Ron Put

Tom, your skepticism seems to me a bit too much like a "god is in the gaps" argument.

There is enough data at this point to  establish some basic probabilities. "Probably" is a key word in life, as well as genetics, period.

To give another analogy, If you wear a seat belt and have airbags in your car, your chances of surviving a crash generally increase compared to someone who does not. But there are specific instances where these safety measures may not work, and even be detrimental. For instance, under very specific circumstances, people of slight stature, may even receive more damage by such safety devices than from a particular crash.

If I understand your absolutist argument, you should be waiting until we have "smart" materials and safety devices which adapt to an individual's physical characteristics AND the conditions. AND have absolutely no error rate....

And yet, you appear to throw your skepticism out of the window the moment you are presented with a PR blurb touting an "app that makes it easy for everyone to understand the right foods for their unique metabolism in order to improve long-term health and manage weight more easily." Or, the moment you see a BBC headline proclaiming that a quarter of a million CENTENARIANS have gone missing in Japan.... 😄

4 hours ago, Dean Pomerleau said:

... Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331503/pdf/12881_2014_Article_138.pdf

Abstract
... ConclusionsOur results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD. ..."

Looking at the Promethease description for rs4977574, it states: "Some studies - but not others - report a slightly increased risk for myocardial infarction."

While this points to an interesting aberration, replacing vegetables with bacon and drinking a bottle of wine a day is probably not a wise  decision for anyone, based on preponderance of all available evidence. Humans are made up of more than rs4977574 and my guess is that other factors may be at play as well.

Here is something else to ponder:

"RESULTS: There were 925 cases with CAD and 634 without CAD enrolled in the present study. The G allele conferred a significant increase in risk of CAD (odds ratio = 1.47, P = 0.003 in the dominant model; odds ratio = 1.36, P = 0.018 in the recessive model). During a median of 11 years (inter-quartile range between 5.2 and 12.5 years) of follow-up, neither the total nor the cardiovascular mortality was different among CAD subjects with different genotypes. Using Cox regression analysis, genotypes of rs4977574 still failed to predict cardiovascular mortality (hazard ratio = 1.25, P = 0.138 in the dominant model; hazard ratio = 1.05, P = 0.729 in the recessive model).

CONCLUSIONS: The rs4977574 at chromosome 9p21 is associated with presence of CAD in Han Chinese. However, rs4977574 could not predict cardiovascular mortality in these CAD subjects during the eleven-year period of the study."

https://www.ncbi.nlm.nih.gov/pubmed/24804228?dopt=Abstract

Good points and data, mccoy. I am still unsure I grasp the data, or at least am not entirely comfortable with what I am grasping from the data.

Part of it may be my confusion of what constitutes "high" levels in a lot of the studies (apart from the Longo studies). From what I read, it would appear that higher IGF-1 levels are beneficial, up to close to 200 ng/ml, as long as one does not have cancer. If cancer is present, then IGF-1 is detrimental. Yet other studies find no relation between IGF-1 and longevity, unless too low or too high.

Even looking at the levels in Fig. 2 above, the A/A homozygous subjects show about 200 ng/ml on average at the age of 75-85, which is actually rather high for that age (kind of like Okinawans having higher levels of testosterone than the general population).

Again, this is likely my own confirmation bias talking, but the questions it rises are still valid, I think.

Tom, I am not sure that I agree with your strongly worded conclusions, based on what I read from your link.
 

• This large variation is only partly explained by genetic factors (less than 50% for glucose, less than 30% for insulin and less than 20% for triglycerides) and there is only a weak correlation between an individual's responses to fat and carbohydrates.
• Identical twins who share all their genes and most of their environment often had different responses to identical foods. The study also finds that identical twins shared just 37% of their gut microbes - only slightly higher than the 35% shared between two unrelated individuals. ...
• The results suggest that personal differences in metabolism due to factors such as the gut microbiome, meal timing and exercise are just as important as the nutritional composition of foods, supporting the idea that simple nutritional labeling is insufficient for assessing food.

This actually seems to support the notion that there are some general guidelines which apply to human populations regardless of specific genetic attributes. If you eat, for example, a (healthy) vegan diet, your microbiome will fit a certain pattern and if you eat lots of meat and dairy, your microbiome will fit a different broad pattern.

In other words, catering to your current microbiome may, or may not be "optimum" for you, whatever that means.

Moreover, your microbiome will dramatically and usually rather rapidly change, based on changes in your diet and lifestyle, too, as seen by testing through companies like uBiome.
 

2 hours ago, TomBAvoider said:

unless you can show that all commonly consumed human diets lead to identical health outcomes in any two individuals, my claim is exactly correct.

Why would one need to show "identical health outcomes in any two individuals?!!"

We are talking probabilities and patterns. To use the smoking argument, one may get lung cancer without ever having smoked and some life-long smokers do not get lung cancer. But it doesn't mean that smoking tobacco does not significantly increase the likelihood of developing a p53 mutation which leads to cancer.

2 hours ago, TomBAvoider said:

I feel very justified in claiming that any truly optimal diet will need to be tailored to the particular individual

What does this even mean? We already know what diets broadly improve the healthspan of populations -- we just can't make most people to follow them. What makes you think that if a "truly optimal diet tailored to the particular individual" (whatever this means to you) was possible to design, that individual would follow it, any more than they follow the general broad guidelines?

And, finally, speaking of BS meters, this is quite notable:

"About ZOE:

ZOE is a nutritional science company on a mission to help people eat with confidence. We are leading the world's largest ongoing scientific nutritional research project to understand our unique responses to food, developing a consumer at-home test and app that makes it easy for everyone to understand the right foods for their unique metabolism in order to improve long-term health and manage weight more easily."

It reminds me of one of popular "blood type diet" apps which had a tagline going something like: "Everybody is different! Ever body is different! Personalized nutrition for everybody!" 😄

4 hours ago, TomBAvoider said:

... Now, for what I say to be wrong, you'd have to assume that each food and food combination has exactly the same impact on every human being (that's generally healthy, as you indicated) - and that's clearly wrong, just on the face of it. But, my point isn't merely technical tiny effects at the margin - the effects are much more dramatic. How do we know that? At least in part because each individual has a different gut microbiome, in addition to our individual genetic and epi-genetic profile and physiology....

Actually, all that's needed for you to be wrong is to show broad correlations which can be tested by their broad predictive power. And this is exactly how we know that certain habits are healthier than others and certain habits are worse than others.

Such reasoning is easy to be exploited and it often is. The anti-vaxers fall into this category. But probably the most glaring example is the case with tobacco smoking and its correlation with increased mortality, which had been noted as early as the 17th century in Europe. But tobacco companies were able to seed enough doubt to exploit the confirmation bias of smokers and would be smokers and make them ignore the broad evidence. Exceptions such as the odd old geezer who smoked (including Calment, who actually smoked one cigarette on most days) were touted to make the point of each one's "uniqueness." Even after the exact effect of tobacco smoking on the mutation process of the p53 gene was shown in the 1990s, there is enough random nonsense floating around the web touting uniqueness and the very real ability of some individuals to resist such mutations.

But the fact is, for the vast majority of humans, smoking is bad. Just like for the vast majority of humans, eating more fruits and vegetables is much better than eating a lot of sausages, steaks and buckets of KFC.

As to microbiomes, yes, they are different. But if you look at the data provided by uBiome, for instance, you'll find broad similarities between vegans and vegetarians, and obese meat-eaters. You can choose to ignore it, because you convince yourself that the probabilities do not apply to you, but the science behind it remains valid, nevertheless.

As to this Russian-driven Calment conspiracy theory, it has all the credibility of Pizza-gate. But there were lots of folks who believed in that, too.

On 8/18/2019 at 2:03 PM, mccoy said:

The following plot though shows extremely scattered values of IGF-1 with age and the correlation coefficient is close to zero. (r=-0.18).

In the technical fields, such a coefficient would suggest no correlation at all.

I really do not understand how the basic assumption of a study can be based on such scattered and almost uncorrelated data.

mccoy, I think the issue with the scatterplot in that particular figure is that the relationship they are describing is not linear, so r=0.18 is misleading in this context.

Note this statement:

"age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level."
 

Then look at the A/As in this figure and their plasma IGF-1 at 70-85 and then at 85+, compared to G/G and G/A:

Thanks for the great summary, Sibiriak. I am still confused though, because they effectively say that there is no correlation between longevity in humans and total IGF-1 or IGF-1/IGFBP-3 ratio, only with IGF-1 bioactivity. The study I cited above also appears to indicate higher IFG-1 being beneficial until about 85 and then lower IFG-1 being beneficial to survival.

See also this one:

"It’s not quite the elixir of life, but researchers have at last identified gene variants that make people live longer. Men may miss out, as all carriers identified so far are women. They are also slightly shorter than average.

...

Both mutations affect the receptor for insulin-like growth factor 1 (IGF1), a driver of bodily growth and maturity, especially during puberty. By making the receptor slightly faulty, the mutations may disrupt IGF1 binding and decelerate the process of maturation and ageing.

In support, they found circulating levels of IGF1 to be 37% higher in carriers of the mutation, probably to compensate for the underperforming receptor. Carriers were also 2.5 centimetres shorter on average than the general population. ..."

https://www.newscientist.com/article/dn13403-long-life-genes-found-in-100-year-old-humans/

I am debating if I should dramatically reduce my (plant) protein intake (currently at about 1.4g per kg), since my IGF-1 is now above 180. My guess is this will adversely affect muscle mass, which is also an issue. And then I look at the human studies about IGF-1 and am starting to think that maybe I shouldn't worry so much about IGF-1 levels (confirmation bias may also play a role in my case) 🙂

And to make the whole IGF-1 thing more confusing, an older article:

"Elderly men with higher activity of the hormone IGF-1--or insulin-growth factor 1--appear to have greater life expectancy and reduced cardiovascular risk, according to a new study.

Thanks, Sibiriak. Very informative and rather convincing, to me at least.

I've reduced my Alpha CPG dose to 150 (from 300 over the past six months or so), but will continue taking it, since by my count, there are plenty of days I don't hit 400.

1 hour ago, Dean Pomerleau said:

...

Perhaps the Levine approach to estimating age from biomarkers isn't as good as Ron suggests.

...

Well, if one does a little research, its predictive abilities are rather good and better than most. It also jives with other research on the subject (e.g., https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12557 )

As to increased MCV values, as I noted above, the key is being asymptomatic (although I ran into a study I'll cite below which seems to indicate otherwise). For instance, during fasting, MCV values generally increase, as folate, B-12 and iron are depleted. Chronic deficiencies in those would also trigger an increase in MCV. Rapid turnover of RBCs will also do it. RBCs also depend on glucose for survival, so very low glucose levels would impact them as well (not so in my case). Or B malabsorbtion. In my case, I was thinking of double checking my B-12, since my folate appears fine.

But it also appears rather well documented that increased MCV are predictive of mortality in many clinical instances. Here are a couple of examples:

The prognostic value of interaction between mean corpuscular volume and red cell distribution width in mortality in chronic kidney disease

Mean corpuscular volume levels and all-cause and liver cancer mortality

"Elevated MCV level was related to an increased risk of liver cancer mortality in men (aHR, 3.55; 95% CI, 1.75-7.21). Conclusions: This study suggests that the elevated MCV level in non-anemic cancer-free individuals was associated with increased all-cause mortality in both men and women, and with cancer mortality, in particular liver cancer mortality in men."

There may be an interesting genetic component to IGF-1 levels, too, at least among men, which facilitates speedier decline in IGF-1 after about the age of 85 and thus promotes longevity (as long as they make it there):

"Males showed an age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between rs2229765 genotype and IGF-1 in the females.

Conclusion

These findings confirm the importance of the rs2229765 minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found."

https://bmcgeriatr.biomedcentral.com/articles/10.1186/1471-2318-9-19

Interesting.

They mention age-related narrowing of blood vessels as possible part of the mechanism. I'd guess that CR and low, plant based protein diet, may help ameliorate such effect.

Yeah, my MCV has gone up to just over 100, but it seems that if asymptomatic, elevated MCV is not an issue. You look younger than that 😄 😄

It looks like RDW has a large effect. Also CRP. I am 42.49 for phenotypic and 42.04 for DNAm age. I really wanted to be in my 30s.... 😄

So, after running close to 1:1 ration of Omega-3 to Omega-6, I noticed some significant changes:

Cholesterol: 153
LDL: 72
HDL: 71
Triglycerides: 51

My testosterone has gone up a bit, to just over 900 ng/dL

Interestingly, my IGF-1 has also gone up to over 180 ng/mL, although my insulin is pretty low at 2.5 uIU/mL, with glucose at 83. My protein intake (all plant) is 1.39g per kg, which is kind of high, I guess, but I don't know if I can drop it significantly and still stay all green for all the nutrients in Cronometer.

Today Withings has me at 64.2kg, 18.7 BMI,  9.6% body fat and 85.8% muscle mass.

 

I am a vegetarian, almost vegan, so my Omega 3 comes from stuff like flax, chia, legumes, walnuts and greens. Almost no olive oil (maybe 3-4 times a month, about 2 tbsp at a time or so). I do take olive leaf powder almost every day.

So, the big change is the drop in total cholesterol. I wonder what's with the IGF-1, but I am happy with my numbers overall and will likely keep the the 1:1 Omega 3 to Omega 6 ratio going forward.

Wow....

Nobody here was interested enough to run their numbers?

It seems to be the most accurate of the phenotypic age and mortality predictors I've come across.

2 hours ago, TomBAvoider said:

Unless you're homozygous for C677T MTHFR variant - which I am - in which case, also according to Chris Masterjohn, you need closer to 1 g of choline a day.

I'd take this and some other claims by Chris Masterjohn with a grain of salt.

https://blog.23andme.com/health-traits/our-take-on-the-mthfr-gene/

This seems to support the theory:

"In the new study, researchers conducted a number of experiments in mice to determine whether the protective effect of resveratrol against atherosclerosis was related to changes in the gut microbiome. They found that resveratrol reduces levels of trimethylamine-N-oxide (TMAO), a known contributor to the development of atherosclerosis. They also found that resveratrol inhibits TMA production by gut bacteria; TMA is necessary for the production of TMAO.

"In our current study, we found that resveratrol can remodel the gut microbiota including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Prevotella, and increasing the relative abundance of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in mice," said Dr. Mi. "Resveratrol reduces TMAO levels by inhibiting the gut microbial TMA formation via remodeling gut microbiota."
https://www.sciencedaily.com/releases/2016/04/160405105547.htm

Thanks, Sibiriak! This is helpful and it makes sense.

I guess I'll stick with taking a bit of Alpha GPC and make sure that I add garlic to mitigate the increase in platelet aggregation promoted by Alpha GPC.

Eating enough raw, crushed garlic every day can certainly crimp one's social interactions, so I am sticking to garlic powder when need to be social 🙂

Although only raw garlic has allicin, the study below seems to indicate that garlic powder and extracts retain their antiplatelet properties:

"... Raw garlic, garlic oil and other extract of garlic have been shown to inhibit platelet aggregation in in vitro induced by ADP, collagen, arachidonate, epinephrine and calcium ionophore [57,61,73-75]. Chronic intake of garlic powder and garlic oil also inhibits platelet aggregation [28,50,55,76-79]. ..."
 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139960/
 

This may be a silly question, but is supplementation with Alpha GPC choline likely to have similar effects, since it seems to work through somewhat different pathways than phosphatidylcholine?

Apologies if this has been posted before, my search didn't find anything. Below is the abstract from the paper summarizing certain identified biomarkers of aging.

An epigenetic biomarker of aging for lifespan and healthspan

"Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging." https://www.ncbi.nlm.nih.gov/pubmed/29676998

I ran across a discussion on the subject, which includes a spreadsheet linked in the first post which may be of interest to some here.

A Spreadsheet for Calculating Your Levine Phenotypic Age

 "An excellent paper by M. E. Levine, et al, entitled "An epigenetic biomarker of aging for lifespan and healthspan" describes a technique for combining nine blood-work values with calendar age to calculate your Mortality Score (probability of death in the next ten years) and your Phenotypic Age, i.e., your apparent biological age as implied by your blood variables.  The calculation procedure is rather arcane, involving non-obvious unit conversions, exponentials, and logarithms, so I have produced an Excel spreadsheet (LINK) for performing these calculations. ..."

https://forum.age-reversal.net/t/h4b2b5/a-spreadsheet-for-calculating-your-levine-phenotypic-age
 

Sibriak, you are right.

1g is a really high dose, and very profitable to the NR patent holders.

I actually thought the oversupplementation argument made above was interesting and deserves some pondering -- is anyone aware of a long-term study of B-Complex or similar supplementation, which would support or invalidate such line of thinking?

And then, there is this:

"What is the Difference Between NMN and NR? Is it Superior? Nicotinamide Mononucleotide Vs Nicotinamide Riboside

Nicotinomide Riboside Linked To Proxy For Healthier Aging In Pilot Study

"In a small pilot study consume who consumed a natural dietary supplement called nicotinomide riboside (NR) daily showed signs of mimicking caloric restriction, which in mice has been linked to health benefits.

Caloric restriction is a starvation diet. When lower level organisms such as fruit flies, roundworms, rodents are raised on such a diet from birth, slashing of caloric intake by about a third has health benefits and, in some cases, extended lifespan. No humans have done that, it would be a human rights violation to wean a baby on a starvation diet, and claims about benefits in adults who took it up have too many confounders to be anything more than anecdotes. 

In a small pilot study, 12 lean and healthy men and women ages 55 to 79 from the Boulder area were given a placebo for six weeks, then took a 500 mg twice-daily dose of nicotinamide riboside chloride (NIAGEN). Another 12 took nicotinamide riboside for the first six weeks, followed by placebo. The researchers took blood samples and other physiological measurements at the end of each treatment period. They found that the supplement slightly improved blood pressure and arterial health, particularly in those with mild hypertension but what they wanted to find was that 1,000 mg daily of nicotinamide riboside boosted levels of another compound called nicotinamide adenine dinucleotide (NAD+) by 60 percent. NAD+ is required for activation of enzymes called sirtuins, which is hypothesized to be involved in the beneficial effects of calorie restriction. It's involved in a host of metabolic actions throughout the body, and tends to decline with age.

...

The pilot study also found that in 13 participants with elevated blood pressure or stage 1 hypertension (120-139/80-89 mmHg), systolic blood pressure was about 10 points lower after supplementation. A drop of that magnitude could translate to a 25 percent reduction in heart attack risk but this is a pilot study in healthy people, so it should only be considered a viable technique if a company is willing to enter it into clinical trials. Otherwise, it will remain just another supplement for people who want to believe."

https://www.science20.com/news_staff/nicotinomide_riboside_linked_to_proxy_for_healthier_aging_in_pilot_study-240388

50 minutes ago, Sibiriak said:

That pig study, btw,  is noted in the review I linked above:  Contribution of Red Wine Consumption to Human Health Protection (2018)

"Hypercholesterolemic swine"  makes a good epithet!

 

Oops, didn't catch it.... LOL.

BTW, while most studies are on red wine, here is something on rice wine (I still think that perhaps the largest protective impact is from the alcohol itself, but that other factors found in wine and other drinks contribute as well):

"The beneficial effect of Chinese rice wine on atherosclerosis has been proved, but the exact components that have the cardiovascular protective effect are still unknown. This study aimed to explore the exact ingredients in Chinese rice wine that could inhibit homocysteine (Hcy)-induced vascular smooth muscle cell (VSMC) proliferation and migration. VSMCs were divided into 7 groups: control, Hcy (1 mmol/L), Hcy + oligosaccharide, Hcy + polypeptides, Hcy + polyphenols, Hcy + alcohol, and Hcy + Chinese rice wine. methyl thiazolyl tetrazolium (MTT) assay, Transwell chambers, and wound-healing assay were used to test the proliferation and migratory ability of the VSMCs. Western blot and gelatin zymography were used to investigate the expressions and activities of metal matrix proteinase 2/9 (MMP-2/9) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in VSMCs. Polypeptides and polyphenols in the Chinese rice wine reduced the proliferation and migration ability of the VSMCs. Furthermore, they also decreased the expression and activity of MMP-2/9 but had no obvious impact on the expression of TIMP-2 in each group. This study further confirms that polypeptides and polyphenols in the Chinese rice wine could inhibit Hcy-induced proliferation and migration of VSMCs and maintain the balance between matrix metalloproteinases (MMPs) and TIMPs."
https://www.ncbi.nlm.nih.gov/pubmed/26836482

Here is an interesting study showing the effects of red wine and vodka in pigs:

"... In this study, we demonstrated that both red wine and vodka improve perfusion to ischemic myocardium, but they do so by different mechanisms. Both beverages also decrease myocardial fibrosis in ischemic myocardium, but only red wine increases perfusion during ventricular pacing, improves segmental shortening and microvessel function, and reduces oxidative stress.

Serum alcohol levels in the swine were somewhat lower than we expected considering the body weight of the animals at the time of euthanasia was only 30 to 40 kg. It may simply be that swine metabolize alcohol differently than humans or that swine serum alcohol levels peak at a different time than that which we chose to draw their blood. Fortunately, the serum alcohol levels achieved in the swine in this experiment approximate that of an adult human after one to 2 alcoholic drinks and were sufficient to produce significant effects.

We specifically chose to use a model of hypercholesterolemia and chronic myocardial ischemia in this study because these comorbidities are very likely to be present in the at-risk patient population that might benefit from the cardioprotective effects of alcohol. Like other studies,¹⁶ we found that alcohol supplementation was associated with increased serum HDL cholesterol, whereas total cholesterol levels were unaffected. Although some groups, including our own, have shown that high doses of resveratrol decrease total cholesterol and the low-density lipoprotein:HDL ratio,¹⁷ we did not see these effects with the low doses of resveratrol present in our red wine. HDL cholesterol transports low-density lipoprotein from the periphery to the liver where it is metabolized; thus, the favorable lipid profile created by alcohol supplementation may play a role in cardioprotection and the prevention of atherosclerosis.

A key finding in this study is that both red wine and vodka significantly increased perfusion in the ischemic territory at rest. Two mechanisms can lead to increased blood flow in the setting of chronic ischemia: neogenesis of vessels or dilation of resistance arterioles. Hypercholesterolemia has been shown to cause endothelial dysfunction, reducing the ability of coronary arterioles to dilate.¹⁸ In a previous study, we found that high-dose purified resveratrol reversed this endothelial dysfunction in the ischemic territory of hypercholesterolemic swine related to its antioxidant effects.¹⁷ Similarly, despite a manyfold reduction in resveratrol content, red wine in this study significantly decreased oxidative stress and improved endothelium-dependent microvessel relaxation, phenomena that were not seen in vodka-treated swine. The finding that Sirt-1 and the antioxidant transcription factor phospho-FOXO1 were also upregulated only in the wine group suggests that these effects were in fact mediated by resveratrol.

On the other hand, the increased perfusion in the vodka-treated group appears to be related to increased capillary density, mediated by increases in phospho-endothelial nitric oxide synthase, vascular endothelial growth factor, and phospho-mammalian target of rapamycin, all potent mediators of angiogenesis in ischemic myocardium.^19,20 Interestingly, alcohol has actually been shown to inhibit mammalian target of rapamycin activity in cultured myocytes,²¹ but it may act differently in vivo or in the setting of ischemia. Phospho-endothelial nitric oxide synthase and vascular endothelial growth factor were upregulated in the wine-treated group as well but likely did not stimulate neogenesis of capillaries because perfusion was already improved by arteriolar relaxation.

The different mechanisms by which red wine and vodka improve perfusion may also explain why perfusion was only increased in the wine group under ventricular pacing. In the setting of greater oxygen demand, capillaries in the ischemic territory of vodka-treated swine would provide minimal benefit with regard to perfusion because of their small size and fixed number. On the other hand, the improved ability of resistance arterioles to relax in the wine-treated animals likely allows them to adjust for the increased oxygen demand of ventricular pacing and increase blood flow accordingly. Thus, the antioxidant properties of resveratrol-containing red wine provide additional benefit over alcohol alone with regard to myocardial perfusion.

Although wine and vodka supplementation had no effect on global left ventricular function as measured by developed left ventricular pressure and first derivative of left ventricular pressure, there were significant differences in regional function in the ischemic territory. Red wine supplementation improved contractility in the ischemic territory, likely related to the improvements in blood flow discussed previously. Vodka supplementation, however, actually decreased regional contractility in the vertical axis, although myocardial fibrosis in the AAR was decreased compared with controls. Chronic ethanol ingestion has been associated with increased myocardial fibrosis and global contractile dysfunction,²² but the amounts of alcohol given in this study were insufficient to cause cardiomyopathy. It may be that at lower doses, alcohol actually decreases fibrosis in the ischemic territory. Although we did not specifically examine the molecular basis for decreased fibrosis in these animals, this finding likely relates to the increased myocardial perfusion in the ischemic myocardium in these groups. Antioxidants have also been shown to decrease myocardial remodeling and fibrosis after ischemic injury, so this may play a role in the wine treated animals as well, although they did not demonstrate any less fibrosis than the vodka-treated animals. The decreased contractility in the vodka group could be related to some other mechanism that we did not examine such as increased apoptosis.

A number of studies have shown that the cardioprotective effects of alcohol may actually be related to an inhibitory effect on platelet aggregation.^23,24 Our results showed no significant difference in platelet aggregation with either red wine or vodka supplementation, although the small numbers of animals assayed led to substantial margins of error. Nonetheless, both red wine and vodka clearly had beneficial effects on myocardial perfusion, fibrosis, and serum lipid profiles with red wine leading to additional improvements in perfusion and regional function due to its antioxidant properties. These findings shed new light on the mechanisms by which moderate alcohol intake might reduce cardiovascular risk. Whether these beneficial effects are also seen in patients remains to be seen."
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.111.082172