infoaging guides

BIOLOGY OF AGING

Caloric Restriction An introduction to aging science brought to you by the American Federation for Aging Research WHAT IS CALORIC ­RESTRICTION?

Caloric restriction is an experimental tool that utilizes ­“undernutrition without malnutrition.” In other words, caloric restriction means lowering typical calorie consump- tion by 30 to 40 percent, while maintaining all the necessary nutrients and vitamins to ­support life. Until recently, researchers found this to be the only ­reliable way to increase longevity in mam- mals. Two new studies, however, have shown that a diet containing very low levels of an amino acid called methionine can also extend lifespan in mice and rats.

THE IMPORTANCE OF CALORIC RESTRICTION

Caloric restriction has been shown to increase both the ­average and Caloric restriction has been observed to retard and even the maximal lifespan in ­paramecia ­reverse oxidative damage in aging animals. ­Oxidative (creatures made of a single cell), ­damage is caused when free radicals and peroxides worms, spiders, ­insects, and rodents. Non-human primates ­bombard cells. are now being tested, but the ­complete outcome of these tests sociated diseases and conditions, THE ROLE OF CALORIC will not be known for several such as heart disease, dementia, RESTRICTION IN AGING decades because monkeys have and cancer. If scientists can figure relatively long lifespans compared out how it works, they might be Overview to other animals. Preliminary re- able to develop drugs that mimic Caloric restriction seems to slow sults suggest that calorie-restricted its effects without requiring people down some of the destructive monkeys are healthier and tend to drastically reduce their calorie processes that take place in cells to live longer than their freely fed intake and risk potentially danger- and tissues as they age. Scientists counterparts. For example, one ous side effects. don’t yet know exactly how or why new study shows that the immune it works, but they have developed systems of aged rhesus monkeys Caloric restriction may or may not several theories. on a calorie restricted diet r­esembles, extend the total number of years in several ways, the immune a human can expect to live, but First, caloric restriction seems to ­systems of younger animals. of equal or greater importance, reduce damage from chemical perhaps, is the possibility of add- metabolic processes, particularly Although caloric restriction diets oxidative and glycation damage, are so difficult to maintain that ing to the number of years we can expect to remain healthy. Reduc- thought to be leading causes of they are unlikely to be a ­practical cell aging and death. approach to delayed aging for ing or delaying age-related diseas- people, studying the mechanisms es until the very end of life would represent an enormous improve- On a larger scale, caloric restric- of calorie restriction is still very im- tion slows the effects of aging on portant. Caloric restriction seems ment in quality of life for many, if not most, older adults. the nervous system, the reproduc- to prevent or delay many age-as- tive organs, and the production

2 | Infoaging Guide to Caloric Restriction of hormones in some animals. It disease, and stroke are all conse- Calorie restricted rodents are has also been shown to delay the quences of insulin resistance in ­harder to kill by hyperthermia, onset of certain age-related can- humans. but why this should be true cers. However, whether or not CR isn’t yet clear. Some scientists enhances or decreases immune Caloric restriction protects against speculate that this protection function has not been resolved. insulin resistance. The tissues occurs ­because older mammals of an animal whose total calorie are less likely to produce pro- Reducing cellular damage (and thus energy) intake is limited tective ­substances called heat Oxidative damage results when become more sensitive to insulin shock ­proteins. Others say that free radicals, the potentially for driving glucose into cells. This a ­rodent’s ability to cope with toxic byproducts of cell energy has been observed in numerous ­hyperthermia may not involve heat ­production, break down DNA; cell species of laboratory mice and shock ­proteins at all. Instead, it ­membranes; and mitochondria, the rats; recent studies in non-human might be related to weight. Calorie energy factories of cells. Caloric primates have also demonstrated restricted rats are extremely lean restriction has been observed to caloric restriction’s beneficial and this helps them to stay cooler, retard and even reverse oxidative effects on reducing insulin resistance. even in a hot room. Control rats, damage in aging animals. in contrast, are obese. Obesity Glucocorticoids interferes with heat loss in a hot Glycation is the addition or insertion Caloric restriction has been shown environment. of sugar molecules into DNA and to increase the ability of aging proteins, which takes place in a rodents to produce glucocorti- Downsides variety of physiological ­reactions. coids, which are natural steroids Caloric restriction leads to reduced Glycation causes damage to produced when the body is under ability to deal with hypothermia proteins and DNA and is thought stress. They help stop glucose (lowered body temperature)— to be a major cause of degenera- from being stored and instead possibly associated with the tion associated with diabetes and redirect it into tissues that need individual’s lower body fat content. other diseases. Caloric restriction it. As mammals age, the neuro- Another problem is that wounds also reduces glycation damage in transmission of signals between don’t heal as quickly in calorie- tissues. the brain and the adrenal gland restricted animals as in normal-fed is altered and the release of laboratory animals. Hormonal effects these stress hormones falters. Insulin Caloric restriction also increases EXTENDING LIFE: BEHIND Caloric restriction in animals also the daily peak free-glucocorticoid THE SCENES has potent effects on glucose and ­concentration in plasma, but has insulin regulation. Glucose is a little or no effect during most of In 1935, Clive McCay, a ­nutritionist simple sugar that serves as a major the remainder of the day. Although at Cornell University, made the source of energy for mammals and many scientists have suggested stunning discovery that rats fed assists in the formation of biologi- potential functional roles for this daily fewer calories (just enough to cally important ­molecules. Insulin increase in peak concentration, maintain a steady body weight) plays an important regulatory role there is no evidence that it exerts than their littermates lived ­ in these metabolic processes. With any effect on the extension of lifes- considerably longer. This discov- age and obesity, mammals such pan or any other anti-aging action ery opened the door to a new field as mice, monkeys, and humans of caloric restriction. of medicine dedicated to under- develop insulin resistance, which standing the fundamental biology is a reduction in the ability of Protection against of aging. In the intervening years, insulin to carry out its regulatory temperature effects scientists have come to under- functions. With insulin resistance, Another interesting cellular change stand that a calorie-restricted diet blood glucose (blood sugar) levels noted in aging rodents subjected postpones death and disease in rise, blood insulin levels rise, and to caloric restriction is their ­ability many laboratory animals, including cells and tissues are damaged. to resist the damaging effects of nematodes, fruitflies, and rodents. Diabetes, high blood pressure, hyperthermia, or elevated body Moreover, it decelerates many hardening of the arteries, heart temperature. age-related changes in nearly

Infoaging Guide to Caloric Restriction | 3 every body system and cell type cut back to about 200 meters to produce very old, but vital tested. A review published in the a day [.12 miles]. In contrast, ­rodents. More recently, an associ- Milbank Quarterly explains that calorie-restricted rodents may run ation between deficient production lifespan is extended because the 4,000 to 5,000 meters a day [2.5 or utilization of growth hormones diet delays whatever diseases are to 3 miles] until they are about and longer lifespan has been the key causes of death in each two years old, when they begin to observed in a variety of studies species tested. Notably, animals slow down. They are still running with mutant mice. The ­restriction on calorie-restricted diets remain about 1,000 meters a day at three of the amino acid methionine healthy and active long after their years of age — a year beyond the has also been shown to extend control littermates have died — a median lifespan for the control longevity. Recently, research- finding that has a tremendous rodents. ers have demonstrated that ca- bearing on public health and pre- loric ­restriction doesn’t benefit all ventive medicine. Evidence of the calorie-restricted strains of inbred rodents. The ben- effect — meaning a longer, healthi- eficial ­effects are dependent on an Researchers at the University of er life — is exciting and consistent. animal’s genetic constitution. In Texas Health Science ­Center at These basic observations have fact, caloric restriction has proven San Antonio learned, for ­example, been repeated in more than 100 harmful in some strains of mice. that when rodents in a control rigorous scientific investigations group are given access to a run- in dozens of independent labo- Obstacles to Progress ning wheel, they typically run ratories over many years. For the The goal of caloric restriction re- about 1,000 meters a day [.62 first 50 years or so after its initial search is to recognize the precise miles] until they are about eight discovery, the calorie-restricted mechanisms by which it slows months old, when they ­gradually regimen was the only known way

Animals on calorie-restricted diets remain healthy and active long after their control ­littermates have died — a finding that has a tremendous bearing on public health and ­preventive medicine.

4 | Infoaging Guide to Caloric Restriction aging. If this mechanism were Finally, there exists a subtle public understood, a simple intervention, predisposition against ­longevity such as a pill, might induce these research, which is viewed by same changes without restricting some to be unethical, because the number of calories in one’s diet. of concerns that progress in this Such a discovery would constitute­ field might create a world with a huge landmark in medical too many healthy old people and ­research. However, a number not enough room for the young. of impediments have hindered ­Pointing out that such an argument ­progress. could also be used against past research on antibiotics and current Some of these obstacles are research on cancer does little to scientific. Aging ­experiments dispel this belief. in mammals take years, ­rather than weeks, to complete. These obstacles and others must Young ­scientists must write be overcome before such aging many ­peer-reviewed ­journal research can defer the onset of articles to advance, to get health in laboratory animals on late life illnesses and prolong the ­promoted, and finally,­ to attain calorie-restricted diets, many period of healthy active lives for tenure. The ­relatively slow pace scientists, including those who set millions of Americans. ­required for aging research in national research priorities, shun ­mammals ­interferes with a young research into the biological ­control FUTURE OF CALORIC ­professional’s ­career goals, of aging. Instead, they allocate RESTRICTION RESEARCH limiting the number of researchers funding to doing research on willing to commit their careers to individual diseases, such as heart The major goals of future caloric this kind of work. disease and cancer—and receive restriction research should be a great deal of emotional ­support to learn the basic mechanism(s) The absence of a validated tool to from the public in doing so. If underlying its anti-aging actions accurately measure biological age research funding narrowly targets and to identify more palatable is yet one more impediment to the individual health conditions, it procedures for accomplishing testing of agents believed to slow obviously cannot also target the these actions. Caloric restric- aging, and the fact that the precise broader field of aging research. tion might work at the level of the biochemical pathways involved The fact remains, however, that individual cell. Alternatively, it may in aging remain undiscovered is progress in aging research has the work by stimulating the nervous another. potential to improve public health system in some fashion, which can to a far greater extent than doing affect cells throughout the body, Most obstacles are political, research on one lethal disease at or it may produce its benefits by ­however. Despite the obviously a time. ­inducing our bodies to express improved mental and physical protective hormones.

American Federation for Aging Research (AFAR) Websites: 55 West 39th Street, 16th Floor www.afar.org New York, NY 10018 www.afar.org/infoaging

Phone: (212) 703-9977 Facebook and Twitter: Toll-free: (888) 582-2327 AFARorg Fax: (212) 997-0330 Email: [email protected]

© 2016 American Federation for Aging Research. All rights reserved.