The sweet escape: Are ketones a key player in unlocking healthy aging?

It feels like everywhere we look, there are one size fits all solutions being offered for a wide variety our health concerns. People are searching for the elusive fountain of youth to combat signs of aging, whether it be sagging skin, joint pain, and even forgetfulness. Aging is a complex process that affects many interconnected systems, leading to various declines over time. The hallmarks of aging, like inflammation, mitochondrial dysfunction and stem cell exhaustion, underlie aging physiology. The geroscience hypothesis posits that targeting these hallmarks can mitigate many different age-related diseases and overall age-related dysfunction.

While there are many promising gerotheurapeutics in development, caloric restriction remains one of the most tried and true methods that mitigates aging pathologies in both animal models and humans. Similarly, ketogenic diet (KD) has also shown benefits for some age-related declines. Ketogenic diets are high in fat and very low in carbohydrate intake with the goal of shifting the body’s metabolism away from relying on carbohydrates for energy. This reduction in carbohydrate intake leads to ketogenesis, or the production of ketone bodies (KBs), which serve as an alternative fuel source for some tissues. Adult mice fed a long-term KD showed increased healthspan and lifespan [1]. KD has also been shown to preserve or improve muscle mass and strength [1,2], as well as sustain cognitive function and memory in aged mice [3,4]. KD can also improve responses to infection [5,6], and reduce inflammation in certain contexts [7,8]. However, strict diets, such as KD, are notoriously difficult to follow and it is unclear which specific components of the ketogenic diet contribute to its benefits.

β-hydroxybutyrate (BHB), the main ketone body, has been shown to have direct benefits on various body systems. BHB alone can extend lifespan in Caenorhabditis elegans (C. elegans) [9] and has anticatabolic effects in human skeletal muscle [10]. BHB can also inhibit mitochondrial reactive oxygen species (ROS) production [11] and improves mitochondrial function and morphology in skeletal muscle [12]. Importantly, BHB can directly inhibit the NLRP3 inflammasome in mice [13] which is a key driver of inflammaging [14] and contributes to neurodegenerative diseases such as Alzheimer’s disease [15]. Lastly, drinks containing BHB are able to lower blood glucose and lipid levels [16]. BHB also has been shown to regulate stem cell function and improve resilience in the intestine [17] and skeletal muscle [18], respectively. It is evident that BHB and KD has widespread effects on various age-related declines and pathologies (Fig. 1), which raises an important question: can ketone bodies be used as a therapeutic to promote healthy aging?

Fig. 1.

Potential benefits of ketone bodies and ketogenic diet on common age-related concerns.

Various biological processes decline with age and contribute collectively to age-related diseases and pathologies. Ketogenic diets (KD) and/or ketone bodies (ketone esters, KE) have been shown to improve different aspects of these declines. Proposed benefits to Muscle Health, Mitochondrial Function, Inflammation, Cognitive Function, Stem Cell Function, Weight/Metabolic Health, Longevity, and Malignancy are highlighted as reported from KE and KD studies in mice and humans. While more research is necessary to determine the full utility of these interventions, high potential remains for KD and KE to promote healthy aging and prevent or delay the onset of age-related declines. Created in BioRender. Bartley, J. (2024) BioRender.com/b70g258.

The popularity of exogenous ketone supplements, such as ketone salts and ketone esters have been on the rise. However, there is a lack of studies investigating their utility to address specific conditions and health concerns. These supplements acutely raise blood ketone levels without dietary change and initial studies in healthy middle-aged adults showed overall low incidence of adverse events [19]. To explore this as a possible gerotherapeutic, it is crucial to gather extensive safety and tolerability data for these supplements in older adults who have a high prevalence of co-morbidities.

In a recent issue of The Journal of Nutrition, Health and Aging, Stubbs et al. report on The Buck Institute Ketone Ester (BIKE) Study which sought to evaluate the safety and tolerability of daily consumption of KE in older adults. The data supports that up to 25 g of KE consumed daily is tolerable for older adults, as there was no difference in moderate or severe side effects after the initial acclimation period between the KE and placebo groups. The study also reported no safety concerns in terms of clinical labs and vitals. Together, these studies provide the groundwork supporting the tolerable and safety of KE supplementation in adults. This foundational step paves the way for future studies that examine the effectiveness of KE supplementation to target age-related dysfunction and diseases.

In the battle for healthy aging, KE supplementation has the potential to address various universal age-related declines. However, the ability to target multiple hallmarks of aging remains unclear. Future research will need to evaluate previous findings from preclinical work to determine if these benefits hold true in older adults. Moreover, the utility of KEs in different aging conditions, such as frailty, congestive heart failure, diabetes, mild cognitive impairment, sarcopenia, and many others, will likely require additional in-depth studies. Studying the specific benefits and underlying mechanisms of KE supplementation in aging will undoubtedly be challenging. This difficulty arises from the common presence of chronic conditions, co-morbidities, and other factors like prescription medications that introduce additional variables. However, due to the vast potential benefits of KE supplementation, these studies will be extremely valuable in the continued search for effective gerotherapeautics. Continued efforts to understand the intricate effects of ketone bodies on various body systems and disease states will unveil their potential as targeted interventions for human health.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Jenna M. Bartley reports financial support was provided by UConn Health. Andreia Cadar reports financial support was provided by UConn Health. Jenna M. Bartley reports a relationship with National Institutes of Health that includes: funding grants. Andreia Cadar reports a relationship with National Institutes of Health that includes: funding grants. Corresponding author collaborates with Dr. Brianna Stubbs and Dr. John Newman — JMB. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.