β-hydroxybutyrate and its metabolic effects on age-associated pathology

Abstract

Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments.

Fig. 1. Alleviation of age-associated disease symptoms and improvement of health outcomes by increased β-HB.

Aging is the leading risk factor for the development of various cancers, neurodegenerative diseases, and cardiovascular disease. Dietary manipulation, such as calorie restriction or a ketogenic diet, alleviates these age-associated diseases through upregulation of circulating β-HB. The increase in β-HB, as depicted by the redshift of the arrow in the figure, improves metabolic complications caused by insulin resistance, reduces cellular aging phenotypes, including senescence and inflammation, and regenerates sciatic nerves.

Fig. 2. Dietary manipulation or supplementation to induce β-HB elevation.

There are multiple ways to increase β-HB in circulation. The β-HB level is controlled by lipolysis in adipose tissue. A ketogenic diet and calorie restriction are the most well-known dietary manipulations used to stimulate lipolysis. Lipolysis-induced FFA is converted to β-HB through β-oxidation in the liver. SGLT2 inhibition also elevates β-HB levels by shifting substrate utilization from carbohydrate to ketone bodies through lipolysis or glucosuria. KEs have recently been developed as a commercially available β-HB supplement.

Fig. 3. Inhibition, activation, and posttranslational modification by β-HB.

β-HB directly or indirectly interacts with many cellular proteins in different organelles. β-HB acts as an agonist or antagonist to the two GPCRs FFAR3 and HCAR2 in the plasma membrane. β-HB directly binds to hnRNP A1 to regulate Oct4 mRNA stability. β-HB suppresses inflammation through inhibition of NRLP3 inflammasome formation or its activity. Specifically, β-HB also regulates nuclear proteins. β-HB is an HDAC inhibitor that also regulates histones and p53 through β-hydroxybutyrylation.

Fig. 4. The overall molecular mechanisms underlying the β-HB-associated effects on aging.

Target molecules and cellular signaling of β-HB are associated with the aging process, which is accelerated by senescence and inflammation. β-HB delays senescence via HDAC inhibition, hnRNP A1-mediated Oct4 expression, and β-hydroxybutyrylation on p53. Furthermore, β-HB suppresses inflammation by NLRP3 inhibition or HCAR2 activation and reduces the contribution to aging-associated diseases.