventual earlier death.

 

The same potential confounders (e.g. low-weight / weight-loss associated with latent disease) discussed above are relevant to this study. And the relevance of this population (largely overweight / obese, mostly relatively poor African Americans from the southern US) to CR practitioners is particularly suspect. Therefore I don't believe this study says very much about the mortality effects of weight loss pursuant to beginning CR in adulthood.

 

But it does seem to refute Rodney's argument that being naturally thin is a bad thing, at least among this population.

 

--Dean

 

-------------------------------

[1] Body Mass Index in Young Adulthood, Obesity Trajectory, and Premature 
Mortality.
Hirko KA, Kantor ED, Cohen SS, Blot WJ, Stampfer MJ, Signorello LB.
Am J Epidemiol. 2015 May 13. pii: kwv084. [Epub ahead of print]

Abstract

Although much research has been conducted on the role adult body mass index 
(BMI) plays in mortality, there have been fewer studies that evaluated the 
associations of BMI in young adulthood and adult weight trajectory with 
mortality, and it remains uncertain whether associations differ by race or 
sex. We prospectively examined the relationships of BMI in young adulthood 
(21 years of age) and adult obesity trajectory with later-life mortality 
rates among 75,881 men and women in the Southern Community Cohort Study. 
Study participants were enrolled between 2002 and 2009 at ages 40-79 years 
and were followed through December, 2011. Multivariable Cox proportional 
hazards models were used to estimate hazard ratios and 95% confidence 
intervals. There were 7,301 deaths in the 474,970 person-years of follow-up. 
Participants who reported being overweight or obese as young adults had 
mortality rates that were 19% (95% confidence interval: 12, 27) and 64% (95% 
confidence interval: 52, 78) higher, respectively, than those of their 
normal weight counterparts. The results did not significantly differ by race 
or sex. Participants who reported being obese in young adulthood only or in 
both young and middle adulthood experienced mortality rates that were 
40%-90% higher than those of participants who were nonobese at either time. 
These results suggest that obesity in young adulthood is associated with 
higher mortality risk regardless of race, sex, and obesity status in later 
life.

 

PMID:25977515

Edited by Dean Pomerleau

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Saul raises some interesting questions, especially this one:

 

(3) What controls metabolic efficiency?  Obviously, it's at least partly genetic; probably also partly epigenetic.  It's even possible (but I doubt it) that various forms of pollution, or the lack thereof, might be a factor.

 

This entire thread has been about the genetics of obesity, but I think you are probably right Saul, that epigenetics (changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself), probably plays a big role as well. Evidence for this is discussed in this very interesting paper [1] about how epigenetics influences the development of chronic disease.

 

In particular, it reviews the evidence that prenatal and early life nutritional deficiencies can lead to lifelong changes in metabolism that increase one's propensity for developing chronic conditions like diabetes via alterations in gene expression. In particular, the "thrifty phenotype hypothesis" is that in order to survive famine / malnutrition, fetuses and infants make (permanent) adjustments to their gene expression which favor shunting resources to the important organs (like the brain) and away from less important organs (like the pancreas and kidneys). Intuitively, this might manifest itself as developing fewer / less effective beta cells in the pancreas, so those resources can be devoted to brain development. This shift would make those individuals less able to produce insulin and therefore process glucose, making them more susceptible to diabetes later in life. But from an evolutionary perspective, the tradeoff is worth it because the individuals were able to survive their tough childhood and reach reproductive age. Evidence for this sort of idea is that underweight (and overweight!) babies are much more likely to develop diabetes later in life [2].

 

So the origins of obesity are no doubt quite a complicated mix of genetics, epigenetics, psychology, sociology, and economics. But it seems that however it originates, obesity (particularly early in life and through middle age at least) is detrimental to health and longevity.

 

As far as I can see the jury is still out on Saul's (and Rodney's?) question about whether for people it is better to have a tendency towards obesity but nonetheless remain slim vs. remaining slim without much effort. Intuitively I can imagine it being beneficial to be in the former category, but harder to pull off than the latter.

 

--Dean

 

-------------

[1] Int J Epidemiol. 2013 Oct;42(5):1223-7. doi: 10.1093/ije/dyt130.

Commentary: The thrifty phenotype and the hierarchical preservation of tissues
under stress.

Wells JC(1).

 

Free full text

PMID: 24159066

 

-------------

[2] Am J Epidemiol. 2007 Apr 15;165(8):849-57. Epub 2007 Jan 10.

Birth weight and subsequent risk of type 2 diabetes: a meta-analysis.

Harder T(1), Rodekamp E, Schellong K, Dudenhausen JW, Plagemann A.

Author information:
(1)Obstetrics Clinic, "Experimental Obstetrics" Research Group,
Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.

The "small baby syndrome hypothesis" suggests that an inverse linear relation
exists between birth weight and risk of type 2 diabetes. The authors conducted a
meta-analysis to examine this association. They included studies that reported
odds ratios and 95% confidence intervals (or data with which to calculate them)
for the association of type 2 diabetes with birth weight. Fourteen studies
involving a total of 132,180 persons were identified. Low birth weight (<2,500
g), as compared with a birth weight of >/=2,500 g, was associated with increased
risk of type 2 diabetes (odds ratio (OR) = 1.32, 95% confidence interval (CI):
1.06, 1.64). High birth weight (>4,000 g), as compared with a birth weight of
</=4,000 g, was associated with increased risk to the same extent (OR = 1.27, 95%
CI: 1.01, 1.59). Pooled estimates increased further when normal birth weight
(2,500-4,000 g) was used as the reference category (low birth weight: OR = 1.47,
95% CI: 1.26, 1.72; high birth weight: OR = 1.36, 95% CI: 1.07, 1.73).
Meta-regression and categorical analyses showed a U-shaped relation between birth
weight and diabetes risk. These findings indicate that there exists a relation
between birth weight and later-life risk of type 2 diabetes which is not linearly
inverse but U-shaped.

PMID: 17215379

Edited by Dean Pomerleau

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All,

 

See this continuation thread for discussion of [2], which found that mice that were able to retain fat due to their genetics benefited more, and/or were harmed less, by CR.

 

--Dean

 

----------------------

[2] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub

2011 Apr 25.

Fat maintenance is a predictor of the murine lifespan response to dietary
restriction.

Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.

Dietary restriction (DR), one of the most robust life-extending manipulations, is
usually associated with reduced adiposity. This reduction is hypothesized to be
important in the life-extending effect of DR, because excess adiposity is
associated with metabolic and age-related disease. Previously, we described
remarkable variation in the lifespan response of 41 recombinant inbred strains of
mice to DR, ranging from life extension to life shortening. Here, we used this
variation to determine the relationship of lifespan modulation under DR to fat
loss. Across strains, DR life extension correlated inversely with fat reduction,
measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63,
P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in
fat were more likely to show life extension, and those with the greatest
reduction were more likely to have shortened lifespan. We identified two
significant quantitative trait loci (QTLs) affecting fat mass under DR in males
but none for lifespan, precluding the confirmation of these loci as coordinate
modulators of adiposity and longevity. Our data also provide evidence for a QTL
previously shown to affect fuel efficiency under DR. In summary, the data do not
support an important role for fat reduction in life extension by DR. They suggest
instead that factors associated with maintaining adiposity are important for
survival and life extension under DR.

PMCID: PMC3685291
PMID: 21388497

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Here is an interesting new paper [1] in this month's Journal of Neuroscience on one potential mechanism by which the FTO gene we've been discussing may impact obesity. Here is a good commentary on the paper.

 

In a nutshell, the authors put people in an FMRI machine to monitor their brain activity while they learned a new discrimination task in a negative reinforcement paradigm. It turns out people with the obesity-predisposing variant of the FTO gene (and another gene linked to obesity) didn't learn from their mistakes as well as people with the normal variants for these two genes This poorer learning from mistakes correlated with reduced dopamine signalling between the 'executive' area of the brain (prefrontal cortex) and more primitive areas of the brain associated with reward and motivation.

 

The authors postulate that this weaker neural link could result in reduced self-control, and therefore an increased tendency towards obesity.

 

From the commentary on the paper:

 

While the researchers did not establish a direct link between the dopamine-signaling effect and obesity, their results could help untangle the mechanism by which genes linked to obesity might function. “What this research supports is the idea of obesity as a disorder of higher-level cognitive function—a disorder of how we control our own behavior,” said Dagher. “The main take-home message is that the genetic causes of obesity are rooted in the brain.”

 

--Dean

 

---------------

[1] J Neurosci. 2015 Sep 9;35(36):12584-92. doi: 10.1523/JNEUROSCI.1589-15.2015.

An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward
Learning.

Sevgi M(1), Rigoux L(1), Kühn AB(2), Mauer J(3), Schilbach L(4), Hess ME(1),
Gruendler TO(5), Ullsperger M(6), Stephan KE(7), Brüning JC(8), Tittgemeyer M(9).

Variations in the fat mass and obesity-associated (FTO) gene are linked to
obesity. However, the underlying neurobiological mechanisms by which these
genetic variants influence obesity, behavior, and brain are unknown. Given that
Fto regulates D2/3R signaling in mice, we tested in humans whether variants in
FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling
and is also associated with obesity. In a behavioral and fMRI study, we
demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain
brain responses to reward learning and behavioral responses associated with
learning from negative outcome in humans. Furthermore, dynamic causal modeling
confirmed that FTO variants modulate the connectivity in a basic reward circuit
of meso-striato-prefrontal regions, suggesting a mechanism by which genetic
predisposition alters reward processing not only in obesity, but also in other
disorders with altered D2R-dependent impulse control, such as
addiction.SIGNIFICANCE STATEMENT: Variations in the fat mass and
obesity-associated (FTO) gene are associated with obesity. Here we demonstrate
that variants of FTO affect dopamine-dependent midbrain brain responses and
learning from negative outcomes in humans during a reward learning task.
Furthermore, FTO variants modulate the connectivity in a basic reward circuit of
meso-striato-prefrontal regions, suggesting a mechanism by which genetic
vulnerability in reward processing can increase predisposition to obesity.

Copyright © 2015 the authors 0270-6474/15/3512584-09$15.00/0.

PMID: 26354923

Edited by Dean Pomerleau

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Yes.  This supports the finding in a previous study of an inverse association between BMI and the ability even to list everything the individual had eaten over a three week period.

 

Having been asked to record everything they had eaten, those with a high BMI were found to have failed to record a substantial percentage of what they had actually eaten while those with the lowest BMIs had recorded almost everything.  Not only were those with a high BMI unable to control the amount they ate, they also were less able to keep track of what they were eating over the three weeks of the study.

 

Actual caloric intake in the study was measured using doubly-labeled water.

 

Rodney.

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It seems to me that there are really two threads here, which would be usefully separated. The main thread is on the genetics of obesity, and especially FTO SNPs: what are the genetic determinants of predisposition to obesity genetically, and what do they functionally do to drive weight gain? The other is on the role of baseline weight and/or propensity to store fat on responsiveness to CR. There is some overlap between the two: as Dean notes in the opening post in the thread:

 

I'm curious what other CRONies who are also subscribers to 23andMe have for these SNPs, and whether they consider themselves to have a 'thrifty genotype' (easily gain weight) or not. I also wonder whether long-term success on a CR lifestyle is in any way correlated with the values for these SNPs. There is some indication [4] that some of the FTO SNPs (including rs9939609) have an effect on energy intake and preference for energy dense (i.e. high fat) foods, and from [2] we saw that people with the 'obese' allele for rs9939609 and who eat a high-fat, low-carb diet have a higher BMI, which could discourage people trying to practice CR in order to lose weight. Conversely, having a 'thrifty genotype' might make it easier to maintain a low calorie intake without becoming terribly skinny, which can sometimes result in social pressure to eat more to avoid looking like a concentration camp victim. :)

Even that, however, is not about the effectiveness of CR in extending lifespan (the subject of what I perceive to be the second thread), but the ease of practicing CR. The animal models to which we're looking for evidence on the second subject, of course, have their food chosen for them.

 

More subtly, the thread also went somewhat sideways on another BMI-and-life-expectancy paper, which isn't about CR at all, of course, but about people's waist-to-height ratio whether they got there 'naturally', by intentional reduction in energy intake by exercise, or by disease.

 

The posts on the role of the propensity to put on and maintain fat in reaping the benefits of CR on longevity include:

 

https://www.crsociety.org/topic/11250-genetics-of-obesity/?do=findComment&comment=12958

https://www.crsociety.org/topic/11250-genetics-of-obesity/?do=findComment&comment=12963

https://www.crsociety.org/topic/11250-genetics-of-obesity/?do=findComment&comment=12973

https://www.crsociety.org/topic/11250-genetics-of-obesity/?do=findComment&comment=12974

https://www.crsociety.org/topic/11250-genetics-of-obesity/?do=findComment&comment=13011

https://www.crsociety.org/topic/11250-genetics-of-obesity/?do=findComment&comment=13053

https://www.crsociety.org/topic/11250-genetics-of-obesity/page-2?do=findComment&comment=13153

https://www.crsociety.org/topic/11250-genetics-of-obesity/page-2?do=findComment&comment=13155

https://www.crsociety.org/topic/11250-genetics-of-obesity/page-2?do=findComment&comment=13157

 

I would like to merge those posts into this thread, which is largely dedicated to that subject:

https://www.crsociety.org/topic/11271-good-non-technical-cr-science-overview/

 

Would all of teh authors of these posts consent to it? Or, if not, could we orchestrate the authors posting in order duplications of those posts into said thread, to make one neat centralized one?

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I would like to merge those posts into this thread, which is largely dedicated to that subject:

https://www.crsociety.org/topic/11271-good-non-technical-cr-science-overview/

 

Would all of teh authors of these posts consent to it? Or, if not, could we orchestrate the authors posting in order duplications of those posts into said thread, to make one neat centralized one?

 

 

Sure Michael. Merging those posts with the other thread is fine with me.

 

--Dean

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