Fasting is required to see the full benefit of calorie restriction in  
  mice  
    
    Date:  
        October 18, 2021  
    Source:  
        University of Wisconsin-Madison  
    Summary:  
        Over the last few decades, scientists have discovered that  
        long-term calorie restriction provides a wealth of benefits in  
        animals. Researchers have largely assumed that reduced food intake  
        drove these benefits by reprogramming metabolism. But a new study  
        finds that reduced calorie intake alone is not enough; fasting is  
        essential for mice to derive full benefit.  
    
    
    
  FULL STORY  
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  Over the last few decades, scientists have discovered that long-term  
  calorie restriction provides a wealth of benefits in animals: lower  
  weight, better blood sugar control, even longer lifespans.  
    
    
  ==========================================================================  
  Researchers have largely assumed that reduced food intake drove these  
  benefits by reprogramming metabolism. But a new study from University of  
  Wisconsin- Madison researchers finds that reduced calorie intake alone  
  is not enough; fasting is essential for mice to derive full benefit.  
    
  The new findings lend support to preliminary evidence that fasting can  
  boost health in people, as trends like intermittent fasting continue to  
  hold sway.  
    
  These human and animal studies have added to the growing picture of how  
  health is controlled by when and what we eat, not just how much.  
    
  The research further emphasizes the complexity of nutrition and metabolism  
  and provides guidance to researchers trying to untangle the true causes  
  of diet- induced health benefits in animals and humans.  
    
  The researchers discovered that, combined with eating less, fasting  
  reduces frailty in old age and extends the lifespan of mice. And fasting  
  alone can improve blood sugar and liver metabolism.  
    
  Surprisingly, mice that ate fewer calories but never fasted died younger  
  than mice that ate as much as they wanted, suggesting that calorie  
  restriction alone may be harmful.  
    
    
    
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  The research was led by UW School of Medicine and Public Health metabolism  
  researcher Dudley Lamming, his graduate student Heidi Pak and their  
  colleagues at UW-Madison and other institutions. The team published  
  their findings Oct. 18 in Nature Metabolism.  
    
  Pak and Lamming were inspired to conduct the study because researchers  
  began to realize that previous studies had unintentionally combined  
  calorie restrictions with long fasts by providing animals with food just  
  once a day. It was difficult, then, to distinguish the effects of one  
  from the other.  
    
  "This overlap of treatment -- both reducing calories and imposing a fast  
  -- was something that everybody saw, but it wasn't always obvious that  
  it had biological significance," says Lamming, who has long studied the  
  effect of restricted diets on metabolism. "It's only been in the past few  
  years that people started getting interested in this issue."  To untangle  
  these factors, Lamming's group designed four different diets for mice  
  to follow. One group ate as much as they wanted whenever they wanted.  
    
  Another group ate a full amount, but in a short period of time -- this  
  gave them a long daily fast without reducing calories.  
    
  The other two groups were given about 30% fewer calories either once a  
  day or dispersed over the entire day. That meant that some mice had a  
  long daily fast while others ate the same reduced-calorie diet but never  
  fasted, which differed from most previous studies of calorie restriction.  
    
    
    
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  It turned out that many of the benefits originally ascribed to calorie  
  restriction alone -- better blood sugar control, healthier use of fat  
  for energy, protection from frailty in old age and longer lifespans --  
  all required fasting as well. Mice who ate fewer calories without fasting  
  didn't see these positive changes.  
    
  Fasting on its own, without reducing the amount of food eaten, was just  
  as powerful as calorie restriction with fasting. Fasting alone was  
  enough to improve insulin sensitivity and to reprogram metabolism to  
  focus more on using fats as a source of energy. The livers of fasting  
  mice also showed the hallmarks of healthier metabolism.  
    
  The researchers did not study the effect of fasting alone on lifespan  
  or frailty as mice aged, but other studies have suggested that fasting  
  can provide these benefits as well.  
    
  While the mice that ate fewer calories without ever fasting did show some  
  improved blood sugar control, they also died younger. Compared with mice  
  who both ate less and fasted, these mice that only ate less died about  
  8 months earlier on average.  
    
  "That was quite surprising," says Lamming, although other studies  
  have also shown some negative effects from restricting calories. The  
  team also measured frailty through metrics like grip strength and coat  
  condition. "In addition to their shorter lifespans, these mice were worse  
  in certain aspects of frailty, but better in others. So, on balance  
  their frailty didn't change much, but they didn't look as healthy."  
  The primary studies were done in male mice, but Lamming's lab also found  
  similar metabolic effects of fasting in female mice.  
    
  The research reveals how difficult diet studies are, even in a laboratory  
  environment. That difficulty is magnified for human studies, which  
  simply can't match the level of control possible in animal models. The  
  new study can provide direction to future work trying to answer whether  
  fasting improves human health.  
    
  "We need to know whether this fasting is required for people to see  
  benefits," Lamming says. "If fasting is the main driver of health,  
  we should be studying drugs or diet interventions that mimic fasting  
  rather than those that mimic fewer calories."  This work was supported in  
  part by the National Institutes of Health (grants AG050135, AG051974,  
  AG056771, AG062328, AG061635, DK125859, R37GM059785, P30AG050886,  
  S10OD028739, DK124696, F31 AG066311, T32 AG000213 and T32 DK007665)  
  and the Department of Veterans Affairs (grant I01-BX004031).  
    
  ==========================================================================  
  Story Source: Materials provided  
  by University_of_Wisconsin-Madison. Original written by Eric  
  Hamilton. Note: Content may be edited for style and length.  
    
    
  ==========================================================================  
  Journal Reference:  
     1. Pak, H.H., Haws, S.A., Green, C.L. et al. Fasting drives the  
     metabolic,  
        molecular and geroprotective effects of a calorie-restricted diet  
        in mice. Nat Metab, 2021 DOI: 10.1038/s42255-021-00466-9  
  ==========================================================================  
    
  Link to news story:  
  https://www.sciencedaily.com/releases/2021/10/211018112513.htm  
    
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