Beneficial Effects Of Exogenous Ketogenic Supplements On Aging Processes And Age-Related Neurodegenerative Diseases Part 5

3.2. Beneficial Effects of EKSs-Evoked Ketosis (βHB) on Lifespan, Aging, Age-Related Diseases, as well as Learning and Memory Dysfunctions 

Administration of βHB generated anti-aging and life-extending effects in C. elegans [22,60]. 

This result suggests that lifespan extension by βHB may also be mediated in mammals through signaling pathways similar to C. elegans [60,294], likely by activation of AMPK/SIRT1/mTOR/FOXOs/Nrf2 pathways, HDAC inhibition (and related increase in FOXOs activity) or reduction of insulin signaling pathway activity (Figures 1 and 2). Indeed, for example, it was demonstrated that inhibition of IIS pathways, thereby activation of FOXOs are important processes for lifespan extension [295] and the FOXO3A gene is strongly associated with human longevity [296]. 

The relationship between human longevity and memory has always attracted much attention. With the development of modern medicine and health management, people's lifespans are getting longer and longer. At the same time, we are increasingly aware of the importance of memory to our lives and work.

The relationship between longevity and memory is simple. Humans are living longer, which means we need to maintain good physical and mental health for longer. People live longer through a healthy diet, proper exercise, and a positive attitude towards life. These measures not only help slow down the body's aging process but can also help improve our memory.

Memory refers to the human ability to acquire, store, and reuse information. It is the basis of our study and work. Our memory can be divided into short-term memory and long-term memory. Short-term memory lasts for a few minutes, while long-term memory lasts for a long time or even a lifetime.

As we age, our memory declines. However, with proper training and lifestyle habits, we can maintain good memory. For example, exercise your brain regularly to improve learning efficiency. Some simple ways include learning to speak a new language, learning a new skill, or playing mind games. In addition, good sleep and healthy living habits can also promote memory retention.

Overall, longevity and memory are closely linked. We can maintain good memory through healthy living habits and proper training, and be able to better enjoy life and work as our life span is extended. Let's face the future with positivity and work hard for our health and memory! It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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An increase in autophagy by caloric (or dietary) restriction can enhance lifespan not only in C. elegans but also in mammals through similar pathways, which may also be activated by the administration of EKSs, such as KEs and KSs. For example, in mammals, this effect may be mediated through βHB-evoked inhibition of mTOR activity, activation of FOXOs (via both activation of SIRT1 and direct inhibition of Akt), and ketone body metabolism-evoked decrease in blood glucose and insulin levels, which also decrease the activity of IIS pathways [52,77,180,297,298]. 

Moreover, long-lived animals showed a decrease in mitochondrial ROS production [299] suggesting both inverse correlation between longevity and mitochondrial ROS production (and mitochondrial DNA damage) [52,299] and βHB-evoked enhancement of longevity (lifespan) (Figures 1 and 2). 

It was also suggested that the ketogenic diet (likely through ketogenic diet generated ketosis/elevated blood βHB, at least partly) can reduce midlife mortality [300], extend longevity and healthspan in adult mice [51], increase lifespan in Kcna1-null mice [301] and decreased senescence may be partly through β-hydroxybutyrylation-evoked decrease in p53 activity (in addition, β-hydroxybutyrylation also can attenuate acetylation of p53, because β-hydroxybutyrylation interferes with acetylation) [302]. 

These results suggest that βHB-generated activation of different signaling pathways may have a role in the modulation of aging processes, thereby both lifespan and healthspan. Indeed, it was demonstrated that βHB can alleviate cellular senescence through increased autophagy and decreased plasma insulin level and inflammatory processes in male rats [303], likely through AMPK/SIRT1 pathways (Figure 1). 

It has also been demonstrated that increased level of blood βHB can delay the age-related processes, for example, by inhibition of SASP, thereby senescence, likely through βHB/hnRNP A1-binding-evoked increase in binding of hnRNP A1 and Oct4 (embryonic stem cell regulator octamer-binding transcriptional factor 4) leading to stabilization of Oct4 mRNA (complex formation with Oct4 mRNA and upregulation of Oct4 expression) and SIRT1 mRNAs [59,304]. 

βHB-evoked activation of Oct4 not only triggers (maintains) the quiescent state of cells (e.g., AMPK activation and mTOR inhibition), but also decreases induction of the senescent state of cells (e.g., reduction of the blood level of a pro-senescence marker IL-1α and SASP expression) leading to protection of cells against senescence, and likely, induction of autophagy [59]. 

These results above suggest that, indeed, EKSs(βHB)-evoked ketosis can alleviate aging processes (aging hallmarks), at least theoretically, through βHB-evoked activation of AMPK/SIRT1 or SIRT3 downstream signaling pathways (e.g., βHB/HCAR2/AMPK/SIRT1/NF-κB pathway), inhibition of mTOR- (e.g., βHB/HCAR2/AMPK/mTOR pathway) and NLRP3/IL-1R-generated effects, HDAC inhibition, β-hydroxybutyrylation and hnRNP A1-binding (Figures 1 and 2) leading to improved healthspan, delayed aging, thereby extended lifespan. 

A great deal of evidence suggests that the progression of aging processes by age can lead to not only the emergence of aging hallmarks but also enhanced risk for the development of neurodegenerative diseases and impaired learning and memory functions through, for example, mitochondrial dysfunction, epigenetic alterations, and enhanced inflammation, which processes may be alleviated by EKSs-generated ketosis (βHB) (Figures 1 and 2). 

For example, impaired mitochondrial functions, increased oxidative stress and neuronal injury were demonstrated in different CNS diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis [305–308].

Moreover, mitochondrial dysfunction evoked increases in ROS levels may enhance inflammatory processes [309,310], leading to impaired cognitive functions, for example in patients with neurodegenerative diseases (e.g., Alzheimer's disease) [311–313]. It has been suggested that ketogenic diet- and EKSs-evoked ketosis can improve or prevent impaired cognitive functions, learning, and memory, for example, via enhanced mitochondrial respiration and antioxidant mechanisms [49,314–317]. 

Indeed, not only the ketogenic diet (and related ketosis) and βHB but also KE, KS, and MCT supplementation improved cognitive functions, learning, and memory, as well as their age-related decline in animal models of Alzheimer's disease and patients with Alzheimer's disease or mild cognitive impairment [32,43,47,50,317–320] (Table 1), in a mouse model of Angelman syndrome [41] and old animals and elderly humans [321,322]. 

EKSs may exert these beneficial effects via increased ketone body level, which can improve mitochondrial functions. For example, an increased level of βHB can compensate for glucose hypometabolism-generated decrease in energy sources in humans and restore ATP synthesis [16,289,318,319,323]. Glucose hypometabolism may contribute to the development of, for example, Alzheimer's disease [324,325]. 

It has also been demonstrated that MCT supplementation-evoked improvement in cognitive functions was observed in patients with mild to moderate Alzheimer's disease or mild cognitive impairment without apolipoprotein E (APOE) ε4 allele [326,327], but the mechanism of action of APOE-ε4 status on MCT/ketosis-generated alleviating effects was not identified. 

Moreover, improved learning and memory were also demonstrated about ketone bodies-evoked decrease in both oxidative stress and intracellular Aβ42 accumulation, and increased mitochondrial complex I activity in models of Alzheimer's disease [50,328,329] (Table 1). 

It was demonstrated that βHB can protect neurons and alleviate symptoms in models of not only Alzheimer's disease but also Parkinson's disease [328,330], likely via improvement of mitochondrial function (e.g., by increased ATP synthesis) and activation of other neuroprotective mechanisms, leading to improvement (or protection) in neurodegeneration, motor functions (e.g., tremor) and impaired cognition [258,259,328,331]. 

Moreover, indeed, βHB administration can decrease aggregation of α-synuclein and delay the toxicity of Aβ [60]. The ketogenic diet- and EKSs-generated ketosis, βHB or the Deanna protocol, containing (among others) MCTs, can also generate alleviating effects on (i) motor neurons and motor performance in preclinical rodent models, such as animal models of amyotrophic lateral sclerosis [48,332–336] and (ii) dopaminergic neurons and motor performance in animal models of Parkinson's disease [55,258] likely through improved mitochondrial function and ATP synthesis (Table 1). 

   Dysregulation of different neurotransmitter systems may have a role in the pathophysiology of neurodegenerative diseases, for example, in animal models and patients with impaired motor function (e.g., dopaminergic dysfunction; GABA and glutamate imbalance) [337–340], Parkinson's disease (e.g., decrease in serotonin level and increase in glutamatergic transmission), Alzheimer's disease (decreased cholinergic neurotransmission) and both Alzheimer's disease and Parkinson's disease (deficits in dopaminergic signaling) [337,339,341–343]. 

Moreover, dysfunctions in neurotransmitter systems (e.g., GABAergic, glutamatergic, and cholinergic) can lead to impaired learning and memory [340,342,344]. It has also been demonstrated that dysregulation of acetylation and deacetylation can lead to neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and learning and memory deficits [345–348]. 

Moreover, HDAC inhibitors can improve symptoms or impede the development of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis and restore learning and memory functions [347,349–352]. 

Low BDNF levels were demonstrated in patients with Alzheimer's disease, which decrease in BDNF level correlates with loss of cognitive functions [353,354], suggesting that ketosis (elevated blood βHB levels) can exert its beneficial effects on Alzheimer's disease and cognitive functions, among others, through HDAC/BDNF system leading to enhancement of alleviating BDNF effects (e.g., by stimulation of hippocampal neurogenesis) [355]. 

Thus, EKSs (via ketosis/βHB) can exert alleviating effects on neurodegenerative diseases, learning, and memory functions through modulation of not only mitochondrial functions and inflammatory processes but also neurotransmitter systems and via epigenetic modification (Figure 2). Indeed, for example, it was suggested that EKSs may be able to prevent or improve neurodegenerative diseases and learning and memory, among others, through HDAC inhibition [30].

HCAR2 ligands can generate alleviating effects on Parkinson's disease, Alzheimer's disease, impaired learning, memory and motor functions, as well as amyotrophic lateral sclerosis via anti-inflammatory effects [43,50,57,258], suggesting that EKSs-evoked ketosis (βHB) exerts its alleviating effects on learning, memory, as well as age and age-related diseases through βHB/HCAR2-evoked downstream signaling (Figure 2). 

Indeed, previous studies show that ketosis (βHB) may evoke therapeutic effects in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and enhance learning and memory through anti-inflammatory effects induced by HCAR2 [50,55,57,58,275,279]. It was also demonstrated that enhanced expression of proinflammatory cytokines and oxidative stress has a role in the development of Alzheimer's disease [276,356,357], Parkinson's disease [55,276,356,357], amyotrophic lateral sclerosis [356–358], impaired motor functions [337,359] and impairment of learning and memory [309,310,360]. 

Thus, ketosis may also improve symptoms of neurodegenerative diseases, and motor, learning, and memory dysfunctions through anti-inflammatory and anti-oxidative effects via HCAR2 [50,275,361] (Figure 2). 

It has been demonstrated that SIRT1 levels were decreased in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease [97,362] suggesting alleviating effects of SIRT1 activation-modulated pathway(s) in the treatment of neurodegenerative diseases [363]. It was also suggested that activation of SIRT1-dependent pathways can modulate learning and memory by which ketone bodies may be able to improve both learning and memory functions [327]. 

Indeed, overexpression of SIRT1 was protective against learning and memory impairment in animal models of Alzheimer's disease [364,365] and increased SIRT1 activity could promote memory processes, whereas SIRT1 knockout animals showed impaired cognitive abilities [366,367]. 

Moreover, activation of SIRT1 generated protective influences in mouse models of amyotrophic lateral sclerosis (e.g., enhanced biogenesis of mitochondria and suppressed deterioration of motor neurons) [94,368,369], preserved dopaminergic neurons in a mouse model of Parkinson's disease [370] and evoked protection against Aβ plaque formation in mouse models of Alzheimer's disease [94,371] likely via, for example, SIRT1/PGC1-α/MnSOD pathway [173,372]. 

It has been demonstrated that PGC1- α-deficiency may be in connection with neurodegenerative lesions [373], and decreased PGC1-α expression may be one of the most important factors in the development of both Parkinson's disease [374,375] and Alzheimer's disease [174,376]. 

Moreover, PPARγ agonist pioglitazone (an antidiabetic agent) and overexpression of PGC1-α were able to improve symptoms of amyotrophic lateral sclerosis in mouse models [377,378] and other PPARγ agonists can improve not only symptoms of neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis) but also impaired cognitive functions, learning and memory [379,380]. 

As oxidative stress has a role in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease, Nrf2 thereby, for example, AMPK/SIRT1/Nrf2 pathway may be an important therapeutic target in the treatment of these diseases [381,382]. Moreover, it was also suggested that activation of SIRT3/PGC1-α/MnSOD pathways could also generate alleviating effects on Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis [383–385].
Consequently, indeed, EKSs-generated ketosis (βHB) can alleviate or delay the development of neurodegenerative diseases, and improve learning and memory dysfunctions likely through different βHB/HCAR2/AMPK-modulated downstream signaling pathways (Figure 2).

4. Conclusions

A great deal of evidence suggests that EKSs-generated ketosis may improve healthspan and, therefore can delay aging and the onset of age-related neurodegenerative diseases, as well as learning and memory dysfunctions through neuroprotective effects. Despite the overwhelming amount of promising mechanistic findings, only a limited number of studies focused on and demonstrated the beneficial effects of EKSs-evoked ketosis on lifespan, aging processes, age-related diseases, and impaired learning and memory functions. 

However, their beneficial effects on healthspan and lifespan-likely through improving mitochondrial functions, anti-oxidant effects, anti-inflammatory influences, and modulation of histone and non-histone acetylation, as well as neurotransmitter systems-, can be hypothesized. Indeed, it has been suggested that EKSs-evoked ketosis may alter the activity of different downstream signaling pathways (e.g., AMPK-, SIRTs- and mTOR-modulated pathways) and modulatory effects, through which not only chemotherapeutic drugs, but also ketosis (βHB) can improve symptoms and delay development of age-related hallmarks, age-associated neurodegenerative diseases, and learning and memory dysfunctions, and extend lifespan. 

Consequently, administration of EKSs may be a potential therapeutic tool as an adjuvant therapeutics in combination with different therapeutic drugs (such as metformin and rapamycin) for regenerative medicine to enhance the effectivity of drugs to rejuvenate aging hallmarks, decrease the risk for age-related neurodegenerative diseases and increase the healthspan of the aging human population. 

However, modulating aging processes and related diseases by administration of EKSs needs careful attention, because insufficient clinical data is available currently on its positive effects, efficacy, and safety, regarding this specific application. 

Thus, long-term studies are needed to investigate the exact mechanisms of action by which EKSs-evoked ketosis modulates aging processes, age-related diseases, learning and memory functions, health span, and lifespan. Moreover, to develop effective treatments for patients with different age-related diseases more studies are needed to identify the most effective doses, administration routes, treatment duration, and different formulations of EKSs.

Author Contributions: Writing-original draft, Z.K., and B.B.; Writing-review and editing, C.A. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by ELTE BDPK Excellence Program 12/2020 (to Zsolt Kovács) and Ketone Technologies LLC. The funding body did not influence the writing of the manuscript.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest: Patent: #10980764, University of South Florida, C.A., D.P.D. "Exogenous ketone supplements for reducing anxiety-related behavior"; Non-provisional patents: Ari, C., Arnold P., D'Agostino, D.P. Technology Title: "Elevated Blood Ketone Levels by Ketogenic Diet or Exogenous Ketone Supplements Induced Increased Latency of Anesthetic Induction" USF Ref. No. 16A018PR; Ari, C., Arnold P., D'Agostino, D.P. Technology Title: "Exogenous Ketone Supplementation Improved Motor Function in Sprague-Dawley Rats." USF Ref. No: 16A019; Ari, C., Arnold P., D'Agostino, D.P. Technology Title: "Lowering of Blood Glucose in Exercising and Non-Exercising Rats Following Administration of Exogenous Ketones and Ketone Formulas." USF Ref. No: 16A049; Ari, C., Arnold P., D'Agostino, D.P. Technology Title: "Neuroregeneration improved by ketone." USF Ref. No: 16B128 (provisional patent); Ari, C., D'Agostino, D.P. Dean, J.B. Technology Title: "Delaying latency to seizure by combinations of ketone supplements." USF Ref. No: 16B138PR. C. Ari is co-owner of Ketone Technologies LLC and owner of Fortis World LLC. These interests have been reviewed and managed by the University by its Institutional and Individual Conflict of Interest policies. All authors declare that there are no additional conflicts of interest.

Abbreviations

Aβ: amyloid-β; ACCs, acetyl-CoA carboxylases; Akt, Akt kinase/protein kinase B; AMPK, AMP-activated serine-threonine protein kinase; BDNF, brain-derived neurotrophic factor; βHB, beta-hydroxybutyrate; CNS, central nervous system; EKSs, exogenous ketogenic supplements; ER, endoplasmic reticulum; ETC, electron transport chain; FOXOs, Forkhead box Os; HATs, histone acetyltransferases; HCAR2, hydroxycarboxylic acid receptor 2; HDACs, histone deacetylases; hnRNP A1, heterogeneous nuclear ribonucleoprotein A1; IGF 1, insulin-like growth factor 1; IIS pathway, insulin/insulin-like growth factor (IGF) 1 pathway; IL-1β, interleukin-1β; IL-1R, IL-1 receptor; KE, ketone ester; KS, ketone salt; MCT, medium chain triglyceride; miRNAs, microRNAs; MnSOD, manganese superoxide dismutase; mPT pore, mitochondrial permeability transition pore; mTOR,mechanistic target of rapamycin; NAD+ , nicotinamide adenine dinucleotide; 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; Oct4, embryonic stem cell regulator octamer-binding transcriptional factor 4; p53, transcription factor tumor suppressor protein 53; PARP-1, poly(ADP-ribose)- polymerase-1; PGC-1α, peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α; ROS, reactive oxygen species; SASP, senescence associated secretory phenotype; SIRT, Sirtuin; SOD, superoxide dismutase; SREBP1, sterol regulatory element-binding protein 1; TNF-α, tumor necrosis factor-α; UCP, uncoupling protein; ULK1, Uncoordinated/Unc-51-like kinase 1.

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