The quest for eternal life and enhanced mental acuity has intrigued humanity for ages. Coincidentally, one of the key breakthroughs in longevity science was discovered during an experiment originally aimed at boosting farm animal yield. It was unveiled that reduced caloric intake not only slowed down the animals’ growth but also extended their lifespan[^1^]. This discovery by Clive Maine McCay in the 1930s triggered countless studies and paved the way for an intriguing field: the exploration of exogenous ketones, their potential as calorie restriction mimetics and their implications for longevity and cognitive health/brain health.
The Science Behind Exogenous Ketones for Calorie Restriction and Longevity
Calorie restriction, the practice of reducing daily caloric intake without malnutrition, has been observed to slow down the ageing process across a range of species, from minuscule worms[^2^] and flies[^3^] to larger mammals like rats[^4^], dogs[^5^], and even non-human primates[^6^]. Human studies have also indicated that calorie restriction can dramatically decrease the risk of major age-related ailments such as diabetes, cancer, and cardiovascular disease[^7^].
However, while the health benefits of calorie restriction are impressive, they often remain inaccessible due to the difficulty in adhering to a prolonged period of calorie restriction. This is where the role of exogenous ketones comes into play.
Exogenous Ketones as Calorie Restriction Mimetics
Exogenous ketones, particularly β-hydroxybutyrate (BHB), have shown immense potential to act as calorie restriction mimetics[^8^] due to their evolutionary link to states of starvation[^9^]. Besides serving as an alternative fuel source for the brain during periods of foraging[^10^], recent research has confirmed that BHB also functions as a signaling molecule, instructing cells on their course of action[^11^].
Through the signals transmitted by ketones, the body can activate the necessary molecular processes to survive starvation, conserve energy, and enhance energy production efficiency. Importantly, these processes not only help us survive starvation but also make us more resilient and contribute to the longevity benefits of calorie restriction[^9^].
How Exogenous Ketones Enhance Stress Resilience
Contrary to popular belief, our lifespan is not entirely predetermined by our genes. Genes account for only about 25% of our lifespan[^12^], highlighting the significance of a healthier lifestyle. However, genetic studies on longevity have revealed some interesting insights.
Fascinatingly, out of approximately 20,000 human genes, only two have been shown to correlate with longevity[^14^]. One of them is the FOXO3 gene, whose activity is increased during calorie restriction. A more active variant of this gene can slow down ageing as FOXO3 regulates a wide range of biological processes required for stress response[^18^].
A 2013 study[^19^] showed that treating cells with BHB increases levels of the FOXO3 protein. BHB activates FOXO3 by altering the conformation of proteins called histones, which our DNA winds around. This results in unwinding the part of DNA that codes for the FOXO3 gene, making the gene more active[^19^]. This ability to activate FOXO3 makes exogenous ketones a promising tool to unlock the benefits mediated by calorie restriction[^21^].
Exogenous Ketones and Cellular Senescence
Cellular senescence is a state when a cell’s ability to replicate is halted due to accumulated damage[^22^]. While senescent cells can still perform their function, their inability to replicate greatly affects the capacity of tissues to regenerate, leading to an overall functional decline associated with ageing[^23^]. BHB, however, interacts with some of the proteins that regulate senescence[^24^], thus delaying cellular senescence and preserving the function of ageing tissues[^26^][^27^].
The Role of Exogenous Ketones in Preventing Age-Associated Inflammation
Senescent cells secrete pro-inflammatory cytokines, collectively known as the senescence-associated secretory phenotype (SASP)[^30^]. As we age, the function of our immune system declines and the number of senescence cells increases, resulting in more SASP secretion and contributing to age-associated inflammation, or inflammaging[^32^]. Evidence suggests that BHB might stop this cycle. A 2018 study[^35^] reported that BHB prevents SASP production in vascular cells, thereby potentially alleviating the toxic effects of SASP and preventing the spread of senescent cells.
Exogenous Ketones and Autophagy
Autophagy is a process of cellular recycling of proteins, preventing the aggregation of damaged proteins that would compromise cellular function[^40^]. Unfortunately, as we age, the process of autophagy becomes less efficient, potentially leading to the accumulation of damaged or misfolded proteins in the cell[^41^]. BHB plays a crucial role in this process. Studies have shown that BHB stimulates autophagy in neurons[^44^], suggesting that autophagy activation during calorie restriction might be mediated by BHB[^45^].
The role of exogenous ketones extends beyond serving as a fuel source. They stimulate adaptations that help cells deal with energy deficits, mitigate cellular senescence and senescence-associated inflammation, and stimulate autophagy. These adaptations also mediate the longevity benefits of caloric restriction. Therefore, exogenous ketones are a promising tool for longevity and cognitive health, brain health, potentially slowing down our ageing clocks.
[^1^]: McCay, C.M., et al., 1935. The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. The Journal of Nutrition, 10(1), pp.63-79.
[^2^]: Lakowski, B. and Hekimi, S., 1998. The genetics of caloric restriction in Caenorhabditis elegans. Proceedings of the National Academy of Sciences, 95(22), pp.13091-13096.
[^3^]: Partridge, L., et al., 2005. Dietary restriction in Drosophila. Mechanisms of Ageing and Development, 126(9), pp.938-950.
[^4^]: Masoro, E.J., 2009. Caloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms. Biochimica et Biophysica Acta (BBA)-General Subjects, 1790(10), pp.1040-1048.
[^5^]: Kealy, R.D., et al., 2002. Effects of diet restriction on life span and age-related changes in dogs. Journal of the American Veterinary Medical Association, 220(9), pp.1315-1320.
[^6^]: Mattison, J.A., et al., 2017. Caloric restriction improves health and survival of rhesus monkeys. Nature Communications, 8(1), pp.1-12.
[^7^]: Anderson, R.M. and Weindruch, R., 2012. The caloric restriction paradigm: implications for healthy human aging. American Journal of Human Biology, 24(2), pp.101-106.
[^8^]: Madeo, F., et al., 2014. Caloric restriction mimetics: towards a molecular definition. Nature Reviews Drug Discovery, 13(10), pp.727-740.
[^9^]: Cahill Jr, G.F., 2006. Fuel metabolism in starvation. Annu. Rev. Nutr., 26, pp.1-22.
[^10^]: Dilliraj, L.N., et al., 2022. The Evolution of Ketosis: Potential Impact on Clinical Conditions. Nutrients, 14(17), p.3613.
[^11^]: Rojas-Morales, P., et al., 2016. β-Hydroxybutyrate: A signaling metabolite in starvation response?. Cellular Signalling, 28(8), pp.917-923.
[^12^]: Passarino, G., et al., 2016. Human longevity: Genetics or Lifestyle? It takes two to tango. Immunity & Ageing, 13(1), pp.1-6.
[^14^]: Broer, L., et al., 2015. GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 70(1), pp.110-118.
[^18^]: Fasano, C., et al., 2019. FOXO3a from the nucleus to the mitochondria: a round trip in cellular stress response. Cells, 8(9), p.1110.
[^19^]: Shimazu, T., et al., 2013. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116), pp.211-214.
[^21^]: Shimokawa, I., et al., 2015. The life‐extending effect of dietary restriction requires F oxo3 in mice. Aging Cell, 14(4), pp.707-709.
[^22^]: Chen, J.H., et al., 2007. DNA damage, cellular senescence and organismal ageing: causal or correlative?. Nucleic Acids Research, 35(22), pp.7417-7428.
[^23^]: Antelo-Iglesias, L., et al., 2021. The role of cellular senescence in tissue repair and regeneration. Mechanisms of Ageing and Development, 198, p.111528.
[^24^]: Mijit, M., et al., 2020. Role of p53 in the Regulation of Cellular Senescence. Biomolecules, 10(3), p.420.
[^26^]: Fang, Y., et al., 2021. The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults. Kidney International, 100(5), pp.1037-1053.
[^27^]: Han, Y.M., et al., 2018. β-Hydroxybutyrate prevents vascular senescence through hnRNP A1-mediated upregulation of Oct4. Molecular Cell, 71(6), pp.1064-1078.
[^30^]: Young, A.R. and Narita, M., 2009. SASP reflects senescence. EMBO Reports, 10(3), pp.228-230.
[^32^]: Olivieri, F., et al., 2018. Cellular senescence and inflammaging in age-related diseases. Mediators of Inflammation, 2018.
[^35^]: Han, Y.M., et al., 2018. β-Hydroxybutyrate prevents vascular senescence through hnRNP A1-mediated upregulation of Oct4. Molecular Cell, 71(6), pp.1064-1078.
[^40^]: Mizushima, N., 2007. Autophagy: process and function. Genes & Development, 21(22), pp.2861-2873.
[^41^]: Ichimiya, T., et al., 2020. Autophagy and autophagy-related diseases: a review. International Journal of Molecular Sciences, 21(23), p.8974.
[^44^]: Bujak, A.L., et al., 2015. AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metabolism, 21(6), pp.883-890.
[^45^]: Camberos-Luna, L., et al., 2016. The ketone body, β-hydroxybutyrate stimulates the autophagic flux and prevents neuronal death induced by glucose deprivation in cortical cultured neurons. Neurochemical Research, 41(3), pp.600-609.