We are not meant to live forever. But for as long as life has existed, organisms have been battling to forestall death by any means possible. The diet industry has promised many things--but can it add forestalling death to its list, too? In the past decade, countless studies on caloric restriction in everything from yeast to mice has shown that limiting calorie intake and the daily intervals in which animals feed can significantly improves lifespan and important markers of health. Research in primates, however, has yielded mixed results, calling into question the validity of caloric restriction as a means to longevity. Is there any validity to the science behind it? 14 Ounces of Wine (A History of Restriction) Caloric restriction as a means to prolong life was first promoted as early as the 15th century. At the turn of the century, Venetian nobleman Luigi Cornaro found himself severely ill at the age of 35, plagued by gastrointestinal disorders and perpetual feverishness. Desperate to avoid an untimely death, Luigi examined his habits and reasoned that his liberal eating and drinking were to blame for his disease. He immediately pledged to adhere to a “quantifying principle,” restricting himself to only 12 ounces of food (bread, egg yolks, meat, and soup) and 14 ounces of wine a day. Within weeks, Luigi was cured of his various afflictions and spent much of the remainder of his life preaching his teachings to those around him. His treatises became immensely popular, earning him relative fame and recognition until his eventual death at the age of 98 (though some sources claim he lived to be 102). Despite this success, the scientific bases of Cornaro’s and his followers’ experiences remained uninvestigated until the early 1900s. A small handful of chance observations in rodents repeatedly demonstrated that severely reduced calorie diets extended lifespan by almost two-fold; as long as all nutritional requirements (i.e., for vitamins and minerals) were fulfilled, the animals seemed to live longer, more robust lives than their ad libitum-fed (that is, they had unlimited access to food) laboratory counterparts. Mice on restricted diets, however, were not without side effects. The lack of adequate nutritional intake often stunted their growth and delayed their reproductive development. It seemed that the timing of caloric restriction mattered—and unsurprisingly, mice that were malnourished in their adolescence suffered more than benefited. Still, the consensus seemed to hold true: eat less, live longer. As science progressed, researchers enthusiastically expanded their studies into other species. Flies, yeast, worms, chickens, and dogs all yielded results reasonably consistent with those in mice: eating less meant living longer. However, a few more caveats began to emerge as research tools increased in sensitivity and sophistication. As mice became more and more inbred, testing on different strains became possible, but yielded inconsistent results. In fact, the effects of calorie restriction appeared to differ by genetic background. The results were sobering: while caloric restriction seemed to work when all the research was averaged, its effects were not universal. Considering the enormous genetic and phenotypic diversity in the human population, scientists now realized that they had to approach their results with more caution—maybe caloric restriction was not the panacea it had once seemed. Freezing Time: The Science Behind Caloric Restriction To this day, the mysterious mechanisms that underlie diet-modulated longevity still elude scientists. Much research has been done, but an incomplete understanding of how metabolism is modulated by diet has left many gaps in the story. Caloric restriction appears to lower the body’s metabolic rate and its production of free radicals and oxidants. Reducing exposure to these cellular stressors appears to lead to reduced inflammation and enhanced DNA repair. Thus, at the organism level, these changes translate to more robust organ function, enhanced immunity, and increased insulin sensitivity. Interestingly, some work has also been done regarding intermittent fasting, a practice often exemplified by alternating unrestricted consumption of food with periods of caloric restriction. Periods of short-term fasting seem to confer moderate health benefits similar to those of chronic caloric restriction, and it appears that when restricting feeding intervals—that is, consuming calories only within a 5-7 hour window each day—has some positive effects on cardiovascular health and weight loss. The results that have come out of these studies seem to imply that caloric restriction does not have to be chronic to provide positive effects: as long as cells experience some period of fasting, stressors and general markers of inflammation are reduced. Still, much remains to be uncovered about the mechanisms that maintain tissue function during aging, and how they may be affected by diet and specific nutrients. Currently, researchers are investigating topics ranging from the effects of caloric restriction on the gut microbiome to the heritability of the metabolic benefits of caloric restriction. Ask A Rhesus Due to high cost and long generation times, only a few studies have been conducted in primates, and these report conflicting results. In some studies, rhesus monkeys on a calorie-restricted diet lived longer than controls, while in other studies, there were mild or no health and longevity benefits in the experimental group. In cases where positive results were yielded, other markers of health were also examined. Here, food restriction appeared to improve metabolic health, prevent obesity, and delay the onset of many age-related syndromes and disorders, including brain atrophy, cancer, and cardiovascular disease. In 2012, one study used control methods that differed significantly from previous studies. Instead of using controls that were fed ad libitum as had been the case in mouse studies, the control group ate during only predetermined meal times, and were provided with healthful choices. In this study, researchers found no differences between calorie-restricted rhesus monkeys and controls. Unsurprisingly, the study results pointed to the fact that having continuous and unlimited access to food in a laboratory setting (or, really, in any setting), is fairly conducive to overeating, obesity, metabolic syndrome, and many accompanying disorders and diseases. In other words, a liberal interpretation of the data generated thus far might be that ad libitum diets resemble the Western diet—high calorie, high sugar, high fat, and unrestricted. The control diet of the 2012 rhesus monkey study, on the other hand, might more closely mimic that of a fairly health-conscious human who consumes portion-controlled quantities of a balanced diet. However, the results are by no means definitive; they have yet to be repeated, and more importantly, while rhesus monkeys in a laboratory environment are perhaps a better model for humans than, say, invertebrate worms or yeast, they are a far cry from an actual human. A Reality Check Other observational studies conducted in humans accumulate additional evidence that short term fasting and lower overall caloric intake may be beneficial for health, lowering cholesterol and blood pressure, increasing insulin sensitivity, and yielding substantial fat loss. For instance, some attention has been paid to religious fasting and to geographically isolated cultures with unusual and sparse diet, such as those restricted to islands or those that maintain a hunter-gatherer lifestyles. However, much of this research is based on case studies, limited to correlations, riddled with confounds, and lacking controls, and thus cannot be used to draw definitive conclusions. In fact, due to high cost and poor compliance, only a few randomized, controlled clinical studies have been initiated in humans. The difficulty of designing these studies is perhaps a cautionary note: as with all diets, calorie restriction is difficult, as well as financially and psychologically expensive, particularly long-term. Few studies involving humans have maintained good patient compliance, and even those that have only studied patients for two years at the longest. In addition, not all calories are created equal: dietary restriction must occur without malnourishment to offset the potential risks. Maintaining an appropriate macronutrient balance and sufficient vitamin and mineral intake is extraordinary difficult to during caloric restriction, and requires diligence, careful meal planning, and often expensive supplementation. Furthermore, some concerning pieces of evidence point to caloric restriction becoming a preamble to anorexia nervosa. Finally, even if caloric restriction is mechanistically viable, issues of practicality are inevitably prohibitive. Lastly, a handful of troubling studies have shown that, in some cases, caloric restriction can negatively affect lifespan in both mice and humans. In one paper, non-obese mice fed a restricted diet experienced fat loss—but also suffered a reduced lifespan. Several studies monitoring caloric restriction in humans with normal, non-obese BMIs have also yielded mixed or negative health results. Perhaps unsurprisingly, calorie restriction also decreases muscle mass, making it both impractical for those looking to increase their exercise fitness and ultimately counterproductive for long-term metabolic rate. Furthermore, weight loss itself is a stressor—and though the body appears to become more tolerant to stress as a result of calorie restriction, in a non-obese individual, the effects may be a negative. One study cautioned that the starting weight and health status of the individual may dictate whether the effects experienced are positive or negative. So, is there a diet out there that can bequeath eternal life? No. Is there one that can prolong it? Perhaps—if your current habits are already in need of some changing. In all other cases, it may not be worth suffering such a rigid and restrictive lifestyle. However, research has shown that diet has a much more pervasive role in modulating the process of aging than was previously thought: the nutrients we take in affect far more than our stores of energy and fat, altering bodily functions as varied as cellular aging and immunity. The research surrounding senescence and our ability to forestall it certainly does not end here—and, through biomedical research, we may yet discover new and better ways to maximize our health. Further Reading \tLuigi Cornaro, “How To Live 100 Years, Or Discourses on the Sober Life” \tSohal RS and Forester MJ. “Caloric restriction and the aging process: A critique.” Free Radical Biology and Medicine 73: 366-82 (2014). \tFontana L and Partridge L. “Promoting Health and Longevity through Diet: From Model Organisms to Humans.” Cell 161: 106-118 (2015). \tRoth LW and Polotsky AJ. “Can we live longer by eating less? A review of caloric restriction and longevity.” Maturitas 71: 315-319 (2012). \tSzafranski K and Mokhail K. “The fine line between lifespan extension and shortening in response to caloric restriction.” Nucleus 5(1): 56-65 (2014).