International Business Department           Liu Bojia           November 20, 2023

  Among the various types of dietary interventions, intermittent fasting has been attracting a lot of attention. It is also more accessible to the general population as it is not complicated to implement, requiring only food intake during a specific window of time and fasting at other times. Various studies in the past have confirmed that fasting promotes metabolic health, helps maintain blood sugar and lipid levels and reduces the risk of diabetes. In addition to this, fasting can improve neurological function and extend an individual's lifespan.

  Despite the many benefits of fasting, in various model organism experiments, it appears to be effective only in young individuals, and if fasting is introduced when the animals are older, they do not reap the benefits and do not live longer. Why do the same method have different results in young and old individuals?

  In new research in the journal Nature Aging, scientists at the Max Planck Institute for the Biology of Aging in Germany reveal the secret with the help of a special fish, the killifish. Killifish are animals that age rapidly, often going from young to old in a matter of months, and therefore allow for quick observation of the results of experiments.

  In their experiments, the authors attempted to subject both young and old killifish to intermittent fasting, and since adipose tissue changes significantly during fasting, they first examined the killifish's adipose tissue.

  For the young killifish, fasting directly altered the transcriptome of adipocytes by downregulating the activity of several metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and fatty acid synthesis, and inducing genes related to autophagy, a negative regulator of cell proliferation, which suggests that fasting reduces the rate of cell proliferation by decreasing energy expenditure.

  However, the aging killifish did not seem to accept this, and even when fasting was performed, there was little response in their adipose tissue, and the gene transcriptome changes were very inactive, as if there was no difference between fasting and normal feeding at all. Fasting even caused upregulation of genes associated with inflammation in the aged killifish, increasing their levels of inflammation.

  Unexpectedly, even when the fasting aged killifish were allowed to resume their diet, their metabolic state and genetic level did not change. Taken together, these results lead the authors to conclude that with age, killifish have permanently been placed in a fasting-related physiological state and therefore no longer respond to the fasting method or change in response to food intake.

  After comparing adipose tissue from different age groups, the authors found the reason for such a large difference: a class of proteins called AMP kinases (AMPK) changes in older individuals.AMPK consists of different subunits that are involved in energy-sensing processes in the body. During cycles of fasting and eating, subunits γ1 and γ2 of AMPK are oscillatingly expressed as a way to regulate the body's response to different eating states.

  As the activity of the γ1 subunit of AMPK declines with age, this regulatory ability is lost and leaves the body in a prolonged fasting-related metabolic state. When the authors attempted to restore expression of the γ subunit to aging killifish, their permanent fasting state changed, while the killifish also showed better health and increased longevity.

  According to the study's analyses, this change in killifish is also present in humans. Decreased expression of the γ1 subunit of AMPK was also seen in some tissue samples from older people, and the healthier the tissue sample, the higher the level of expression of the γ1 subunit.

  The authors note that these results are not enough to directly prove that the AMPK γ1 subunit is associated with healthy aging, but provide a potential clue. They also plan to build on them to further explore molecules that have affected AMPK activity during the aging process as a way to achieve a healthier aging process.