Research published in Aging Cell has revealed that a nematode species commonly used for aging research lives much longer on an alternate-day fasting regimen, but only when it is administered in middle age and only when the worms are consuming an animal-based protein source.
Deciding what to restrict and when
Dietary restriction practices have been broadly reported as being beneficial for health [1]. Some of these focus on restricting calories over time, while others restrict when food can be taken in at all. Alternative-day fasting, which limits food intake to every other day, is one of the most stark forms, and it has been previously reported to lengthen the lifespan of C.elegans, a roundworm that is commonly used in longevity experiments [2].
While the biological mechanisms of dietary restriction have been explored, there are still questions remaining as to how it relates to aging and the role of protein restriction, and protein sources, in this sort of intervention [3]. To answer them, these researchers studied C.elegans with a focus on the lysomes, the cellular organelles responsible for breaking down proteins.
Strong benefitss in a single population
In this experiment, the researchers began alternate-day fasting (ADF) at three different time periods in these worms’ lives, with either plant-based or animal-based food sources. Young worms suffered badly from ADF: egg-laying was greatly impaired, with eggs hatching inside the worms. Even when a sterile strain was used, early-life ADF caused dramatic decreases in lifespan. Examination of the specific genes involved suggested that fundamental developmental pathways were being harmed.
On the other hand, ADF greatly lengthened the lives of middle-aged worms that were fed animal-based protein solution instead of a plant-based one. This finding is surprising, as C.elegans‘ lifespan is only moderately lengthened by feeding the worms plant-based instead of animal-based protein sources. Additionally, beginning ADF in worms near the end of their lifespans yielded no benefit.
These results were found to be due to the upregulation of cpr-2 and cpr-5, two genes related to lysosomal function. In C.elegans, lysosomes grow long tubes with aging, decrease in acidity, and decrease in number; however, ADF restricted this lengthening and helped the worms retain more lysosomes with the proper acidity. This lysosomal protection and lifespan extension was counteracted when genetic or other interventions were used to block these genes or their downstream effects, showing that they indeed were the cause. Once more, these effects were only in worms fed animal protein; ADF had no measurable effects on worms fed plant-based proteins.
While it did not affect cells’ self-consumption of damaged organelles (autophagy), ADF had notable positive effects on fat consumption (lipophagy) and the clearance of aggregated proteins. As aggregated proteins are a fundamental aspect of aging and are core to such crippling brain diseases as Alzheimer’s and Parkinson’s, the researchers closely examined model worms for their ability to deal with the key proteins involved. Once more, ADF was found to have beneficial effects in clearing out these dangerous aggregates, but again, these effects only occurred in worms fed animal-based protein.
These findings will take considerably more work to apply to other animals, including human beings. These experiments demonstrated the effectiveness of fasting every other day in a worm that usually lives for less than a month. Furthermore, the researchers could not ascertain exactly why ADF only showed measurable effects in worms fed animal-based protein; a careful assessment of lysosomal protein relationships will be needed to determine why this is the case.
Literature
[1] Longo, V. D., Di Tano, M., Mattson, M. P., & Guidi, N. (2021). Intermittent and periodic fasting, longevity and disease. Nature aging, 1(1), 47-59.
[2] Honjoh, S., Yamamoto, T., Uno, M., & Nishida, E. (2009). Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature, 457(7230), 726-730.
[3] Solon-Biet, S. M., Mitchell, S. J., Coogan, S. C., Cogger, V. C., Gokarn, R., McMahon, A. C., … & Le Couteur, D. G. (2015). Dietary protein to carbohydrate ratio and caloric restriction: comparing metabolic outcomes in mice. Cell reports, 11(10), 1529-1534.