Chocolate was originally brought to America as a nutritional supplement, actually a medicine; it became a candy, confectionery and baking ingredient only later.  Back in the early 1700s chocolate was considered a primary medicine for use in the treatment of small pox. Benjamin Rush MD prescribed chocolate and biscuits both to prepare patients for their small pox inoculations and as a major constituent in the diet for all patients during recovery from the disease.  Seeing a potential business opportunity, Dr James Baker, who had trained at Harvard as both a minister and physician, hired an Irish chocolate maker named John Hannon, to make chocolate for the New England Colonies.  In 1764, they started grinding chocolate beans using a water-powered gristmill on the Neponset River outside of Boston.  Thus the John Hannon Chocolate Company, the first serious producer of chocolate in Colonial America, came into being, manufacturing what we would now call a medicinal food.  They sold bricks of molded unsweetened chocolate.  Melted in boiling water, this chocolate was taken as medicine. Hannon was lost at sea in 1779, on his way to the West Indies to procure cacao beans, so Baker took over the company.  In 1780 he renamed the business, Bakers Chocolate.  This is the same Bakers Chocolate we still make brownies with today.

 

The Bakers Chocolate Factory, once upon a time
The Bakers Chocolate Factory, once upon a time

We should still think of chocolate as medicine.  Two recent Harvard studies, the most recent by Steinhaus et al suggest that eating chocolate regularly is associated with a decreased incidence of heart failure.  The most recent was published in January 2017 and examined data from a large cohort of Swedish men, 31,917 of them, who had no history of myocardial infarction, diabetes, or heart failure (HF) at baseline. These men were followed for HF hospitalization or mortality for 14 years starting in 1998. Chocolate consumption was assessed through self-administrated food frequency questionnaires and was compared with hospitalizations or death from heart failure.

 

During follow-up, 2,157 of the men ended up in the hospital or in the grave from heart failure. Compared with guys who never ate any chocolate, eating just 1-3 servings of chocolate per month was associated with a 12% lower risk [HR 0.88 (95% CI 0.78-0.99)] while 1-2 servings per week lowered risk 17%. The greatest reduction in risk, 18% below the guys who never ate chocolate, was for men eating 3-6 servings a week.  Here’s where it gets interesting.  Any more chocolate than this seemed to backfire; in guys eating 1 or more servings of chocolate per day, risk of heart failure increased to 10% higher than for those who never ate chocolate.   Let’s put this into simple terms: Some chocolate is better than none; a little more is even better than none, but a lot of chocolate is worse than none at all.

 

 

An earlier 2010 Harvard study by Elizabeth Mostofsky et al reported similar but more pronounced findings when 31,823 women were tracked in a like manner. Women consuming 1 to 3 servings of chocolate per month compared with no regular chocolate, had a 26% lower risk of heart failure.  Those consuming 1 to 2 servings per week, had a 32% decrease in risk. At higher levels of consumption, HF risk also appeared to increase. For women eating more than a serving a day relative risk was 23% higher than for those who ate no chocolate, (though this last trend did not reach statistical significance).

 

While the idea that chocolate is good for your health gets lots of attention as it justifies our occasional nibbling on something tasty, it’s the graphical representation of these results that is most intriguing.

 

When benefits seem to vary with dose like this, they are described as J-shaped or sometimes U-shaped.  The results from both of these chocolate studies the results display this pattern.  Moderate chocolate consumption is associated with a lower rate of hospitalization or death from heart failure, but this protective association disappears among individuals consuming ≥1 serving per day.  Risk went down with increasing dosage up to a point and then increased higher than the starting point, forming a J-shape.

 

A similar J-shaped relationship between dark chocolate consumption and serum c-reactive protein (CRP) was reported in 2008; individuals who consumed up to 1 serving of dark chocolate every 3 days had serum CRP concentrations that were significantly lower than non-consumers or higher consumers.  If regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein, it is no surprise that these decreased levels of inflammation appear to translate into differing risk for heart failure.  This J-shaped curve of effect persists through all three studies.

 

J-shape curves of dose response are the hallmark characteristic of what used to be called hormesis.  Hormesis is an old idea in medicine, one that has recently been dusted off and is coming back into more common usage.  It was originally used to refer to the beneficial and stimulatory action of low doses of toxic substances, including radiation, but technically any dose-response relationship that plots as a J or U-shaped curve is now describes as a hormetic response.

 

Calabrese and Baldwin, toxicologists at the University of Massachusetts, Amherst, have written several comprehensive historic reviews on hormesis that are worth reading.    This rather fascinating concept in biology has been neglected yet it is valuable to understanding how many of our plant medicines and naturopathic treatments work.

 

Hugo Schulz’s research done back in the late 1800’s is probably the first reported demonstration of hormesis. (There is debate about this: Rudolf Virchow is also given this honor for a line he wrote in 1854. ) In the later decades of the 19th century, low dose chemical stimulation was taken seriously as a method to effect plant and fungal growth.

“In fact, prior to 1900, the general belief had emerged in the realm of chemical toxicology that low doses as a general rule had the capacity to stimulate, while higher doses would inhibit the activity.  This so-called truism became referred to as either the Arndt-Schulz Law or Hueppe’s Rule as a results of Hugo Shulz’s research on chemical stimulation of yeast metabolism and Ferdinand Hueppe’s research on chemical stimulation of bacterial growth”

 

 

My fellow naturopathic doctors will recall Schulz’s name from the Arndt-Schulz Law often mentioned in our homeopathic coursework. This is a similar idea to hormesis, that low doses will trigger the opposite effect as larger doses.  The actual term hormesis did not come into use until 1943 when Southam and Erhlich proposed it.

 

Association of the Arndt-Schulz Law with homeopathy put the fledgling science of hormesis into trouble.  Even though respected scientists were publishing solid research in the early 20th century,

 “… the area of low dose chemical stimulation was to become the object of intense criticism… ……This criticism was to have its origin in the fact that this area of research was too closely allied to the controversial medical practice of homeopathy.  The area of chemical hormesis had become used as an explanatory factor by advocates of the medical practice of homeopathy.…..the concept of hormesis, especially chemical hormesis, became a cultural victim of guilt by association with homeopathy.  This marginalization was encouraged by traditional medical philosophy because of the long standing antipathy with homeopathy…… it was only natural to ….lump hormesis with homeopathy and the marginalization was complete.” 

 

Thus the ideas of hormesis and hormetic action were, and continue to be, under represented in scientific thought.  That’s why these chocolate studies caught my attention.  These days, don’t expect to see the terms hormesis in studies.  The telltale hints are these curves, J-shaped curves.

 

Before abandoning the topic of chocolate, it should be added that the Steinhaus and Mostofsky findings are consistent with other papers that suggest chocolate has beneficial effects on cardiovascular health.        Multiple studies have reported both acute and chronic chocolate consumption reduces systolic and diastolic blood pressure.   In addition, habitual chocolate eating is associated with lower incidence of stroke and myocardial infarction (MI), lower incidence of mortality from coronary heart disease, lower cardiac mortality and HF after incident MI, and improved vascular function in patients with HF. Thus these current Harvard results should come as no surprise.

 

Yet it is the J-shaped dose response that is most interesting.  Such dose responses occur more frequently then we notice and often describe responses to natural substances.  J-shaped or U-shaped curves are classic sign of hormetic responses, characterized by a beneficial effect at low doses and a toxic (or inhibitory or opposite) activity at higher doses.

 

 

Our intuitive assumption is that dose relationships should follow straight lines varying only by slope angle.  In a straight-line dose response, a little bit of a substance triggers a particular response and as the dose increases so does the degree of response; small doses, small responses; big doses, big responses.  But in J-shaped curves the nature of the response may change with the dose, even to the degree of having the opposite effect in high doses as what occurs at low doses.  Sometimes the smaller doses have an outsized beneficial response.

These chocolate studies are both good examples as consumption of moderate amounts of chocolate is associated with a decreased risk of heart failure.  But as the dose increases, rather than working better, the benefit disappears.  Risk decreases by 18% (in the newest study) for those consuming 3-6 servings per week but that benefit is lost when consumption increases to a serving a day.  In other words there is a sweet spot associated with the most benefit.  For chocolate that sweet spot appears to be less than a serving per day, somewhere in the range of 3-6 servings per week.  For dark chocolate, using CRP as a gauge, this sweet spot appears closer to 3 servings a week.

 

I like the term “sweet spot”; it describes our desire to eat chocolate, and serves as a substitute term for hormesis, a term that always makes me think of some sort of bodily secretion that we shy away from speaking about in public.

 

Chocolate is not the only natural substance for which the data suggests there is a sweet spot, a dose that will yield a maximum benefit.  Recent studies report J-shaped curves for coffee, alcohol, fish oil, BMI, blood sugars, vitamin D, vitamin C, and iodine.  There is very likely a sizeable list of other supplements that also have a dosing sweet spot that we should be watching for.

 

Coffee:

A meta-analysis published in May 2016 examined data from nine prospective cohort studies on coffee intake and risk of cognitive disorders.  The authors reported a “… ‘J-shaped’ association … between coffee intake and incident cognitive disorders, with the lowest risk of incident cognitive disorders at a daily consumption level of 1-2 cups of coffee.”   In other words, the ‘sweet spot’ for coffee may be at a cup or two per day.

 

A related meta-analysis examined coffee, tea and caffeine consumption against risk of depression.  Published in July 2016, this analysis combined twelve studies (n= 346,913). Compared to individuals with lower coffee consumption, those with higher intakes had a 24% lower relative risk of depression (RR 0.76, 95% CI: 0.64, 0.91). The dose-response graph again suggested a J-shaped relation between coffee consumption and depression risk with the protective effect peaking at 400 mL/day, that’s about a cup and a half. Some coffee appears to help, a lot doesn’t. 

 

 

Alcohol:

Studies have for years suggested similar patterns for alcohol consumption.  Small daily amounts of alcohol have been associated with decreased mortality while higher consumption is associated with greater risk of death.  A 2006 meta-analysis by Di Castelnuovo et al that pooled findings from 34 prospective studies, that included more than 1 million people and almost 100,000 deaths, reported a J-shaped relationship between alcohol intake and total mortality. Consumption of up to 2 drinks per day in women and 4 drinks per day in men was associated with lower mortality than zero consumption, with about one-half drink per day associated with the lowest mortality risk.

 

A March 2016 meta-analysis by Stockwell et al has however called these findings into question.  The earlier studies may not have adequately accounted for why abstainers or low volume consumers drank so little. Low-volume drinkers may appear healthier only because the “abstainers” with whom they are compared didn’t drink because of ill health.  In this newer meta-analysis after adjusting for these factors, low-volume alcohol consumption no longer had a benefit compared with lifetime abstention or occasional drinking.   Thus it is no longer clear if alcohol does have a J-shaped curve.

 

BMI:

Body Mass Index (BMI) is the currently accepted method for defining healthy weight and there clearly seems to be a sweet spot for this measurement. A 2010 prospective study (n=1.46 million) reported a J-shaped association between BMI and all-cause mortality after adjusting for potential confounders, including smoking and alcohol intake.  All-cause mortality was lowest among those with BMI of 20.0 to 24.9 and higher on either side of that interval.   Thus being too skinny or too fat increases risk of death. Another sweet spot.

 

A1c:

There appears to be a sweet spot for blood sugar levels in patients undergoing coronary angiography.   In July 2016 Almeida et al reported that hemoglobin A1c levels were associated with mortality risk in those undergoing these procedures and that this association followed a J-shaped curve.  Patients in the lowest and highest HbA1c groups had significantly higher mortality rates compared to in-between groups; A1c levels less than 5 or greater than 7% were significant predictors of death in these patients.

 

 

Vitamin D:

Too little or too much vitamin D may also pose a problem.  An October 2016 analysis of the EPIC-Norfolk Cohort reported, “In older adults, the relationship between vitamin D status and fracture risk was observed to be J-shaped.”

 

Schwartz had reported back in 2014 that in the SELECT trial data on prostate cancer prevention, that the effects of vitamin D followed a U-shaped curve. “The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. … There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83], 0.74, 0.86 (95% CI, 0.69-1.07; P = 0.181), and 0.98 , for the second through fifth quintiles, respectively.   The authors reported, “… significantly reduced risks among men with moderate concentrations (approximately 45 – 70 nmol/L)”  [18- 28 ng/ml].   This ‘sweet spot’ is notably lower than most of us might guess.

 

Studies that have looked at vitamin D levels and cardiovascular disease and overall mortality also report J-shaped associations.  A 2014 analysis reported that, as expected, mortality risk increases in those who are D deficient but mortality also increases at serum vitamin D levels above 125 nmol/l, which is about 50 ng/ml. This is a serum level that many patients, because of suggestions from their practitioners, still think they should exceed.

 

A similar J-shaped curve in mortality was reported a year earlier in 2013, in an analysis of the NHANES data. The authors reported that the lowest risk of mortality, what they called, “The nadir of risk” was as 81 nmol/L (95% CI, 73-90 nmol/L) or 32.4 ng/ml. 

 

 

Fish Oil:

A November 2016 meta-analysis suggests that fish oil’s impact on depression also follows a J-shaped pattern. Data from 31 studies were pooled (n= 255,076) with over 20,000 cases of depression.  Fish consumption was associated with a 22% reduction in relative risk of depression (RR=0.78, 95% CI: 0.69, 0.89).  Examination of EPA and DHA supplement use revealed a J-shaped association with a peak decreased risk at 1.8g/d intake of n-3 PUFA (RR=0.30, 95% CI: 0.09, 0.98).   A sweet spot for fish oils, higher or lower doses do not appear to be as effective.

 

A 2010 study suggested a J-shaped curve for fish consumption, in this case specifically for reducing psychotic-like symptoms. The associations were J-shaped with the strongest reduced risk for an intermediate intake of fish or PUFA. For fatty fish (herring/mackerel, salmon-type fish), the strongest inverse association was found for an intermediate intake (RR: 0.81, 95% CI, 0.66-0.98), whereas a high intake of fatty fish was associated with an increased risk of psychotic-like symptoms (RR: 1.90, 95% CI, 1.34-2.70).

 

Vitamin C and breast cancer:

There is now reason to believe that dietary vitamin C from the diet affects post-menopausal risk of breast cancer and this too has a sweet spot.   A paper published in July 2016 reports on data from the E3N cohort in France, a group of 57,403 women followed for 13 years, in which 2,482 cases of invasive breast cancer occurred.  Dietary vitamin C intake was assessed via regular questionnaires during the study.

 

Vitamin C supplement use was not associated with breast cancer risk overall. Vitamin C supplement use was associated with a significantly higher risk in postmenopausal breast cancer risk in women who had a high vitamin C intake from foods. Women in the fourth quartile of vitamin C intake from foods had a 32% increase in risk (HR: 1.32; 95% CI: 1.04, 1.67). This suggests a potential U- or J-shaped relation between total vitamin C intake and postmenopausal breast cancer risk.  This could suggest menopausal women might be better off not taking vitamin C supplements if they already have a healthy diet. 

 

Iodine:

We’ve long known that too little or too much iodine is a problem clinically.  In pregnancy this narrow range of safety is even more critical.   A 2015 paper (n=7,190) on pregnant women in China suggests that, “The upper limit of iodine intake during early pregnancy in an iodine-sufficient region should not exceed UIC 250 μg/L, because this is associated with a significantly high risk of subclinical hypothyroidism, …“ A safe range that is much smaller than previously thought.

 

Everything else?

Data from in vitro research suggests that a significant number of other herbal and nutritional supplements possess hormetic effect yet ex vivo data, in particular data from humans, is still lacking.  While we probably should suspect that these substances may also have a dosing ‘sweet spot’, at this time those ideal doses remain unknown.  Because of reports of J-shaped dose response curves that indicate hormetic action, sweet spots probably do exist for resveratrol, curcumin, berberine, green tea, licorice, olive oil polyphenols, and even blueberries.   We often only notice the phenomenon in the world that our brains are primed to expect.  It’s time to let go of the simplistic idea that if a little bit helps, more is going to work better. Life has proven to be more complicated.  It’ time to take notice.

 

 

 

Steinhaus DA, Mostofsky E, Levitan EB, et al. Chocolate intake and incidence of heart failure: Findings from the Cohort of Swedish Men. Am Heart J. January 2017 Volume 183, Pages 18–23

Mostofsky E, Levitan EB, Wolk A, Mittleman MA. Chocolate intake and incidence of heart failure: a population-based prospective study of middle-aged and elderly women. Circ Heart Fail. 2010 Sep 1;3(5):612-6.

di Giuseppe R, Di Castelnuovo A, Centritto F, et al. Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population. J Nutr. 2008 Oct;138(10):1939-45.

Calabrese EJ and Baldwin LA  Radiation hormesis: its historical foundations as a biological hypothesis. Hum Exp Toxicol. 2000 Jan;19(1):41-75.

Calabrese EJ, Baldwin LA. Defining hormesis. Hum Exp Toxicol. 2002 Feb;21(2):91-7.

Calabrese EJ.  Hormesis: changing view of the dose-response, a personal account of the history and current status. Mutat Res. 2002 Jul;511(3):181-9.

Henschler D. The origin of hormesis: historical background and driving forces. Hum & Exper Tox (2006) 25:347-351.

Calabrese EJ and Baldwin LA. Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis. Human & Exper Tox. (2000) 19, 85-97.

Ibid. Calabrese EJ and Baldwin LA. Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis. Human & Exper Tox. (2000) 19, 85-97.

Cooper KA, Donovan JL, Waterhouse AL, et al. Cocoa and health: a decade of research. Br J Nutr 2008;99:1-11.

Ding EL, Hutfless SM, Ding X, et al. Chocolate and prevention of cardiovascular disease: a systematic review. Nutr Metab (Lond) 2006;3:2.

Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 2007;85:895-909

Hooper L, Kay C, Abdelhamid A, et al. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr 2012;95:740-51.

Engler MB, Engler MM. The emerging role of flavonoid-rich cocoa and chocolate in cardiovascular health and disease. Nutr Rev 2006;64:109-18.

Esser D, Mars M, Oosterink E, et al. Dark chocolate consumption improves leukocyte adhesion factors and vascular function in overweight men. FASEB J 2014;28:1464-73.

Ried K, Sullivan TR, Fakler P, et al. Effect of cocoa on blood pressure. Cochrane Database Syst Rev 2012;8:CD008893.

Desch S, Kobler D, Schmidt J, et al. Low vs. higher-dose dark chocolate and blood pressure in cardiovascular high-risk patients. Am J Hypertens 2010;23:694-700.

Desch S, Schmidt J, Kobler D, et al. Effect of cocoa products on blood pressure: systematic review and meta-analysis. Am J Hypertens 2010;23:97-103.

Grassi D, Necozione S, Lippi C, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 2005;46:398-405.

Taubert D, Roesen R, Schomig E. Effect of cocoa and tea intake on blood pressure: a meta-analysis. Arch Intern Med 2007;167:626-34.

Buijsse B, Weikert C, Drogan D, et al. Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults. Eur Heart J 2010;31:1616-23.

Ding EL, Hutfless SM, Ding X, et al. Chocolate and prevention of cardiovascular disease: a systematic review. Nutr Metab (Lond) 2006;3:2.

Janszky I, Mukamal KJ, Ljung R, et al. Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program. J Intern Med 2009;266:248-57.

Buijsse B, Feskens EJ, Kok FJ, et al. Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study. Arch Intern Med 2006;166:411-7.

Borriello A, Bencivenga D, Caldarelli I, et al. Resveratrol and cancer treatment: is hormesis a yet unsolved matter? Curr Pharm Des. 2013;19(30):5384-93.

Wu L, Sun D, He Y. Coffee intake and the incident risk of cognitive disorders: A dose-response meta-analysis of nine prospective cohort studies. Clin Nutr. 2016 May 30. pii: S0261-5614(16)30111-X.

Grosso G, Micek A, Castellano S, Pajak A, Galvano F. Coffee, tea, caffeine and risk of depression: A systematic review and dose-response meta-analysis of observational studies. Mol Nutr Food Res. 2016 Jan;60(1):223-34.

Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MB, Iacoviello L, de Gaetano G. Alcohol dosing and total mortality in men and women. Arch Intern Med. 2006;166(22):2437-2445.

Stockwell T, Zhao J, Panwar S, Roemer A, Naimi T, Chikritzhs T. Do “Moderate” Drinkers Have Reduced Mortality Risk? A Systematic Review and Meta-Analysis of Alcohol Consumption and All-Cause Mortality. J Stud Alcohol Drugs. 2016 Mar;77(2):185-98.

Berrington de Gonzalez A, Hartge P, Cerhan JR,  et al.  Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2010;363(23):2211-2219.

Havakuk O, Banai S, Halkin A, et al. HbA1c Levels and Long-Term Mortality in Patients Undergoing Coronary Angiography. Cardiology. 2016;134(2):101-6.

Julian C, Lentjes MA, Huybrechts I, et al. Fracture Risk in Relation to Serum 25-Hydroxyvitamin D and Physical Activity: Results from the EPIC-Norfolk Cohort Study. PLoS One. 2016 Oct 17;11(10):e0164160.

Kristal AR, Till C, Song X, et al. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1494-504.

Zittermann A, Prokop S. The role of vitamin D for cardiovascular disease and overall mortality. Adv Exp Med Biol. 2014;810:106-19.

Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, et al. Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES. J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9.

Grosso G, Micek A, Marventano S, et al. Dietary n-3 PUFA, fish consumption and depression: A systematic review and meta-analysis of observational studies. J Affect Disord. 2016 Nov 15;205:269-281.

Hedelin M, Löf M, Olsson M, et al. Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry. 2010 May 26;10:38.

Cadeau C, Fournier A, Mesrine S, Clavel-Chapelon F, Fagherazzi G, Boutron-Ruault MC. Vitamin C supplement intake and postmenopausal breast cancer risk: interaction with dietary vitamin C. Am J Clin Nutr. 2016 Jul;104(1):228-34.

Shi X, Han C, Li C, et al. Optimal and safe upper limits of iodine intake for early pregnancy in iodine-sufficient regions: a cross-sectional study of 7190 pregnant women in China.  J Clin Endocrinol Metab. 2015 Apr;100(4):1630-8.

Borriello A, Bencivenga D, Caldarelli I, et al. Resveratrol and cancer treatment: is hormesis a yet unsolved matter? Curr Pharm Des. 2013;19(30):5384-93.

Rainey N, Motte L, Aggarwal BB, Petit PX. Curcumin hormesis mediates a cross-talk between autophagy and cell death. Cell Death Dis. 2015 Dec 3;6:e2003.

Zhang C, Li C, Chen S, et al. Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways. Redox Biol. 2016 Nov 4;11:1-11.

Deusing DJ, Winter S, Kler A, et al. A catechin-enriched green tea extract prevents glucose-induced survival reduction in Caenorhabditis elegans through sir-2.1 and uba-1 dependent hormesis. Fitoterapia. 2015 Apr;102:163-70.

Ohno H, Miyoshi S, Araho D, et al. Efficient utilization of licorice root by alkaline extraction. In Vivo. 2014 Sep-Oct;28(5):785-94.

Menendez JA, Joven J, Aragonès G, et al. Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents. Cell Cycle. 2013 Feb 15;12(4):555-78.

Elks CM, Reed SD, Mariappan N, et al. A blueberry-enriched diet attenuates nephropathy in a rat model of hypertension via reduction in oxidative stress. PLoS One. 2011;6(9):e24028.

Advertisements