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According to Weindruch and Sohal in a 1997 article in the Journal, reducing  food  availability  over  a  lifetime  (caloric  restriction)  has  remarkable effects on aging and the life span in animals.1 The authors proposed that the health benefits of caloric restriction result from a passive reduction in the production  of  damaging  oxygen  free  radicals.  At  the  time,  it  was  not  generally  recognized  that  because  rodents  on  caloric  restriction  typically  consume  their  entire  daily  food  allotment  within  a  few  hours  after  its  provision,  they  have  a  daily  fasting  period  of  up  to  20  hours,  during  which  ketogenesis  occurs.  Since  then, hundreds of studies in animals and scores of clinical studies of controlled intermittent fasting regimens have been conducted in which metabolic switching from liver-derived glucose to adipose cell–derived ketones occurs daily or several days each week. Although the magnitude of the effect of intermittent fasting on life-span extension is variable (inf luenced by sex, diet, and genetic factors), studies in mice and nonhuman primates show consistent effects of caloric restriction on the health span Studies in animals and humans have shown that many of the health benefits of intermittent fasting are not simply the result of reduced free-radical production or  weight  loss.2-5  Instead,  intermittent  fasting  elicits  evolutionarily  conserved,  adaptive  cellular  responses  that  are  integrated  between  and  within  organs  in  a  manner  that  improves  glucose  regulation,  increases  stress  resistance,  and  sup-presses inf lammation. During fasting, cells activate pathways that enhance intrin-sic defenses against oxidative and metabolic stress and those that remove or repair damaged  molecules 

Intermittent  Fasting and Metabolic Switching

Glucose and fatty acids are the main sources of energy for cells. After meals, glucose is used for energy,  and  fat  is  stored  in  adipose  tissue  as  triglycerides. During periods of fasting, triglyc-erides are broken down to fatty acids and glycerol,  which  are  used  for  energy.  The  liver  con-verts fatty acids to ketone bodies, which provide a major source of energy for many tissues, espe-cially  the  brain,  during  fasting 

Intermittent Fasting and Stress Resistance

Repeated exposure to fasting periods  results  in  lasting  adaptive  responses  that  confer resistance to subsequent challenges. Cells respond to intermittent fasting by engaging in a coordinated  adaptive  stress  response  that  leads  to increased expression of antioxidant defenses, DNA  repair,  protein  quality  control,  mitochondrial biogenesis and autophagy, and down-regulation  of  inflammation

Effects of Intermittent Fasting on Health and Aging

After  nearly  a  century  of  research  on  caloric restriction in animals, the overall conclusion  was  that  reduced  food  intake  robustly  in-creases the life span. In humans, intermittent-fasting interventions ameliorate obesity, insulin resistance, dyslipid-emia, hypertension, and inf lammation.

Physical and Cognitive Effects of Intermittent Fasting

Studies  in  animals  show  that  intermittent  fasting enhances cognition in multiple domains, including  spatial  memory,  associative  memory,  and working memory; alternate-day fasting and daily caloric restriction reverse the adverse effects of obesity, diabetes, and neuroinf lammation on spatial learning and memory


Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med 2019;381:2541-51.

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