Beneficial Effects Of Exogenous Ketogenic Supplements On Aging Processes And Age-Related Neurodegenerative Diseases Part 1

Abstract: 

The life expectancy of humans has increased continuously up to the present day, but their health status (healthspan) was not enhanced to a similar extent. To decrease the enormous medical, economic, and psychological burden that arises from this discrepancy, improvement of healthspan is needed which leads to delaying both aging processes and the development of age-related diseases, thereby extending lifespan. 

Life expectancy is the length of time a person can survive in this world, and it is affected by many factors, such as genes, diet, living habits, etc. Memory is one of the most important abilities in the human brain. It can help us obtain information, record life fragments, and make correct decisions. Is there a relationship between the two?

Studies have found that there is indeed a relationship between life expectancy and memory. As people age, their life expectancy gradually decreases. However, if they can maintain a certain level of health, such as exercising and maintaining good eating habits, their life expectancy will also be extended. Likewise, people's memory gradually declines as they age. But if they can take steps to improve their memory skills, their brains will stay young and flexible.

As we said, the relationship between life expectancy and memory is complex, but there is a link. Although people cannot determine their genes or life expectancy, they can improve their health and memory through their efforts. For example, exercising, maintaining good sleep habits, and eating more fresh fruits and vegetables, can help improve overall health and brain function. In addition, regular brain exercise, learning new skills and knowledge, participating in social activities, etc. can also help improve memory.

In summary, there is a link between life expectancy and memory, but it is not absolute. Regardless of the length of life expectancy, we should cherish every day of life and improve our health and happiness index through a healthy lifestyle and a positive attitude. Let us enjoy the wonderful journey of life together! It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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Thus, the 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. 

This review aims 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: ketogenic supplement; ketosis; aging; lifespan; neurodegenerative disease; learning; memory.

1. Introduction

Aging processes result in the irreversible decline of normal physiological functions (time-dependent functional decline) and age-related diseases. It has been demonstrated that several genes and environmental factors can modulate cellular functions leading to the appearance of aging hallmarks, such as cellular senescence, mitochondrial dysfunction, loss of proteostasis, telomere attrition, deregulated nutrient sensing, stem cell exhaustion, and epigenetic alterations [1,2]. 

These changes may generate, for example, chronic inflammation and aging that leads to increased risk for age-related chronic diseases, such as neurodegenerative diseases (e.g., Alzheimer's disease), osteoporosis, cardiovascular diseases, cancer, diabetes, sarcopenia, and osteoarthritis [1,2]. A worldwide increase in the elderly population has been predicted, as about 9% of people were over the age of 65 in 2019, and which number was predicted to increase to approximately 17% by 2050 [3,4]. 

Human lifespan is increasing, as a result of more and more effective therapeutic tools and improvement in living conditions, but the health status of patients is not improving by the same intensity. Thus, the prevalence of age-related diseases, such as neurodegenerative diseases are continuously increasing each year [5,6] and the consequences of aging processes and related diseases generate enormous medical, psychological, and economic burdens for humanity [7]. 

To decrease the negative consequences of aging processes and related diseases, thereby mitigating their negative effects on health and the economy, several drugs were developed that are undergoing clinical trials. 

For example, rapamycin and its analogues [8–10], metformin [11,12], sirtuin (SIRT) activators [13,14] and senolytics (for elimination of senescent cells) [15] can modulate aging mechanisms, and, as a consequence, increase lifespan and decrease risk for age-related diseases. 

However, to prevent, alleviate, and delay age-related processes and diseases, to extend health span, and to improve the quality of life of the elderly population, the development of safer and more effective drugs and therapeutic tools is needed. Exogenous ketogenic supplements (EKSs), such as ketone esters (KEs, e.g., R,S-1,3- butanediol-acetoacetate diester), ketone salts (KSs, e.g., Na+/K+-β-hydroxybutyrate/βHB mineral salt), and medium chain triglycerides (MCTs/MCT oils containing, e.g., about 60% caprylic triglyceride and 40% capric triglyceride) have been proven effective when used together with normal diet to induce and maintain an increased blood ketone body level (ketosis) [16–20]. 

It has been demonstrated that the level of EKSs-induced ketosis may change by age and gender [21]. Ketone bodies (e.g., βHB and acetoacetate) can enter the central nervous system (CNS) via monocarboxylate transporters and can be used for ATP (adenosine triphosphate) synthesis via the Krebs cycle in brain cells [22–25]. It has been demonstrated that EKSs can generate rapid (0.5–6 h after administration) and mild to moderate [19,26–29] therapeutic ketosis (about 1–7 mM) [30,31]. 

To sustain therapeutic ketosis leading to positive outcomes, administration of different amounts of EKSs must be repeated for several days or up to several months depending on the disease, the dose, and the type of EKSs. For example, administration of 30 g MCT drink/day for 6 months and 75 g KE/day for 4 weeks was able to evoke beneficial effects in patients with mild cognitive impairment and type 2 diabetes, respectively [32,33]. 

However, it has been suggested that not only these, but other EKSs may be effective and safe ketone body precursors for the treatment of diseases in humans through increased βHB levels (ketosis) [29,32,34,35]. It has been demonstrated that EKSs are well-tolerated and safe (with mild adverse effects, if any) [19,26,28,29,33,36]. Moreover, the administration of EKSs can circumvent both dietary restrictions and adverse effects of ketogenic diets (e.g., nephrolithiasis, constipation, and hyperlipidemia) [37]. Thus, administration of EKSs may be a safe and effective alternative metabolic therapy to the ketogenic diet. 

It has also been demonstrated that the administration of EKSs-generated therapeutic ketosis may evoke beneficial effects on CNS diseases [34,38,39]. For example, KEs, KSs, and MCT oils can evoke anti-seizure and anti-epileptic effects [36,40–42], anxiolytic influence [26,43,44], regeneration of nervous system injuries [45] and alleviating effects on neurodegenerative diseases (such as Alzheimer's disease) [41,46–48]. 

These beneficial effects were induced likely through ketosis-evoked neuroprotective effects, for example, by improved mitochondrial functions, enhanced ATP levels, decreased inflammatory processes, and decreased oxidative stress [23,24,34,49,50]. Moreover, ketone bodies may modulate aging processes thereby extending lifespan and delaying the development of age-related diseases, such as neurodegenerative diseases. 

It has been demonstrated that not only ketogenic diets, but also the administration of EKSs can increase and maintain blood ketone body levels [19,26–29], which ketone bodies, such as βHB, may promote anti-aging effects [35,51,52]. Moreover, it was demonstrated that βHB, as an endogenous ligand molecule, can activate the hydroxycarboxylic acid receptor 2 (HCAR2 or GPR109A receptor) [53,54]. HCAR2 receptors are expressed not only in macrophages but also in the brain cells, mainly in microglia, as well as astrocytes and neurons [54–56]. 

Thus, the βHB molecule via, for example, HCAR2 receptors can modulate not only physiological but also pathophysiological processes in the brain that are connected to aging and neurodegenerative diseases [55,57,58]. Based on the literature, an increase in βHB level may be the main factor contributing to the beneficial effects on aging, lifespan, and age-related diseases after the administration of EKSs. Indeed, it has been demonstrated that βHB decreased the senescence-associated secretory phenotype (SASP) of mammals [59] and extended the lifespan of C. elegans [60]. 

Consequently, in this review paper, we focused on βHB-generated alleviating effects. Although limited evidence supports the alleviating influence of EKSs on lifespan, aging processes, and related CNS diseases, we can hypothesize that EKSs-evoked increase in blood βHB level can modulate (alleviate) aging processes and improve symptoms of age-related diseases through their neuroprotective effects, therefore may delay both aging and the development of related diseases and extend lifespan. 

This review discusses the hallmarks of aging and putative anti-aging molecular mechanisms (pathways) by which EKSs may be able to exert their beneficial effects on lifespan, healthspan, aging, the most common age-related neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), as well as learning and memory.

2. Main Features of Aging Processes

It has been demonstrated that aging is the most common risk factor for the emergence of neurodegenerative diseases [2]. Indeed, as the life expectancy of humans increases, more and more people suffer from different types of neurodegenerative diseases, such as Alzheimer's disease [61]. 

Moreover, it has been demonstrated that development and incidence of the most common neurodegenerative diseases, Alzheimer's disease (e.g., characterized by extracellular senile, amyloid-β/Aβ plaque and neurofibrillary tangle/hyperphosphorylated and misfolded Tau accumulation in the brain; impairment of learning and memory), Parkinson's diseases (e.g., characterized by the accumulation of α-synuclein and the loss of dopaminergic neurons; tremors and muscle rigidity) and amyotrophic lateral sclerosis (e.g., accumulation of TAR DNA-binding protein 43; progressive degeneration of motor neurons a motor defects; muscle weakness) are promoted by aging [6,62–64]. 

It has also been demonstrated that aging hallmarks, such as reduced telomere length and/or genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence, loss of proteostasis, changes in the activity of nutrient-sensing pathways and intercellular communication, as well as stem cell exhaustion can be detected in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. 

However, in amyotrophic lateral sclerosis, the reduced telomere length, genomic instability, cellular senescence, and changes in intercellular communication may be the main contributing factors [63,64]. Thus, in this chapter, we shortly characterize the main aging hallmarks and their connection with the development of the above-mentioned age-related neurodegenerative diseases. 

Moreover, based on the literature (e.g., administration and effects of xenomorphic drugs and caloric restriction) we present the main signaling pathways contributing to the modulation of aging processes, suggesting that inhibition or activation of these pathways may be used for delaying not only aging but also related neurodegenerative diseases, improve impaired learning and memory functions, as well as to promote lifespan.

2.1. Nutrient Sensing Pathways

Changes in the activity of nutrient-sensing pathways may have a role in aging and the development of age-related diseases. It has been demonstrated that caloric restriction and fasting can attenuate aging, expand lifespan, generate neuroprotective effects, and prevent age-related diseases through energy (nutrient) sensing insulin/insulin-like growth factor (IGF) 1 (IIS) pathway, AMP (adenosine monophosphate) activated serine-threonine protein kinase (AMPK), Sirtuin 1 (SIRT1) and transcriptional factor FOXOs (Forkhead box Os) [65–68]. 

Previous studies show that caloric restriction can decrease IGF, insulin, glucose, and amino acid levels, whereas increases NAD+ (nicotinamide adenine dinucleotide) and AMP levels (Figure 1). 

These alterations are sensed by the (i) IIS pathway, activated by increased IGF and glucose levels; (ii) AMPK, which senses low energy states via increased AMP levels; (iii) SIRT1, which also senses low energy states via increased NAD+ levels (NAD+ -dependent protein deacetylase); and (iv) mechanistic target of rapamycin (mTOR), which senses high amino acid levels leading to stress resistance, oxidative metabolism, enhanced DNA repair, epigenetic stability and increase in longevity [69–71]. Nutrients 2021, 13, 2197 4 of 38 Os) [65–68]. 

Previous studies show that caloric restriction can decrease IGF, insulin, glucose, and amino acid levels, whereas increases NAD+ (nicotinamide adenine dinucleotide) and AMP levels (Figure 1). 

These alterations are sensed by the (i) IIS pathway, activated by increased IGF and glucose levels; (ii) AMPK, which senses low energy states via increased AMP levels; (iii) SIRT1, which also senses low energy states via increased NAD+ levels (NAD+-dependent protein deacetylase); and (iv) mechanistic target of rapamycin (mTOR), which senses high amino acid levels leading to stress resistance, oxidative metabolism, enhanced DNA repair, epigenetic stability and increase in longevity.

Reduced activity of the IIS pathways can extend lifespan [72], similar to the mTOR inhibitor rapamycin-evoked increase in lifespan [9]. It was also demonstrated that decreased IIS signaling reduced the aggregation-mediated toxicity of the Aβ1–42 (amyloid β-peptide 1–42), suggesting that decreased insulin signaling may be protective against abnormal aggregation of proteins in neurodegenerative diseases, such as Alzheimer's disease [73]. 

Moreover, mTOR (a serine/threonine protein kinase) is the main regulator of cellular growth and mass accumulation, which contains mTORC1 and mTORC2 complexes [6]. mTORC1 can integrate signals from nutrients, growth factors, energy, and oxygen levels to promote cell proliferation and growth (e.g., enhancement of energy metabolism/glycolysis and nucleotide, protein, as well as lipid synthesis and inhibition of catabolism/autophagy) [74,75] (Figure 1). 

Indeed, for example, mTORC1 supports protein synthesis by phosphorylation of S6K1 (ribosomal protein S6 kinase 1) and 4EBP1 (eukaryotic translation initiation factor 4E binding protein 1) molecules, which processes may be activated by Akt kinase (protein kinase B) [6,75,76] (Figure 1). 

Moreover, mTORC1 can suppress autophagy via inhibition of ULK1 (Uncoordinated/Unc-51-like kinase 1) which impedes the cellular homeostasis-maintaining processes (e.g., providing nutrients under starvation and removing damaged organelles and misfolded proteins) [75,77]. 

Thus, inhibition of mTORC1 effects on autophagy may be an important tool to decrease age-dependent processes (aging hallmarks, such as loss of proteostasis) and promote longevity [6] (Figure 1). It was also demonstrated that mTORC2 has a role in the cytoskeleton reorganization (connected to cell growth) and cell survival modulation [75,78].

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