FOXO and Cider Vinegar

[Dean Pomerleau]

All,

 

Paul McGlothin and I have been having a discussion about the merits or risks of cider vinegar for longevity. Unfortunately the discussion is behind the CR Way paywall  :( , so I won't post Paul's side of the discussion directly, but paraphrase him instead.

 

Paul fears that the acetic acid in vinegar (cider or otherwise) gets converted into acetyl groups, which as discussed in this post, tend to unsilence genes by unwrapping them from histones in the nucleus so they can be transcribed into proteins. In particular, Paul is concerned that vinegar might reverse the effects of the Sirtuins, which are histone deacetylases, meaning they wrap genes tighter around histones, effectively silencing them. 

 

But when I questioned him about evidence for this specific effect of vinegar / acetic acid, he acknowledged that it's just a mechanistic hunch on his part. His hunch seems somewhat naive to me. Clearly some genes should be silenced and some expressed for effective aging, so its not clear a priori whether having more acetyl groups floating around would be good or bad from an aging perspective.

 

In fact, the one piece of hard evidence I came across [1], seems to support the opposite of Paul's argument, i.e. it suggests vinegar / acetic acid may actually be an anti-aging agent, at least in C. Elegans. It found that acetic acid upregulated the expression of DAF-16 in C. Elegans, leading to a 25% increase in lifespan. It doesn't appear to be having this effect by directly unwrapping DAF-16 for increased expression, but by somehow interfering with another gene, DAF-2, which normally suppresses the expression of DAF-16.

 

But whatever the mechanism, it suggests vinegar might not be so bad after all. Of course this is only a single study in worms, so there is no guarantee it is applicable to humans. But encouragingly, the human version of the DAF-16 gene upregulated by vinegar is the FOXO3 gene, the overexpression of which is well-known to be longevity-promoting in humans (e.g. [2]).

 

BTW, 23andMe has a SNP for determining one's FOXO3 variant, rs2802292. From [2], the odds ratio for reaching 100 years of age for rs2802292(G;G) vs (T;T) carriers was 2.75 (p = 0.00009; adjusted p = 0.00135). One's odds of living to 100 with one copy of 'G' for rs2802292 (i.e. G:T), appears to be about 1.5-2 times greater than people with T:T.

 

I'm G:T for rs2802292, so I've got that goin' for me  :)

 

Does anyone have and thoughts on vinegar, and whether you include it in your diet?

 

--Dean

 

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[1] Bioorganic & Medical Chemistry. 2009 Nov 15;17(22):7831-40. doi: 10.1016/j.bmc.2009.09.002. Epub 2009 Sep 6. 

The lifespan-promoting effect of acetic acid and Reishi polysaccharide. 

ChuangMH(1), Chiou SH, Huang CH, Yang WB, Wong CH. Author information: 
(1)Genomics Research Center, Academia Sinica, Taipei 115, Taiwan. 

Using Caenorhabditis elegans as a model organism, various natural substances and commercial health-food supplements were screened to evaluate their effects on longevity. Among the substances tested, acetic acid and Reishi polysaccharide fraction 3 (RF3) were shown to increase the expression of the lifespan and longevity-related transcription factor DAF-16 in C. elegans. 

We have shown that RF3 activates DAF-16 expression via TIR-1 receptor and MAPK pathway whereas acetic acid inhibits the trans-membrane receptor DAF-2 of the insulin/IGF-1 pathway to indirectly activate DAF-16 expression. In addition, a mixture of acetic acid and RF3 possesses a combined effect 30-40% greater than either substance used alone. 

A proteomic analysis of C. elegans using 2-DE and LC-MS/MS was then carried out, and 15 differentially expressed proteins involved in the lifespan-promoting activity were identified. 

PMID: 19837596

 

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[2] Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92. doi:

10.1073/pnas.0801030105. Epub 2008 Sep 2.

FOXO3A genotype is strongly associated with human longevity.

Willcox BJ(1), Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC,
Rodriguez B, Curb JD.

Author information:
(1)Pacific Health Research Institute, 846 South Hotel Street, Honolulu, HI 96813,
USA. bjwillcox@phrihawaii.org

Human longevity is a complex phenotype with a significant familial component, yet
little is known about its genetic antecedents. Increasing evidence from animal
models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important,
evolutionarily conserved biological pathway that influences aging and longevity.
However, to date human data have been scarce. Studies have been hampered by small
sample sizes, lack of precise phenotyping, and population stratification, among
other challenges. Therefore, to more precisely assess potential genetic
contributions to human longevity from genes linked to IIS signaling, we chose a
large, homogeneous, long-lived population of men well-characterized for aging
phenotypes, and we performed a nested-case control study of 5 candidate longevity
genes. Genetic variation within the FOXO3A gene was strongly associated with
human longevity. The OR for homozygous minor vs. homozygous major alleles between
the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived
men also presented several additional phenotypes linked to healthy aging,
including lower prevalence of cancer and cardiovascular disease, better
self-reported health, and high physical and cognitive function, despite
significantly older ages than controls. Several of these aging phenotypes were
associated with FOXO3A genotype. Long-lived men also exhibited several biological
markers indicative of greater insulin sensitivity and this was associated with
homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene,
human longevity and other aging phenotypes is warranted in other populations.

PMCID: PMC2544566
PMID: 18765803

[nicholson]

Over the years I have seen papers claiming benefits of vinegar for glucose regulation.  Here is an example:

 

http://care.diabetesjournals.org/content/27/1/281.full

 

Of course most of us here are not diabetic, so I cannot say if it has any relevence for us.

 

Rodney.

[Zeta]

I added unfiltered apple cider vinegar to my routine -- 12-16 g (~ml) before most higher-than-normal (for me) glycemic load meals. As Rodney points out, the evidence of benefit comes mostly (entirely? I haven't done an exhaustive investigation) from studies on diabetics, but apple cider vinegar seems like a reasonably good bet to me, or for me. I haven't done enough research yet to endorse it more strongly. I actually bought it initially as an alternative to standard shampoo!

 

Zeta

[Dean Pomerleau]

I too like cider vinegar for its purported glucose lowering effects. Paul suggests lemon juice (citric acid) should have the same effect. Although I didn't find any studies on lemon juice specifically, [1] suggests that another citrus fruit juice, grapefruit juice, has a beneficial effect on glucose control, at least in rats. But it may be the flavonols rather than the citric acid itself that has beneficial effects [2].

 

--Dean

 

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[1] Methods Find Exp Clin Pharmacol. 2009 Nov;31(9):563-70. doi:
10.1358/mf.2009.31.9.1435463.

Grapefruit juice improves glycemic control but exacerbates metformin-induced
lactic acidosis in non-diabetic rats.

Owira PM(1), Ojewole JA.

Recent clinical studies have indicated that grapefruit juice (GFJ) improves
insulin resistance and reduces weight gain in humans. The effect of GFJ on
glucose tolerance and metformin-induced lactic acidosis in normal, non-diabetic
in rats is hereby investigated. Three groups (A, B, C) of 20 male Wistar rats
each, were treated with stepwise, escalated oral doses of 0, 1.0, 2.0, 3.0 (group
A), and 3.0 ml/kg body weight (groups B and C) of GFJ. Group C rats additionally
received 250 mg/kg body weight of metformin. All the animals were sacrificed
after 14 days of treatment. Fasting blood glucose levels were significantly (P <
0.0001) lower in GFJ-treated test (2.9 +/- 0.4 mmol/L) compared with control (3.7
+/- 0.39 mmol/L) rats, but 1.5-hr plasma insulin levels were similar. GFJ alone
or in combination with metformin, significantly (P < 0.05) lowered blood glucose
levels compared with control animals. Blood lactic acid levels were similar in
GFJ-treated test (2.81 +/- 1.4 mmol/L) and control (2.54 +/- 0.7 mmol/L) rats,
respectively, but were significantly increased (P = 0.0079) in rats that were
treated with either metformin alone (5.38 +/- 2.53 mmol/L) or in combination with
GFJ (8.31 +/- 3.48 mmol/L). Metformin concentration in liver tissue was
significantly higher (P < 0.05) in GFJ-treated (397 +/- 19 microg/g) than in
control (280 +/- 15 microg/g) rats, respectively. Plasma metformin levels were
comparable between the control (95 +/- 8.1 microg/ml) and GFJ-treated test (108
+/- 20 microg/ml) rats, respectively. Liver tissue metformin concentrations and
plasma lactic acid levels showed significant correlation in both control (P =
0.0122; r(2) = 0.9080) and GFJ-treated test rats (P = 0.0005; r(2) = 0.9893).
Although GFJ may be beneficial to diabetic patients, it may exacerbate lactic
acidosis in diabetic patients taking metformin concurrently.

Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

PMID: 20094639

 

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[2] Curr Top Med Chem. 2015;15(2):187-95.

Emerging potential of citrus flavanones as an antioxidant in diabetes and its
complications.

Sharma M, Akhtar N, Sambhav K, Shete G, Bansal AK, Sharma SS(1).

Author information:
(1)Molecular Neuropharmacology Laboratory, Department of Pharmacology and
Toxicology, National Institute of Pharmaceutical Education and Research (NIPER),
S.A.S. Nagar, Mohali, Punjab, India. sssharma@niper.ac.in.

A proper balance between oxidants and antioxidants is necessary in maintaining
health and longevity. Alterations in this balance may result in oxidative stress
causing functional disorders and diseases. Oxidative stress is considered to play
a vital role in the pathogenesis of diabetes and its complications. Flavanones
and flavanones-rich botanical extracts have been a subject of great interest for
scientific research. Citrus flavanones like naringin and hesperidin exert a
variety of biological activities such as anti-oxidant, anti-inflammatory,
antihyperglycemic, anti-apoptotic etc. Naringin and hesperidin along with their
respective aglycones, naringenin and hesperetin have been shown to attenuate
diabetes and its related complications. This review discusses the role of
flavanones as a possible emerging treatment for diabetes and its complications
along with the possible mechanistic explanations.

PMID: 25547100

[AlPater]

And it is not difficult to find benefits of vinegar in healthy people; the paper is pdf-availed:

 

Effect of neutralized and native vinegar on blood glucose and acetate responses to a mixed meal in healthy subjects.
Brighenti F, Castellani G, Benini L, Casiraghi MC, Leopardi E, Crovetti R, Testolin G.
Eur J Clin Nutr. 1995 Apr;49(4):242-7.
PMID: 7796781

 

Abstract

OBJECTIVE:
 

To investigate the influence of sodium acetate and acetic acid from vinegar on blood glucose and acetate response to a mixed meal in healthy subjects.
 

DESIGN:
 

Five healthy subjects consumed in random order six test meals consisting of 100 g of sliced lettuce dressed with olive oil (Blank), olive oil plus 1 g acetic acid in the form of vinegar (AcOH), or olive oil plus sodium acetate in the form of vinegar neutralized to pH 6.0 with sodium bicarbonate (AcNa). On three occasions test meals were followed by a challenge consisting of 50 g carbohydrate portions of white bread (Bread). Glucose and acetate concentrations were measured in arterialized capillary blood before and until 95 min after the meals. Ultrasonography was performed in four other subjects to measure gastric emptying times after AcOH + Bread and AcNa + Bread.
 

RESULTS:
 

Blood acetate response over 95 min was markedly reduced after AcOH and AcOH+Bread meals compared to AcNa and AcNa + Bread. Similarly, the glucose response was depressed by 31.4% (P = 0.0228) after AcOH+Bread with respect to AcNa + Bread and Blank + Bread. No difference was observed between gastric emptying times after AcOH + Bread and AcNa + Bread.
 

CONCLUSIONS:
 

The results suggest that oral acetic acid and acetate might have a different effect on acetataemia and that a limited dose of vinegar, in the form of salad dressing, is sufficient to influence significantly the glycaemic response to a mixed meal in normal subjects by a mechanism related to acidity but not to gastric emptying.

[Dean Pomerleau]

Thanks Al,

 

This one [1], is even more favorable for vinegar in terms of glycemia. It found eating vinegar along with the bread meal (rather than before the meal, in the study Al posted), reduced both post-meal glucose and insulin in a linear dose-response manner in healthy subjects. Note, from the full text, the highest level of acetic acid in the study corresponded to 30ml (about 1oz) of vinegar.

 

--Dean

 

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[1] Eur J Clin Nutr. 2005 Sep;59(9):983-8.

 

Vinegar supplementation lowers glucose and insulin responses and increases
satiety after a bread meal in healthy subjects.

Ostman E(1), Granfeldt Y, Persson L, Björck I.

 

Full text: http://www.nature.com/ejcn/journal/v59/n9/pdf/1602197a.pdf

OBJECTIVE: To investigate the potential of acetic acid supplementation as a means
of lowering the glycaemic index (GI) of a bread meal, and to evaluate the
possible dose-response effect on postprandial glycaemia, insulinaemia and
satiety.
SUBJECTS AND SETTING: In all, 12 healthy volunteers participated and the tests
were performed at Applied Nutrition and Food Chemistry, Lund University, Sweden.
INTERVENTION: Three levels of vinegar (18, 23 and 28 mmol acetic acid) were
served with a portion of white wheat bread containing 50 g available
carbohydrates as breakfast in randomized order after an overnight fast. Bread
served without vinegar was used as a reference meal. Blood samples were taken
during 120 min for analysis of glucose and insulin. Satiety was measured with a
subjective rating scale.
RESULTS: A significant dose-response relation was seen at 30 min for blood
glucose and serum insulin responses; the higher the acetic acid level, the lower
the metabolic responses. Furthermore, the rating of satiety was directly related
to the acetic acid level. Compared with the reference meal, the highest level of
vinegar significantly lowered the blood glucose response at 30 and 45 min, the
insulin response at 15 and 30 min as well as increased the satiety score at 30,
90 and 120 min postprandially. The low and intermediate levels of vinegar also
lowered the 30 min glucose and the 15 min insulin responses significantly
compared with the reference meal. When GI and II (insulinaemic indices) were
calculated using the 90 min incremental area, a significant lowering was found
for the highest amount of acetic acid, although the corresponding values
calculated at 120 min did not differ from the reference meal.
CONCLUSION: Supplementation of a meal based on white wheat bread with vinegar
reduced postprandial responses of blood glucose and insulin, and increased the
subjective rating of satiety. There was an inverse dose-response relation between
the level of acetic acid and glucose and insulin responses and a linear
dose-response relation between acetic acid and satiety rating. The results
indicate an interesting potential of fermented and pickled products containing
acetic acid.

PMID: 16015276

[Sthira]

I'm walking around through life with a plastic water bottle. For awhile I wouldn't drink much. Then, several months ago, I started adding apple cider vinegar to the stuff -- for taste -- and now I'm way more hydrated.

 

I'm hoping by the time the vinegar steals my teeth new tech will be developed to grow more teeth.