Jump to content
James Cain

Study: Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and

Recommended Posts

http://www.ncbi.nlm.nih.gov/pubmed/25546413

 

 

Rejuvenation Res. 2014 Dec 29. [Epub ahead of print]

Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and Metabolism.
Abstract

Caloric restriction has consistently been shown to extend lifespan and ameliorate aging-related diseases. These effects may be due to diet-induced reactive oxygen species acting to upregulate sirtuins and related protective pathways, which research suggests may be partially inhibited by dietary antioxidant supplementation. Since caloric restriction is not sustainable long-term for most humans, we investigated an alternative dietary approach, intermittent fasting, which is proposed to act on similar biological pathways. We hypothesized that a modified intermittent fasting diet, where participants maintain overall energy balance by alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal) would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by antioxidant supplementation. To assess the tolerability of the diet and to explore effects on biological mechanisms related to aging and metabolism, we recruited a cohort of 24 healthy individuals in a double crossover, double-blinded randomized clinical trial. Study participants underwent two three-week treatment periods: intermittent fasting and intermittent fasting with antioxidant (Vitamins C and E) supplementation. We found strict adherence to study-provided diets and that participants found the diet tolerable, with no adverse clinical findings or weight change. We detected a marginal increase (2.7%) in SIRT3 expression due to the intermittent fasting diet, but no change in expression of other genes or oxidative stress markers analyzed. We also found that intermittent fasting decreased plasma insulin levels (1.01 uU/mL). Although our study suggests that the intermittent fasting dieting paradigm is acceptable in healthy individuals, additional research is needed to further assess the potential benefits and risks.

 

The abstract "hypothesized that a modified intermittent fasting diet....would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by antioxidant supplementation" but then only says "We detected a marginal increase (2.7%) in SIRT3 expression due to the intermittent fasting diet..." without differentiating between IF with or without antioxidant supplementation. Anyone have full access that could clarify this?

 

James

 

Share this post


Link to post
Share on other sites

We assessed expression of SIRT1, SIRT3, SOD2, and TFAM, as these genes have been implicated from previous literature for a role in diet-induced benefits on aging4,7. Additionally, these genes were chosen because they are expressed in PBMCs. Increased gene expression was observed for all selected genes following IF with placebo: SIRT1 (+2.46%; 95% CI [-1.66%, 6.59%]; n = 16), SIRT3 (+2.71%; 95% CI [-0.33%, 5.76%]; n = 18), SOD2 (+2.36%; 95% CI [-3.57%, 8.30%]; n = 18), TFAM (+1.82%; 95% CI [-1.73%, 5.36%]; n = 18). None of these genes reached statistical significance, but SIRT3 trended toward significance (p=0.0772). For IFAO [iF with AntiOxidants], expression changes in SIRT1 (+1.87%; 95% CI [-1.05%, 4.78%]; n = 15) and SIRT3 (+1.92%; 95% CI [-1.10%, 4.95%]; n = 17) showed a trend towards increasing values, while SOD2 (-0.59%; 95% CI [-5.07%, 3.89%]; n = 17) and TFAM (-0.90%; 95% CI [-4.44%, 2.65%]; n = 17) appear unaffected (Figure 3). Finally, while each increase in expression following IF is qualitatively larger than the post treatment change for IFAO, paired t-tests revealed no statistically significant differences by target gene.

 

We also examined whether the interventions affected levels of oxidative stress, as previous studies of alternate-day fasting have found decreased oxidative stress27. We chose to measure RNA (8-oxo-G) and DNA (8-oxo-dG) as they are integrative measures of overall oxidative stress and are perturbed by metabolic changes34. Levels of RNA oxidation relative to pre-study diets remained unchanged for both IF (0.99; 95% CI [0.62, 1.57]; n = 15) and IFAO (0.95; 95% CI [0.69, 1.31]; n = 14). Similarly, DNA oxidation measurements demonstrated no change for IF (1.01; 95% CI [0.71, 1.43]; n = 16) and IFAO (1.03; 95% CI [0.63, 1.68]; n = 14) (Figure 4). Differences in oxidation levels between the two treatments (i.e. the differential effects due to antioxidant supplementation) were also not significant.

 

They had good compliance with the diet, and excellent compliance with pills (vitamins or placebos).

 

I wouldn't be surprised if some of the effects of CR were mediated by increased rather than decreased oxidative stress, or if this proved to be important to inducing some of the specific effects of CR (cf. literature on antioxidants blocking the adaptive response to exercise), but on the other hand (a) see here on taking this to its logical extreme; ( B) despite its suppression of some adaptive responses to exercise, feeding antioxidants to exercising rodents has no effect on exercise's ability to increase mean LS in rats;(1) (-c-) across the lifespan, CR very clearly reduces the generation of oxidative stress and the accumulation of oxidative damage (through the aforementioned reduction in generation and also increasing the robustness of molecular structures); and (d) various studies feeding CR animals antioxidants have thus far had no effect on LS,(eg. (2)) so any possible suppression of CR adaptations can't be all that damned important.

 

References

1: Holloszy JO. Longevity of exercising male rats: effect of an antioxidant supplemented diet. Mech Ageing Dev. 1998 Feb 16;100(3):211-9. PubMed PMID: 9578110.

 

2. Merry BJ, Kirk AJ, Goyns MH. Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev. 2008 Jun;129(6):341-8. Epub 2008 Apr 22. PubMed PMID: 18486188. See my detailed discussion of this study here.

Share this post


Link to post
Share on other sites

 

 
 
 
 
 
 
 
 
 

Here's a discussion of this paper on Eurek Alert - http://www.eurekalert.org/pub_releases/2015-02/uof-fdc022715.php

*********

Feast-and-famine diet could extend life, study shows

UNIVERSITY OF FLORIDA

Think of it as interval training for the dinner table.

University of Florida Health researchers have found that putting people on a feast-or-famine diet may mimic some of the benefits of fasting, and that adding antioxidant supplements may counteract those benefits.

Fasting has been shown in mice to extend lifespan and to improve age-related diseases. But fasting every day, which could entail skipping meals or simply reducing overall caloric intake, can be hard to maintain.

"People don't want to just under-eat for their whole lives," said Martin Wegman, an M.D.-Ph.D. student at the UF College of Medicine and co-author of the paper recently published in the journal Rejuvenation Research. "We started thinking about the concept of intermittent fasting."

Michael Guo, a UF M.D.-Ph.D. student who is pursuing the Ph.D. portion of the program in genetics at Harvard Medical School, said the group measured the participants' changes in weight, blood pressure, heart rate, glucose levels, cholesterol, markers of inflammation and genes involved in protective cell responses over 10 weeks.

"We found that intermittent fasting caused a slight increase to SIRT 3, a well-known gene that promotes longevity and is involved in protective cell responses," Guo said.

The SIRT3 gene encodes a protein also called SIRT3. The protein SIRT3 belongs to a class of proteins called sirtuins. Sirtuins, if increased in mice, can extend their lifespans, Guo said. Researchers think proteins such as SIRT3 are activated by oxidative stress, which is triggered when there are more free radicals produced in the body than the body can neutralize with antioxidants. However, small levels of free radicals can be beneficial: When the body undergoes stress -- which happens during fasting -- small levels of oxidative stress can trigger protective pathways, Guo said.

"The hypothesis is that if the body is intermittently exposed to low levels of oxidative stress, it can build a better response to it," Wegman said.

The researchers found that the intermittent fasting decreased insulin levels in the participants, which means the diet could have an anti-diabetic effect as well.

The group recruited 24 study participants in the double-blinded, randomized clinical trial. During a three-week period, the participants alternated one day of eating 25 percent of their daily caloric intake with one day of eating 175 percent of their daily caloric intake. For the average man's diet, a male participant would have eaten 650 calories on the fasting days and 4,550 calories on the feasting days. To test antioxidant supplements, the participants repeated the diet but also included vitamin C and vitamin E.

At the end of the three weeks, the researchers tested the same health parameters. They found that the beneficial sirtuin proteins such as SIRT 3 and another, SIRT1, tended to increase as a result of the diet. However, when antioxidants were supplemented on top of the diet, some of these increases disappeared. This is in line with some research that indicates flooding the system with supplemental antioxidants may counteract the effects of fasting or exercise, said Christiaan Leeuwenburgh, Ph.D., co-author of the paper and chief of the division of biology of aging in the department of aging and geriatric research.

"You need some pain, some inflammation, some oxidative stress for some regeneration or repair," Leeuwenburgh said. "These young investigators were intrigued by the question of whether some antioxidants could blunt the healthy effects of normal fasting."

On the study participants' fasting days, they ate foods such as roast beef and gravy, mashed potatoes, Oreo cookies and orange sherbet -- but they ate only one meal. On the feasting days, the participants ate bagels with cream cheese, oatmeal sweetened with honey and raisins, turkey sandwiches, apple sauce, spaghetti with chicken, yogurt and soda -- and lemon pound cake, Snickers bars and vanilla ice cream.

"Most of the participants found that fasting was easier than the feasting day, which was a little bit surprising to me," Guo said. "On the feasting days, we had some trouble giving them enough calories."

Leeuwenburgh said future studies should examine a larger cohort of participants and should include studying a larger number of genes in the participants as well as examining muscle and fat tissue.

 

Share this post


Link to post
Share on other sites

All:

 

 

Here's a discussion of this paper on Eurek Alert - http://www.eurekalert.org/pub_releases/2015-02/uof-fdc022715.php

*********

Feast-and-famine diet could extend life, study shows

UNIVERSITY OF FLORIDA

 

[After an initial one week run-in period on a 'normal' diet, participants randomly underwent one of two intermittent fasting regimens, with or without antioxidants]... During [each] three-week period, the participants alternated one day of eating 25 percent of their daily caloric intake with one day of eating 175 percent of their daily caloric intake. For the average man's diet, a male participant would have eaten 650 calories on the fasting days and 4,550 calories on the feasting days. [Then after a one-week washout,] To test antioxidant supplements, the participants repeated the diet but also included vitamin C and vitamin E. ... [before and after each period in the intervention,]   the group measured the participants' changes in weight, blood pressure, heart rate, glucose levels, cholesterol, markers of inflammation and genes involved in protective cell responses ...

 

They found that the beneficial sirtuin proteins such as SIRT 3 and another, SIRT1, tended to increase as a result of the diet. [As noted in excerpts above from the original paper, a "tendency" is all they found: "None of these genes reached statistical significance, but SIRT3 trended toward significance" -MR]. ... The protein SIRT3 belongs to a class of proteins called sirtuins. Sirtuins, if increased in mice, can extend their lifespans, Guo said. [No, damn it, they can't — or at least, the one that's been tried so far (SIRT1) can't; SIRT3 hasn't been properly tested — MR]. Researchers think proteins such as SIRT3 are activated by oxidative stress, which is triggered when there are more free radicals produced in the body than the body can neutralize with antioxidants. However, small levels of free radicals can be beneficial: When the body undergoes stress -- which happens during fasting -- small levels of oxidative stress can trigger protective pathways, Guo said. ... [sIRT3] promotes longevity [it's rather premature to assert that — MR] and is involved in protective cell responses," Guo said.

 

"The hypothesis is that if the body is intermittently exposed to low levels of oxidative stress, it can build a better response to it," Wegman said. ...

 

However, when antioxidants were supplemented on top of the diet, some of these increases disappeared. This is in line with some research that indicates flooding the system with supplemental antioxidants may counteract the effects of fasting or exercise, said Christiaan Leeuwenburgh ... "You need some pain, some inflammation, some oxidative stress for some regeneration or repair," Leeuwenburgh said.

 

On the study participants' fasting days, they ate foods such as roast beef and gravy, mashed potatoes, Oreo cookies and orange sherbet -- but they ate only one meal. On the feasting days, the participants ate bagels with cream cheese, oatmeal sweetened with honey and raisins, turkey sandwiches, apple sauce, spaghetti with chicken, yogurt and soda -- and lemon pound cake, Snickers bars and vanilla ice cream.

 

"Most of the participants found that fasting was easier than the feasting day, which was a little bit surprising to me," Guo said. "On the feasting days, we had some trouble giving them enough calories."

 

Aside from exaggerating the degree of confidence of the findings, and of their importance, I want to highlight the surprisingly crappy diet. The actual paper says,

 

 

Menus were developed and dietary intake data were analyzed using Nutrition Data System for Research software version 2010, developed by the Nutrition Coordinating Center (NCC), University of Minnesota, Minneapolis, MN. [This is the "NCCDB" database that was recently added to the USDA and other databases in CRON-O-Meter -MR]. The 2010 Dietary Guidelines for Americans was used to guide macronutrient composition in the prepared meals, with only small variations allowed to tailor meals according to participant preferences. One exception was the sodium content, which was maintained at average US consumption [ie, way too high -MR] rather than dietary guideline levels.

 

Although they only specify macronutrient composition, I had assumed that the diets were basically nutritious, but evidently they were pretty crappy. I wonder if all that sugar, refined carb, and possibly saturated fat, combined with an apparent lack of fruits and vegetables (which both contain antioxidants, and phytochemicals that induce antioxidant gene expression), might have artificially boosted their oxidative stress, and done so even more on their 'feast' days, creating an exaggerated response that might not occur (if it's even real — again, the nominal increase in SIRT3 expression was not statistically significant, and they only measured gene expression sensu stricto (mRNA transcription), which doesn't always translate to an actual increase in expressed protein levels. Thus, any effect (if real) might be irrelevant to a person eating a healthy diet.

 

 

Leeuwenburgh said future studies should examine a larger cohort of participants and should include studying a larger number of genes in the participants as well as examining muscle and fat tissue. ...

 

Definitely -- and a better diet.

Share this post


Link to post
Share on other sites

Thanks, Michael, for making this psot.  I was digusted by the diet used in this study, for both fasting and feasting days.  A better diet, a much larger study group, and studying more genes would be much more likely to produce meaningful information.

 

;)

 

  -- Saul

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×