Fight Aging!

β-hydroxybutyrate is a ketone body that is produced in greater amounts during exercise and calorie restriction. It has a range of beneficial effects that can influence the pace of aging, such as suppressing the pace at which cells become senescent. Senescent cells accumulate with age, and cause increasingly harmful tissue dysfunction and chronic inflammation. There is good supporting evidence for this and other mechanisms of interest related to β-hydroxybutyrate to exist, the question (as always) is the effect size. How much of the known and well calibrated benefits of exercise and calorie restriction are due to greater levels of β-hydroxybutyrate? Without an answer to that question, it doesn't do to get too excited about this sort of thing.

Accumulating data demonstrate that a ketogenic diet elevates the levels of β-hydroxybutyrate (β-HB), improving many age-related diseases. Indeed, β-HB appears to act as a regulator of cellular signaling via numerous pathways in various cellular organelles in a manner that is independent of nicotinamide adenine dinucleotide (NAD) levels. Reports have verified that β-HB controls many cellular signals via its function as a ligand, regulates gene expression, inhibits or activates protein functions, and plays a role in neuronal functions. Thus, identification of the molecular targets of β-HB will provide a better understanding of how calorie restriction or a ketogenic diet improves age-related disease symptoms. Stemming from the current evidence, investigation of the detailed molecular capacity of β-HB will provide new opportunities for its application as a therapeutic target for the treatment or prevention of human diseases.

Approaches to increase circulating β-HB by dietary manipulation or ingestion of supplements have been examined via four different routes: a ketogenic diet, calorie restriction, ketone ester (KE) administration, and sodium-glucose transport protein 2 (SGLT2) inhibition. The ketogenic diet, calorie restriction, and SGLT2 inhibition induce ketogenesis in the liver through lipolysis. In particular, SGLT2 inhibition decreases insulin secretion from β cells, resulting in lipolysis in adipose tissues, regulation of ketone body reabsorption in the kidney, and increased β-HB. KEs are hydrolyzed by nonspecific gut esterases in the small intestine and liberate β-HB and (R)-1,3-butanediol, thus increasing the level of β-HB in the circulation.

β-HB supplementation extends the lifespan of C. elegans by 20% through the DAF-16/FOXO and SKN-1/Nrf pathways and the regulation of aging and longevity. In mammals, β-HB decreases the senescence-associated secretory phenotype (SASP) and the senescence of vascular cells. Moreover, the ketogenic diet significantly extended the median lifespan of mice and resulted in the preservation of the physical function of aged mice. Thus, β-HB and ketogenic diets can be considered important mediators with regenerative potential that also have the capacity to retard aging-associated phenotypes.

Since individual differences make it difficult to control the optimal circulating β-HB levels by calorie restriction or a ketogenic diet, it is necessary to develop adjustable treatment options, such as KE administration. As abrupt changes in circulating β-HB may disrupt energy homeostasis, the chiral enantiomer s-β-HB may offer a potential option for therapeutics, as this molecule cannot be used as an alternative energy metabolite. Furthermore, s-β-HB is not consumed by the physiological system, and the half-life of s-β-HB in circulation is longer than that of β-HB. As β-HB alleviates various age-associated disease symptoms and aging phenotypes via diverse and yet unknown molecular mechanisms, evaluation of β-HB and/or s-β-HB as a therapeutic agent is an important approach for the treatment of the aging population.

Link: https://doi.org/10.1038/s12276-020-0415-z