Thursday, November 9, 2017
Monday, August 20, 2012
Horizon Eat, Fast and Live Longer
Eat, Fast and Live Longer - Horizon from Steve Hartman on Vimeo.
Tuesday, June 1, 2010
The Anti-Aging revolution
In early 1934, Depression-weary Americans were beginning to see tendrils of hope poking out of the bleak landscape. President Franklin D. Roosevelt's New Deal was bringing the economy back from the dead. Galvanized by the sight of elderly women scrounging for food from garbage, California physician Francis Townsend had launched a crusade for government-funded pensions that would soon spur the creation of Social Security. Things were even looking up for the long-suffering Washington Senators, who had made it to the World Series the previous fall.
But one of the new year's most promising developments passed almost unnoticed. According to a brief article in the Jan. 13 Science News Letter, Cornell University researcher Clive McCay was nearing the end of a four-year study that showed that rats' life spans were greatly extended when they were put on near-starvation diets.
To many of his scientific peers, McCay's data made no sense at all. A glorious new chapter in nutrition science had been opened not long before by the discovery of dietary deficiencies behind scourges such as rickets, pellagra, and beriberi. In the wake of such progress, it seemed almost subversive to suggest that a bunch of rodent Oliver Twists, raised on such short rations that their growth was stunted, could live radically longer than well-fed ones. McCay sheepishly acknowledged in his initial report that his results seemed "little short of heresy."
Over the next several decades, his discovery was all but forgotten outside of the back halls of science -- a laboratory curiosity that didn't actually spark much curiosity. Most scientists were reluctant to risk wasting time probing an anomaly that seemed as baffling as aging itself.
Calorie restriction (CR), as it's now called, eventually was shown to extend many species' life spans by a third or more. Now that anti-aging research is hot, it seems bizarre that CR spent decades on science's back shelf. Simply put, McCay showed that the rate of aging is incredibly plastic, and that it's supremely simple to brake it in animals whose inner workings aren't all that different from ours. No biomedical discovery of the past century was more astonishing or significant.
So here's a prediction: McCay will someday be recognized as one of the last century's most important discoverers. He wasn't a genius with a capital G. But his skinny rats had made history with a capital H.
The idea of mimicking CR with drugs -- and without the hunger pangs that discourage most people from trying it -- finally got traction in the late 1990s when scientists began getting hints on the kinds of compounds that might work. (It had always been clear that such medicines were needed to make CR's broad health- and longevity-enhancing effects available to the masses, but before then researchers knew too little to get started.) Around 2000 several biotech startups were formed to pursue CR mimetics, including LifeGen Technologies of Madison, BioMarker Pharmaceuticals of San Jose, and GeroScience of Pylesville, Md. This first wave of CR-mimetic companies have been low-profile affairs compared with Sirtris Pharmaceuticals, the Cambridge, Mass., biotech juggernaut formed a few years later to develop drugs based on resveratrol, the famous red-wine compound shown to induce CR-like effects in animals. (Sirtris was acquired by GlaxoSmithKline in 2008.) They haven't been idle, though. GeroScience has worked with Procter & Gamble's (PG, Fortune 500) pet food unit, for example, on CR mimetics for pets, including a sugar in avocados called mannoheptulose. I wouldn't be surprised to see Fido and Muffy launch the era of effective anti-aging medicines.
The startups also deserve credit for beginning to transform the anti-aging quest from a guessing game into a fairly routine exercise in drug development. Before the pursuit of CR mimetics took off, most anti-aging investigators were like blind magicians trying to pull rabbits from a barrel of snakes. Not surprisingly, even the serious scientists among them often wound up covered in snake oil, promoting "breakthroughs" such as monkey-testicle implants and radium-laced elixirs.
CR-mimetic developers don't have to solve the monster problem of how aging happens in order to devise interventions that oppose it. Evolution has solved the problem for them. It did so while fashioning CR's machinery, which is poised to carry out all the intricate metabolic adjustments necessary to brake aging when activated by a true CR mimetic. Such drugs will be designed to switch on an ancient, enormously complex mechanism embedded in our genomes to postpone, and possibly attenuate, a myriad of ills brought on by aging: dementia, heart disease, cancer, as well as wrinkles, arthritis, age-related loss of muscle and bone, and the onset of senior moments. In effect, they'll represent the biggest free lunch in medical history. And given that compounds capable of emulating key effects of CR in rodents have already come to light, it's arguable that the Great Free Lunch's appetizers are now on the table.
Just a few weeks before his death in 1996 at age 100, George Burns was still enjoying life, cracking wise at a Christmas party thrown by Frank Sinatra. France's Jeanne Calment, who holds the record for longevity (she died in 1997 at 122), was similarly droll and unsinkable. When a reporter at an annual party in her honor departed with the words "Until next year, perhaps?" she shot back, "I don't see why not! You don't look so bad to me."
Very old people with such élan are obviously rare. But I suspect that many who retain mental clarity in late life make their way toward something like Burns' and Calment's radiant rapprochement with old age. Surveys show that self-reported happiness among older people in reasonably good health is generally higher than among younger groups. I don't want to sugarcoat old age -- it isn't for sissies, as they say. But I'd love to see more well-tempered sages like Burns in the world. Call it the George Burns scenario.
Some critics argue that developing anti-aging drugs is likely to engender a disastrous surfeit of needy oldsters gripped by greed and ennui. Leon Kass, a University of Chicago professor who chaired the President's Council on Bioethics under George W. Bush, has asserted, for instance, that "the desire to prolong youthfulness [is] an expression of a childish and narcissistic wish incompatible with devotion to posterity." Some naysayers add that "greedy geezers" will rack up ruinous Medicare and Social Security bills. Worse, they argue, the drugs may simply drag out late-life morbidity, recreating en masse something like the Greek myth of Tithonus, who was granted eternal life but not everlasting youth and wound up miserably withered forever.
I regard such visions as ill-founded. For one thing, there's evidence that CR mimetics would buy us quality time, not prolong misery. A study of CR's effects in rhesus monkeys has shown that it reduces age-related diseases by about a third in the primates during their later lives -- the calorie-restricted monkeys have greater lean muscle mass, significantly less age-related brain atrophy, half as much cancer, and half as much cardiovascular disease as do peers on normal diets. The world's longest-lived human population, natives of Japan's Okinawa prefecture, whose scant traditional diets are regarded as tantamount to mild CR, have 80% less breast and prostate cancer at advanced ages than North Americans do, suffer about 40% fewer hip fractures, and experience half the rate of dementia between 85 and 90.
It's possible that anti-aging drugs would compress late-life misery, letting us reach a ripe old age in good shape before a speedy demise. That could have huge economic and social payoffs -- much greater, for instance, than a miracle cure for all cancers.
Even if the medicines only postponed aging's deterioration, boosting life expectancy by, say, a decade, the benefits would be monumental. As Richard Miller, a University of Michigan gerontologist, says, "When you ask people, 'Would you like to live to 100?' they picture what today's elderly, infirm person looks and feels like. But the proper question is a different one: 'Would you like to add another 10 or 20 years to the middle of your life, so you reach 80 or 90 in the same condition that people generally are today at around 60 or 70?' "
A drug that increases healthy life-years would deliver large benefits across many sectors of the economy. Healthier, longer-living people can stay in the workforce longer, preserving skilled human capital that might otherwise be lost. Healthier workers are physically and mentally more robust, making them more productive. They're motivated to invest more in developing their skills, because they expect to reap the benefits of such investments for longer periods. They save more for retirement, boosting capital formation that fuels economic growth. They pose lighter burdens on federal entitlement programs and contribute more in federal and state tax revenue. Such factors probably explain why per-capita incomes of nations around the world have long risen in tandem with their populations' life expectancies.
Anti-aging drugs may well have downsides too. For instance, nest eggs that once seemed adequate may prove too small in an era of extended life spans. But the drugs should also help with that problem by keeping us vibrant enough to work after 62, the average age at which U.S. workers have retired in recent years. Of course, it remains to be seen whether the economy will support demand for older workers' services. Still, surveys show many baby boomers expect to work at least part-time in retirement for both fiscal and personal-fulfillment reasons -- they apparently agree with a piece of wisdom George Burns expressed late in life: "As long as you're working, you stay young."
Where does the anti-aging quest stand? As always with cutting-edge science, the quest has had ups and downs. In 2008, Harvard's David Sinclair and colleagues reported that resveratrol failed to extend the life spans of mice on normal diets, suggesting that it is at best a partial CR mimetic -- the group had earlier made a splash by showing that the compound induces CR-like effects in mice on high-fat diets. But last year a major turning point was reached: Researchers showed for the first time that a drug could convincingly extend life span in mammals.
The drug was rapamycin, a medicine long prescribed to help prevent rejection of transplanted organs. In parallel mouse experiments in three different labs, scientists funded by the National Institute on Aging found that rapamycin dramatically boosted longevity in mice on normal diets in a way reminiscent of CR's effects. Stunningly, the study showed that when rodents were first put on the drug at 20 months of age, roughly equivalent to 60 years in humans, the life expectancies of males were boosted by 28%, and that of females by 38%. Even CR itself hasn't been shown to exert such large effects on animals so close to the end of their lives. Former perma-bears about the anti-aging quest are now sounding upbeat.
Unfortunately, the drug industry has shown little interest in trying to translate such breakthroughs into anti-aging medicines. Both drug regulators and the medical establishment still essentially view aging as totally mysterious, inexorable, and intractable -- they wouldn't dream of adding it to the official list of drug indications. Thus, drug companies have no way to develop anti-aging compounds as high-margin prescription drugs. And that means that spending many hundreds of millions of dollars on clinical trials of the drugs' efficacy just doesn't compute. (The relatively small proceeds from marketing them as low-margin dietary supplements can't justify such costly, high-risk trials either.)
Besides, vetting the drugs would require first developing reliable biomarkers of aging, telltale signs of normal bodily decline over time that could be used to register how fast people are going downhill. Such biomarkers would enable the vetting of CR mimetics' efficacy in trials that last only a few years, rather than the impossibly long time it would take to assess their longevity-boosting effects in humans.
In short, the hugely promising anti-aging quest is now stuck between the R and the D stages, and I fear it will stay there until the federal government greatly steps up funding in the area. I, for one, don't plan to take purported CR mimetics until there's some reasonably rigorous clinical trial data showing that they're safe and effective. And until such data are available, the anti-aging revolution is likely to remain little more than the enthusiastic pursuit of placebo effects by wishful thinkers.
All this is terribly ironic. In effect, it means that authorities charged with promoting public health are fatalistically standing and watching the "silver tsunami" of population aging -- with its huge economic and human costs -- bearing down on us as if there were no way to shelter ourselves from its full force. Meanwhile, the authorities are perfectly willing to devote many billions of dollars annually to the pursuit of ever costlier palliatives for diseases of aging, which are typically applied when it's too late to do much good -- the federal government now annually spends less than 0.04% as much on research about the biology of aging as it does on Medicare.
So here's the moral of the story: The George Burns scenario is within our grasp if we collectively recognize what has happened in aging science and seize the day. And while anti-aging drugs may not enable all of us to live as long as Burns, they promise to let many of us age as gracefully as he did and thus aspire to our own version of his timelessness. As Burns once quipped, "You can't help getting older, but you don't have to get old." Words to remember from a wise guy to the end.
Wednesday, February 17, 2010
MAS o Menos Blog
Intermittent Fasting – Protection From Cancer
Intermittent Fasting – Reports From the Field
The Mas o Menos Blog can be found at: criticalmas.com
Wednesday, January 20, 2010
Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems.
Abstract
Intermittent fasting (IF; reduced meal frequency) and caloric restriction (CR) extend lifespan and increase resistance to age-related diseases in rodents and monkeys and improve the health of overweight humans. Both IF and CR enhance cardiovascular and brain functions and improve several risk factors for coronary artery disease and stroke including a reduction in blood pressure and increased insulin sensitivity. Cardiovascular stress adaptation is improved and heart rate variability is increased in rodents maintained on an IF or a CR diet. Moreover, rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ischemic injury in experimental models of myocardial infarction and stroke. The beneficial effects of IF and CR result from at least two mechanisms--reduced oxidative damage and increased cellular stress resistance. Recent findings suggest that some of the beneficial effects of IF on both the cardiovascular system and the brain are mediated by brain-derived neurotrophic factor signaling in the brain. Interestingly, cellular and molecular effects of IF and CR on the cardiovascular system and the brain are similar to those of regular physical exercise, suggesting shared mechanisms. A better understanding of the cellular and molecular mechanisms by which IF and CR affect the blood vessels and heart and brain cells will likely lead to novel preventative and therapeutic strategies for extending health span.
Improvements in body fat distribution and circulating adiponectin by alternate-day fasting versus calorie restriction
Abstract
Calorie restriction (CR) and alternate-day fasting (ADF) beneficially affect several aspects of adipose tissue physiology, but direct comparisons between regimens have yet to be performed. The present study evaluated the effects of ADF versus CR on body fat distribution and circulating adiponectin levels and examined the kinetic mechanisms that underlie changes in fat distribution. Thirty female C57BL/6J mice were randomized to one of five groups for 4 weeks: (a) CR-25% (25% energy restriction daily), (b) ADF-75% (75% restriction on fast day), (c) ADF-85% (85% restriction on fast day), (d) ADF-100% (100% restriction on fast day) and (e) control (ad libitum fed). Body weights of the CR mice were lower than that of the ADF and control groups posttreatment. After 4 weeks of diet, the proportion of visceral fat decreased (P<.001) and the proportion of subcutaneous fat increased (P<.001) similarly in ADF and CR animals. Adiponectin increased (P<.05) by 62-86% in the ADF groups and by 69% in the CR group. Triglyceride (TG) synthesis and de novo lipogenesis were augmented (P<.05) in the subcutaneous fat pad of ADF and CR animals, relative to control. No differences in net lipolysis were observed, resulting in greater TG accumulation in the subcutaneous fat pad, with a shift in the ratio of TG between depots. These findings indicate that ADF (both modified and true) produces similar beneficial modulations in body fat distribution and adiponectin levels as daily CR
Life extension by calorie restriction in humans
Abstract
Long-term reduction in energy intake in the diet (calorie restriction [CR]) extends the life of the laboratory rat by about 25%. However, in humans there are no life-long studies of CR, but only short-term trials which indicate that 20% CR acting over periods of 2-6 years is associated with reduced body weight, blood pressure, blood cholesterol, and blood glucose--risk factors for the major killer diseases of cardiovascular disease and diabetes. In addition, recent research has shown that CR for 6 months is able to improve biomarkers for longevity (deep body temperature and plasma insulin) and thus should increase life expectancy. The magnitude of the life-extension effect of CR in humans can only be estimated. The Okinawans, the longest-lived people on earth, consume 40% fewer calories than the Americans and live only 4 years longer. Similarly, women in United States consume 25% fewer calories than men and live 5 years longer. From the survival studies of overweight and obese people, it is estimated that long-term CR to prevent excessive weight gain could add only 3-13 years to life expectancy. Thus the effects of CR on human life extension are probably much smaller than those achieved by medical and public health interventions, which have extended life by about 30 years in developed countries in the 20th century, by greatly reducing deaths from infections, accidents, and cardiovascular disease
Effects of modified alternate-day fasting regimens on adipocyte size, triglyceride metabolism, and plasma adiponectin levels in mice
Calorie restriction (CR) affects adipocyte function and reduces body weight. However, the effects of alternate-day fasting (ADF) on adipose biology remain unclear. This study examined the effects of ADF and modified ADF regimens on adipocyte size, triglyceride (TG) metabolism, and adiponectin levels in relation to changes in body weight and adipose mass. Twenty-four male C57BL/6J mice were randomized for 4 weeks among 1) ADF-25% (25% CR on fast day, ad libitum on alternate day), 2) ADF-50% (50% CR on fast day), 3) ADF-100% (100% CR on fast day), and 4) control (ad libitum). The body weight of ADF-100% mice was lower than that of the other groups (P < 0.005) after treatment. Adipose tissue weights did not change. Inguinal and epididymal fat cells were 35-50% smaller (P < 0.01) than those of controls in ADF-50% and ADF-100% animals after treatment. Net lipolysis was augmented (P < 0.05) in ADF-100% mice, and the contribution from glyceroneogenesis to alpha-glycerol phosphate increased in ADF-50% and ADF-100% mice, whereas fractional and absolute de novo lipogenesis also increased in ADF-50% and ADF-100% animals, consistent with an alternating feast-fast milieu. Plasma adiponectin levels were not affected. In summary, modified ADF (ADF-50%) and complete ADF (ADF-100%) regimens modulate adipocyte function, despite there being no change in body weight or adipose tissue weight in the former group.
hypothesis: Pretreatment with alternate day modified fast will permit higher dose and frequency of cancer chemotherapy and better cure rates
Johnson JB, John S, Laub DR (2009) Pretreatment with alternate day modified fast will permit higher dose and frequency of cancer chemotherapy and better cure rates. Med Hypotheses.72(4):381-2
Abstract
It is established that calorie restriction (CR) increases the resistance of cells to various stressors such as oxidative damage, excitotoxins, mercury and acetaminophen. Alternate day feeding (ADF) may confer greater stress resistance than daily CR of 30% or 40%. A recent study in three strains of mouse showed that a fast of 48 or 60 h prevented toxic effects due to administration of doses 2-4 times the maximum human dose of etoposide, a chemotherapy agent which acts through increased oxidative stress. In addition, mice inoculated with neuroblastoma survived longer when pretreated with fasting, then given high dose etoposide, as well as not exhibiting toxicity. This increased survival was construed as evidence of differential stress resistance between normal and cancer cells, the cancer cells being only partially protected by the pretreatment fast. In clinical practice, increased differential stress resistance could lead to the use of much higher doses of chemotherapy agents, and in the absence of toxicity, make it possible to repeat the treatment to kill residual cancer cells. Humans are unlikely to comply with a total fast of longer than 24 or 48 h, which may be insufficient to activate the same gene expression process. Based on published data we estimate that an optimal time period for development of stress resistance is 2-3 weeks when alternate day feeding is employed. Our previously published experience suggests that 2-3 weeks of alternate day modified fast in which subjects eat ad libitum one day and <20% of one's estimated caloric requirement the next will confer a similar stress resistance. Compliance with this diet is high and greater maintenance of body weight is feasible. We hypothesize that a pretreatment of 2-3 weeks with the alternate day modified fast will improve outcomes in cancer chemotherapy, decreasing morbidity and raising cure rates.
Caloric restriction delays disease onset and mortality in rhesus monkeys
Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4.
Abstract
Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.
On the left is Canto (27) and on the right is Owen (29). Canto is fed with about 30% less calories than Owen (CR).
From the LATimes: Feast, fast and reduce risks
http://www.latimes.com/features/health/la-he-eat10dec10,1,883044.story
Feast, fast and reduce risks
An irregular eating cycle worked for ancient humans. Small studies show benefits in such calorie restriction.
By Susan Bowerman, Special to The Times
Our hunter-gatherer ancestors spent hours each day searching for food that was only intermittently available. They'd fast, and then they'd feast. These ancient humans developed a "thrifty" genotype that helped them adapt to these cycles of want and plenty.
Today, we carry this same genetic makeup with us, and several animal studies and few small human trials indicate that there may be, for us too, health benefits to alternate-day fasting -- a regimen that somewhat mimics the irregular and unpredictable food intake pattern on which our ancestors evolved.
Evidence has been accruing for some time that chronic calorie restriction, in which daily intake is reduced to between 60% and 85% of an individual's daily needs, appears to have significant health benefits. Such restriction has been shown to reduce risk factors for several chronic diseases in animals and humans and to increase life span in rats, mice, fish, flies, worms and yeast.
But the effects of alternate feast and fast days on body weight and health have only recently been explored.
In a study published in the American Journal of Clinical Nutrition in 2005, scientists at the Pennington Biomedical Research Center examined the effects of alternate-day fasting on heart disease risk in 16 subjects.
Subjects ate whatever they wanted on feast days but consumed only calorie-free beverages and sugarless gum on fast days. After three weeks, blood levels of triglycerides fell in men, but not in women. Women, but not men, experienced increases in "good," or HDL, cholesterol.
There was no clear explanation for the differing results between men and women, but the same group of scientists have observed other sex-specific effects. In a different report, they measured the rise in insulin and blood sugar levels in response to a meal before and after three weeks of alternate-day fasting.
Men -- but not women -- had increased insulin sensitivity so that they cleared sugar from the bloodstream more efficiently after three weeks on the regime, suggesting that alternate-day fasting may be more beneficial to men than women in reducing the risk of Type 2 diabetes.
Similar improvements in insulin sensitivity were observed after two weeks of alternate-day fasting in a small study of eight male subjects at the University of Copenhagen, published in the Journal of Applied Physiology in 2005.
The effects of alternate-day fasting on body weight differ according to the study (and none have been reported in overweight people). Men in the Copenhagen study maintained a stable body weight over the two week period -- but they were specifically instructed to attempt to do so.
In the Pennington study, subjects were informed that they would need to double their usual intake on non-fasting days in order to maintain their weight. But taking in enough food on the feasting days to avoid weight loss proved difficult. The participants lost about 2.5% of their initial weight and 4% of their initial fat mass.
All in all, the few human studies on alternate-day fasting have been small in size, short in duration and have lacked control groups so more studies are warranted. Still, the animal studies suggest that the effects of alternate-day fasting on chronic disease prevention are similar to those reported for chronic calorie restriction.
How such dietary calorie restriction may impart its benefits is not clear, but it may include increased resistance to stress, a reduction in free-radical production (which in turn reduces cellular damage) or the slowing of certain metabolic processes that might damage the body.
From a practical standpoint, it's unclear whether people could stick to an alternate-day fasting regimen for any length of time. Researchers have suggested that the regimen is easier than daily calorie restriction, but is it easy enough? Many subjects in the Pennington study reported feeling hungry and irritable on the days they fasted -- and that would probably limit the number of people who could sustain this pattern of eating for very long.
Anyone wishing to attempt either chronic or alternate-day calorie restriction needs to remember that consuming nutrient-dense foods is key. There are no extra calories to spare, so every bite of food needs to be packed with nutrition.
But a carefully planned diet based on vegetables and fruits, lean proteins, a few whole grains and small portions -- rather than a continuous and abundant food intake -- may be a better nutritional match for those "thrifty" genes.
Susan Bowerman is a registered dietitian and assistant director of the UCLA Center for Human Nutrition.
Alternate-day fasting and chronic disease prevention: a review of human and animal trials
http://www.ajcn.org/cgi/content/full/86/1/7
Abstract
Calorie restriction (CR) and alternate-day fasting (ADF) represent 2 different forms of dietary restriction. Although the effects of CR on chronic disease prevention were reviewed previously, the effects of ADF on chronic disease risk have yet to be summarized. Accordingly, we review here animal and human evidence concerning ADF and the risk of certain chronic diseases, such as type 2 diabetes, cardiovascular disease, and cancer. We also compare the magnitude of risk reduction resulting from ADF with that resulting from CR. In terms of diabetes risk, animal studies of ADF find lower diabetes incidence and lower fasting glucose and insulin concentrations, effects that are comparable to those of CR. Human trials to date have reported greater insulin-mediated glucose uptake but no effect on fasting glucose or insulin concentrations. In terms of cardiovascular disease risk, animal ADF data show lower total cholesterol and triacylglycerol concentrations, a lower heart rate, improved cardiac response to myocardial infarction, and lower blood pressure. The limited human evidence suggests higher HDL-cholesterol concentrations and lower triacylglycerol concentrations but no effect on blood pressure. In terms of cancer risk, there is no human evidence to date, yet animal studies found decreases in lymphoma incidence, longer survival after tumor inoculation, and lower rates of proliferation of several cell types. The findings in animals suggest that ADF may effectively modulate several risk factors, thereby preventing chronic disease, and that ADF may modulate disease risk to an extent similar to that of CR. More research is required to establish definitively the consequences of ADF.
