Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases

Abstract

Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.

Keywords: aging; ketogenic supplement; ketosis; learning; lifespan; memory; neurodegenerative disease.

Figure 1

Main downstream signaling pathways and some effects, by which different senomorphic drugs (e.g., metformin), interventions (e.g., caloric restriction) and, theoretically, exogenous ketogenic supplements-evoked ketosis (βHB) can improve age-dependent impaired processes (aging hallmarks). Abbreviations: Akt, Akt kinase/protein kinase B; AMPK, AMP activated serine-threonine protein kinase; ATP, adenosine triphosphate; βHB, beta-hydroxybutyrate; FOXOs, Forkhead box Os; HCAR2, hydroxycarboxylic acid receptor 2; IGF 1, insulin-like growth factor 1; mTORC1, mechanistic target of rapamycin C1; NAD⁺, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide (NAD) + hydrogen (H); NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; PGC-1α, peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α; PI3K, phosphatidyl inositol-3-kinase; ROS, reactive oxygen species; SASP, senescence associated secretory phenotype; SIRT1, Sirtuin 1.

Figure 2

Signaling pathways and effects by which exogenous ketogenic supplements-generated ketosis (βHB) may extend lifespan, delay both aging and development of neurodegenerative diseases, and improve learning and memory dysfunctions. Abbreviations: AMPK, AMP activated serine-threonine protein kinase; βHB, beta-hydroxybutyrate; BDNF, brain-derived neurotrophic factor; FOXO, Forkhead box O; HATs, histone acetyltransferases; HCAR2, hydroxycarboxylic acid receptor 2; HDAC, histone deacetylase; IL-1R, IL-1 receptor; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-like receptor pyrin domain 3; Nrf2, nuclear factor erythroid 2-related factor 2; PGC1-α, peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α; ROS, reactive oxygen species; SIRT, sirtuin; UCP, uncoupling protein.