β-Hydroxybutyrate Supplementation Slows Aging in Mice
β-hydroxybutyrate is also known as 3-Hydroxybutyrate. An increase in the circulating levels of this compound is thought to mediate some of the beneficial effects of exercise and calorie restriction. Here researchers supplement with β-hydroxybutyrate in mice, starting in mid-life, and observe an increase in median life span that is perhaps larger than one might expect for this intervention, similar to the outcome of rapamycin treatment. The researchers dive into some of the mechanisms involved, but one might think that an intervention of this sort will change most aspects of metabolism; it isn't necessarily the case that those noted here are the most important.
Aging is a significant risk factor for chronic diseases and disability, yet effective anti-aging interventions remain elusive. We explored the potential of 3-hydroxybutyrate (3HB), an endogenous metabolite with established safety, to modulate longevity in mice. In this study, we employed cell models, a yeast model, and naturally aging mouse models to investigate the effects of 3HB on aging in various systems. Additionally, we utilized RNA sequencing and metabolomics technologies to explore the potential mechanisms underlying the action of 3HB.
Our findings demonstrate that 3HB supplementation effectively delays cellular senescence, extending yeast lifespan by 51.3% and the median lifespan of naturally aged mice by 21.0%. Notably, 3HB prolonged healthy lifespan in mice while mitigating age-related tissue morphology changes and organ senescence. Mechanistically, we identified that 3HB's anti-aging properties are mediated through its ability to delay cellular senescence and metabolic reprogramming, while promoting the production of beneficial metabolites like trigoneline and isoguvacine. These findings highlight the promising therapeutic potential of 3HB as an anti-aging intervention and provide novel insights into its underlying mechanisms.
This report is noise. A well-fed, well-cared-for, genetically intact, nonobese mouse will at median live 850 days or more (Kamil Pabis and Matt Kaeberlein argue 900). In this study, the controls were miserably short-lived (587 days median), and the intervention group was STILL miserably short-lived (median LS 710 days). Moreover, you can see from the photos that the animals are overfed.
While your study demonstrates impressive lifespan extension with 3HB in mice, the recent Tomita 2023 findings on age-dependent mortality risks in ketogenic interventions raise critical safety questions that warrant urgent investigation. Your study exclusively used 11-month-old mice, but the concerning mortality increases observed in younger animals (24-week-old mice) with ketogenic compounds suggest that 3HB safety may be fundamentally age-dependent through AMPK-p53 senescence pathways. Given 3HB's GRAS status and potential widespread human use, I strongly recommend conducting age-stratified safety studies across different life stages before clinical translation. The remarkable efficacy you've demonstrated makes it even more crucial to establish clear age-based safety protocols, as the same mechanisms driving beneficial effects in older organisms may prove harmful in younger populations.