Beneficial Effects Of Exogenous Ketogenic Supplements On Aging Processes And Age-Related Neurodegenerative Diseases Part 2

SIRTs and AMPK also have a role in the modulation of lifespan. Activation of AMPK-mediated pathways by low energy levels has a role in the inhibition of glucose production, increase in activity of beta-oxidation (fat burning), and promotion of mitochondrial functions and mitochondrial biogenesis [79,80] (Figure 1). 

As the main energy producers within the cell, mitochondria have an impact that goes far beyond that. In recent years, more and more studies have shown that the function of mitochondria is closely related to our cognitive ability and memory. This connection offers a new way to understand better and prevent cognitive impairment and memory loss.

The role of mitochondria goes beyond reproduction and maintaining cell function. New research shows that mitochondria are crucial in regulating cell metabolism, reducing cell damage, and maintaining health. Their connection to memory, cognitive abilities, and more stems from their critical role in the energy supply process within cells. Brain cells are in a state of high energy consumption and require a large amount of energy to maintain normal metabolic activities. Insufficient energy supply will affect the survival and function of neurons, leading to problems such as memory loss and cognitive impairment.

The function of mitochondria is affected by a variety of substances and life activities. For example, exercise and weight loss promote the proliferation and efficient operation of mitochondria. Proper nutrition and increased intake of antioxidant-rich foods can also improve mitochondrial work efficiency and reduce cell damage.

Although mitochondrial function is linked to our memory and cognitive abilities, not all conditions adversely affect mitochondria. Avoiding excessive stress, reducing air pollution, and learning to regulate positive emotions are also closely related to mitochondrial health.

In summary, mitochondria are integrally linked to our memory and cognitive abilities. Maintaining good living habits and caring for your body and health will help maintain mitochondrial health and move towards mental health. 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, thereby 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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AMPK exerts its effect on energy metabolism by phosphorylation of, for example, (i) ACCs (acetyl-CoA carboxylases), such as ACC1, which ACC1 inhibition lead to enhancement of fatty acid oxidation/mitochondrial-oxidation and suppression of lipogenesis; and (ii) the transcription factor SREBP1 (sterol regulatory element-binding protein 1). 

The inhibitory effect of AMPK results in reduced fatty acid synthesis [80]. It was suggested that AMPK activation may be a promising anti-aging therapeutic target, for example, by improvement of mitochondrial dysfunction. AMPK activation not only decreases the activity of anabolic pathways and increased activity of catabolic pathways leading to an increase of activity of energy (ATP)-generating pathways and a decrease in energy (ATP)-consuming processes, but also increases lifespan in diabetic patients [79,80].

Moreover, an increase in AMPK activity decreases the expression of proinflammatory cytokines, therefore modulating intercellular communication (Figure 1) by inhibition of advanced-glycation end products (AGEs)-evoked an increase in the level of transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) mRNA and protein [81]. 

However, AMPK activation may suppress inflammation through the inflammatory response inducer NF-κB by other pathways, for example, through triggering of inhibitory activity of SIRT1, PGC-1α (peroxisome proliferator-activated receptor γ/PPARγ coactivator 1α), FOXOs and p53 (transcription factor tumor suppressor protein 53) on NF-κB-signaling or via inhibition of NF-κB activator ER (endoplasmic reticulum) stress and oxidative stress [82]. Moreover, AMPK can increase PGC-1α activity not only directly (by phosphorylation, before subsequent deacetylation of PGC1-α by SIRT1) [83] but also via arrest of PGC-1α inhibitory effect of mTORC1 [66] (Figure 1). 

It has also been demonstrated that caloric restriction may exert its effect on lifespan through SIRTs [84], thus SIRTs are considered as putative anti-aging factors. SIRTs, such as SIRT1 and SIRT3 can sense low energy levels via the detection of high NAD+ levels. SIRTs are Class III HDACs histone deacetylases, which enzymes use coenzyme NAD+ to remove acyl groups of proteins, such as acetyl-lysine residues of histones and non-histones, such as PGC-1α, FOXOs, p53 and NF-κB [69,85]. 

Under nutrient deprivation (caloric restriction), the level of a nutrient-sensing deacetylase SIRT1 is elevated (which, e.g., increases hepatic glucose production through PGC-1α), but its level is reduced by overfeeding [86,87]. It has been demonstrated that activation (overexpression) of SIRT1 may increase lifespan and have an alleviating role in all age-related processes (hallmarks) (Figure 1) and several diseases, such as neurodegenerative diseases [88–90]. Indeed, SIRT1 expression was found to decrease with age, for example in the brain [91]. 

Moreover, it was also demonstrated that a decreased level of SIRT1 in microglia can lead to cognitive decline (Tau-mediated memory deficits) in aging and neurodegeneration by upregulation of IL-1β (interleukin-1β) [91]. It was also demonstrated that caloric restriction can attenuate Alzheimer's disease progression, for example, by decreasing the accumulation of Aβ plaque [92] and promoting longevity and healthy aging [93] likely via SIRT1 activation [93–95], whereas higher caloric intake may increase the risk of the development of Alzheimer's disease [96]. 

Reduction of SIRT1 levels was also demonstrated in the parietal cortex in patients with Alzheimer's disease, which was associated with the accumulation of Aβ and Tau [97], whereas activation of SIRT1 can suppress α-synuclein aggregation [98]. It has been demonstrated that SIRT1-evoked neuroprotection may evoke not only a decrease in excitotoxicity and neurodegeneration [99,100] but also improved healthspan and extended lifespan likely through the activation of PGC-1α (regulation of mitochondrial biogenesis) (Figure 1) and FOXOs (enhancing stress response via autophagy, resistance to oxidative stress and DNA damage and FOXO30 s ability to induce cell cycle arrest), as well as inhibition of p53 (regulation of apoptosis and cell cycle) and SREBP1 (regulation of lipid metabolism) activation [6,88,101,102]. 

These pathways can lead to alleviating effects in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis via, for example, SIRT1-generated deacetylation (and activation) of PGC-1α [94]. 

It has been demonstrated that SIRT1 can inhibit cell aging via p53 (deacetylation thereby inhibiting both p53 and its proapoptotic activity) [103] and can modulate the development (fate) of neural progenitor cells [104]. It was also demonstrated that cellular NAD+ level decreased with age (evoked by, e.g., accumulated DNA damages during aging) leading to decreased SIRT activity, mitochondrial dysfunction [88,105], and development of age-related diseases, such as neurodegenerative diseases [106]. Consequently, therapeutic tools, such as the administration of different drugs and metabolic therapies, which increase NAD+ levels can evoke alleviating effects on aging-related processes and diseases, as well as promote longevity [6,106] (Figure 1). 

It was also demonstrated that mutation, lacking, genetic variants or inactivation of insulin/IGF-1 receptor, as well as caloric restriction (inhibiting insulin/IGF-1 signaling) (Figure 1), extends the lifespan, not only in different animals, such as mice but also in humans [6,107,108] via PI3K (phosphatidyl inositol-3-kinase)/Akt/FOXOs pathway promoting stress defense. 

Under these conditions (e.g., caloric restriction-evoked decrease in insulin level) unphosphorylated FOXOs can be transported to the nucleus to promote the transcription of several genes (namely, their phosphorylation impedes their translocation to the nucleus) leading to increased stress resistance, cell cycle arrest, damage repair and increased longevity (lifespan) [72,109].

2.2. Telomere Shortening and Genome Instability

Reduced length of repetitive ribonucleoprotein sequences at the distal ends of eukaryotic chromosomes (telomere) during cell division was demonstrated during physiological ("natural") aging of mammals [110]. 

However, if the length of telomeres is too short it can cause damage to the DNA molecules, cellular senescence, mitochondrial dysfunctions (decreased mitochondrial biogenesis and functions, as well as increased ROS/reactive oxygen species level via p53-evoked repression of PGC-1α/β), and inflammation thereby aging [110–112]. It was also suggested that activation of telomerase activity not only enhances the survival time and increases the lifespan of mammals [3,113] but also may be favorable for cancer cell development (by decreased senescence and immortalization) [2,114]. 

Thus, shorter telomeres- and low (if any) telomerase activity-evoked senescence can prevent tumorigenesis at least in animals with long lifespans [2]. It was also suggested that telomere attrition may have a role in the development of age-related neurodegenerative diseases, such as Alzheimer's disease [111]. AMPK and SIRT1 can attenuate age-related telomere shortening through PGC-1α (Figure 1) suggesting the beneficial role of AMPK/SIRT1 activation on neurodegenerative diseases [115]. 

Not only telomere shortening, but also chromosomal aneuploidy, somatic mutations, and copy mutations may have a role in DNA damage [116]. Moreover, defects of DNA repair mechanisms (such as base excision repair), mitochondrial DNA mutation, and perturbations of the nuclear lamina may also generate genome instability (accumulation of genetic damage), cell dysfunction, and aging via senescence [63,117–119], which processes may evoke (or have a role in) age-related diseases [78]. 

Indeed, DNA damage can trigger the onset of neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis [120]. Changes in the integrity and stability of DNA can be evoked through both exogenous effects (e.g., by chemical, physical, and biological agents) and endogenous influences (e.g., by an increase in ROS level and DNA replication errors) [118]. 

SIRT1 has a positive influence on DNA repair thereby genomic instability (Figure 1), suggesting alleviating the effect of SIRT1 activation on neurodegenerative diseases [115].

2.3. Epigenetic Alterations

The epigenome contains molecular switches by which genes may be activated or inhibited during the entire lifetime [121]. It was demonstrated that epigenetic alterations, such as changes in DNA methylation patterns (which methylation is inversely proportional to gene activation), chromatin remodeling, expression of non-coding RNAs, and posttranslational histone modifications may also promote aging processes [78,122]. 

For example, it has been demonstrated that (hyper)methylation of promoter sequences of the genes (and in general on the DNA) can lead to silencing of genes related to, for example, apoptosis [123], whereas DNA hypomethylation promotes gene activation [124,125]. It was also demonstrated that changes in the pattern of DNA methylation (hypermethylation or hypomethylation) by age may be important in the mechanism of aging [126] and used as an aging clock (e.g., a link between methylcytosine/DNA methylation and age was demonstrated) [125,127]. 

Both global decrease of DNA methylation (which hypomethylation may induce age-associated genomic instability and loss of telomere integrity) and site-specific hypermethylation of promoter sequences were observed by age [122–124,128]. A previous study showed that age-induced hypomethylation was corrected by caloric restriction [129]. 

It has been suggested that caloric restriction can upregulate SIRT1 transcription leading to an increase in histone deacetylation and methylation of DNA, which effects may compensate for the decrease in both SIRT1 activity and DNA methylation, as well as an increase in histone acetylation by age and increase in lifespan (e.g., by maintenance of adequate DNA methylation pattern and genomic stability) [90,130] (Figure 1). 

Histone acetyltransferases (HATs) can attach acetyl groups to histones leading to increased positive charge, and attenuation of interaction with DNA, and thereby enhancing DNA transcription. Conversely, HDACs can remove acetyl groups from histones, which effect enhances the interaction between histones and DNA resulting in decreased transcription. 

Consequently, antagonists of HDACs may facilitate DNA transcription [131,132]. Based on these results above, the expression of genes can be blocked (silenced) through not only methylation of DNA (e.g., methylation of promoter sequences of genes) but also deacetylation of histones, which continuous silencing of genes may be an important factor in progressive aging [123]. 

Moreover, histone methylation and demethylation (by histone methyl transferases and demethylases) and histone acetylation and deacetylation (by HATs and HDACs) can modulate lifespan, aging, and age-related diseases [124,133,134]. For example, SIRT1-evoked deacetylation of Nk2 homeobox 1 can extend lifespan and delay aging processes in mice [133]. It has been demonstrated that inhibitors of HDACs (Classes I, II, and IV HDACs), such as Trichostatin A, may be effective in the treatment of neurodegenerative diseases and the extension of lifespan [135,136]. 

Moreover, HDAC inhibitors decreased the death of motor neurons, enhanced motor performance, increased the survival time, and resulted in life extension in a mice model of amyotrophic lateral sclerosis [137], restored fear learning, decreased Aβ accumulation, and improved cognitive performance in mouse models of Alzheimer's disease [138,139] and generated neuroprotection in a model of Parkinson's disease [140]. 

It was also suggested that miRNAs (microRNAs; a class of small non-coding silencing RNAs, that have a role in the regulation of mRNA translation) may promote longevity and have a role in both neurodegeneration and age-related neurodegenerative diseases [141,142]. For example, hippocampal upregulation of miR-181 and related decrease of SIRT1 expression and, as a result, reduction of synaptic plasticity was demonstrated in a mouse model of Alzheimer's disease [143]. 

As a response to severe, persistent DNA damage (e.g., by oxidative stress), activated poly(ADP-ribose)-polymerase-1 (PARP-1) adds ADP-ribose units to histones leading to the promotion of chromatin relaxation [144], enhances PARylation (generating PAR polymers as epigenetic effect) at sites of DNA damage (alteration) [63] and induce neuronal cell death via modulation of gene expression and mitochondrial dysfunction [145]. 

Moreover, excess PARP1 activation was demonstrated in aging and neurodegenerative diseases resulting in mitochondrial dysfunction, neuroinflammation, ion, and dysregulation of autophagy (and mitophagy; e.g., via mTOR activation) [144,146]. For example, PARP1 enhances inflammation via NF-κB, decreased NAD+ level and SIRT1 activity, and has a role in telomere shortening and, as a consequence, enhances senescence, leading to neurodegeneration and reduced lifespan [144,146,147]. As SIRT1 activity decreases by age [91], under this condition, both acetylation (activation) of PARP1, and PAPR1-evoked neuroinflammation may be increased. However, to retain its functions via the preservation of NAD+ levels, SIRT1 is able to deactivate (deacetylate) Parp1 [148]. 

Moreover, increased expression and excessive activation of PARP1 were demonstrated in Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis [145,149,150]. As it was demonstrated, Aβ and α-synuclein accumulation may generate activation of PAPR1 via, for example, increased level of ROS; thus, enhanced PARP1 activity aggravates Alzheimer's disease and Parkinson's disease symptoms by promotion of Aβ and α-synuclein aggregation, respectively [145,149]. 

Consequently, PARP1 inhibition can alleviate neuroinflammation, dysregulation of autophagy and mitochondrial dysfunction thereby inhibit development of inflammation(age)-related neurodegenerative diseases (or alleviate their symptoms), for example via SIRT1 activation [146,151]. 

It was also demonstrated that an increase in βHB level can evoke epigenetic (posttranslational) gene regulation by β-hydroxybutyrylation of histones resulting in the regulation of gene expression thereby adapting cells to an altered cellular energy source [152].

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