Beneficial Effects Of Exogenous Ketogenic Supplements On Aging Processes And Age-Related Neurodegenerative Diseases Part 3

2.4. Mitochondrial Dysfunction

Mitochondrial dysfunction is associated with the decline of mitochondrial activity, such as defect of the respiratory chain, decrease in ATP synthesis and level, as well as increase in ROS production. 

A growing body of research shows that reduced mitochondrial activity can hurt people's memory. Mitochondria are an important component within the cell. They are responsible for converting energy into the chemicals the cell needs, thereby supporting the cell's survival and function. Mitochondria are not only the center of energy conversion but are also closely connected to cell membranes, endoplasmic reticulum, and other cellular structures. They play a vital role in regulating cell metabolism, maintaining cell homeostasis, and protecting cells from oxidative stress damage.

Studies have found that mitochondrial dysfunction is closely related to memory decline. For example, the number and function of mitochondria in brain cells of Alzheimer's patients are significantly reduced, and mitochondrial DNA damage or mutations can also lead to the occurrence and progression of dementia. In addition, some studies have also found that weakened mitochondrial antioxidant capacity, slowed energy metabolism, and disordered calcium ion metabolism are also related to memory decline.

However, we must also look at the positive side. By promoting mitochondrial function and health, we can improve memory and prevent many age-related diseases. Here are some simple ways to help you maintain healthy mitochondria:

1. Eat a balanced diet. Appropriate amounts of nutrients should be consumed in the diet, including vitamins, minerals, proteins, carbohydrates, and fats. Pay special attention to the intake of antioxidants rich in vitamin B, vitamin C, vitamin E, selenium, zinc, etc.

2. Keep exercising. Moderate exercise can promote the health of the cardiovascular and respiratory systems and improve the metabolic efficiency and operating capacity of mitochondria.

3. Avoid bad habits such as excessive drinking, smoking, overeating, etc., which will damage your health.

4. Get good sleep. Sleep plays an important role in the recovery and maintenance of mitochondrial function. It is recommended to ensure 7-8 hours of sleep at night, maintain a regular biological clock rhythm, and try to avoid staying up late at night.

In short, we should pay attention to the health and function of mitochondria and promote the normal operation and metabolism of mitochondria by maintaining a healthy lifestyle and a balanced diet, thereby enhancing memory and protecting physical health. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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This hallmark of aging may be evoked by, for example, decreased mitochondrial biogenesis, defective mitophagy, and mtDNA mutations leading to processes (e.g., enhancement of inflammatory processes), which can reduce lifespan, enhance aging, and the risk of age-related diseases [69,153]. 

Indeed, it has been demonstrated that t decrease in mitochondrial functions or damage of mitochondria may also be in the background of the development of neurodegenerative diseases [154] through excessive ROS formation leading to inflammation and genomic instability. These processes can enhance cellular senescence, aging processes, and the development of age-related diseases [154]. 

It was also demonstrated, that an increased level of ROS may generate protective, homeostatic (alleviating) processes (e.g., on lifespan limiting cellular processes via ROS-dependent, protective, stress-response pathways), but, by aging progress, above a certain level, ROS can evoke (aggravate) age-related damages [155]. 

It was demonstrated that autophagy (and mitophagy) declined with age [156], which can generate an accumulation of damaged mitochondria thereby increasing inflammation (e.g., via increased ROS level-evoked activation of NLRP3/NOD-like receptor pyrin domain 3 and NF-κB), cell death (e.g., through activation of caspases and mitochondrial permeability transition/mPT pore by excess ROS) and DNA damage (by ROS leading to increase in apoptotic signaling, such as p53) [153]. 

Moreover, it has been demonstrated that defects in mitochondria and autophagy (thereby aggregation of not only α-synuclein and Aβ peptide but also impaired mitochondria) may have a role in development of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease [153,156–158]. 

Thus, drugs or interventions, such as caloric restriction, which can promote autophagy and mitophagy, therefore inhibit mitochondrial dysfunction, ROS production, aggregation of toxic proteins, inflammation, cell death and cell senescence, can delay age-related degeneration, extend healthy lifespan and alleviate neurodegenerative diseases [159–161]. 

Indeed, for example, it was demonstrated that SIRT1 has a role in the elimination of damaged mitochondria via autophagy (by enhanced activity of autophagy proteins) [162–164] and in mitochondrial biogenesis (increase in mitochondrial biogenesis) via increased transcriptional cofactor PGC-1α activity [87] (Figure 1), whereas a mitochondrial deacetylase SIRT3 controls (decreases) ROS level by enhancement of the antioxidant activity of superoxide dismutase 2 (SOD2) during caloric restriction, leading to increased oxidative stress resistance [165]. 

Moreover, it was also demonstrated that increased SIRT3 activity can suppress mPT pore formation which can prevent mitochondrial dysfunctions [166]. It was also demonstrated that PGC-1α activation can enhance mitochondrial biogenesis and improve mitochondrial energy metabolism, therefore increasing lifespan and protecting against neurodegenerative diseases [167]. 

PGC-1α can bind and co-activate the transcription factor PPARγ (belongs to the superfamily of nuclear receptors) and promotes not only mitochondrial biogenesis but also SOD and catalase activity, glucose metabolism, and oxidative phosphorylation [162,168–170], whereas reduces the level of NF-κB and pro-inflammatory cytokines [171,172], as well as Aβ generation [173,174]. 

Indeed, a reduced level of PGC1-α can result in decreased mitochondrial respiration and enhanced inflammatory processes [175]. Moreover, mitochondrial uncoupling via the overexpression of uncoupling protein 1 (UCP1) may also increase the lifespan [176].

2.5. Altered Intercellular Communication: Increased Inflammatory Processes

Aging processes are also connected to dysregulation of cell-cell connectivity and intercellular communication leading to, among others, sterile (activation of immune response without appearance of pathogens), chronic, low-grade inflammation (named "inflammaging") with activation of NF-κB, as well as increased synthesis and release of proinflammatory cytokines (e.g., IL-1β and TNF-α/tumor necrosis factor-α) [69,125,177,178]. 

Increase in inflammatory processes and proinflammatory cytokine levels can also enhance (trigger) aging processes, for example, through increased activation of intracellular multiprotein sensor NLRP3 inflammasome, the senescent cells-evoked release of proinflammatory cytokines and NF-κB level and signaling [177,179,180]. Autophagy failure in old organisms (e.g., decrease in activity of autophagy), and in patients with Alzheimer's disease and Parkinson's disease [181,182] were also demonstrated. 

It was suggested that aging (e.g., decreased autophagy by age) can stimulate NF-κB signaling, which transcription factor NF-κB (similar to increase in ROS by mitochondria and aggregation of Aβ) stimulate inflammatory processes, for example, via increased NLRP3 expression and IL-1β release [161,179,183–185], whereas autophagic uptake of damaged mitochondria (resulting decrease in ROS level) suppresses NLRP3 stimulation [161]. Thus, it was suggested that autophagy may generate an anti-inflammatory effect by inhibition of NLRP3 inflammasome thereby mitigating the NLRP3-evoked cleavage of pro-IL-1β to its active form/IL-1β by caspase-1 [186,187] leading to delay in aging processes [180]. 

Moreover, the responsiveness of AMPK signaling decreases with age [180,188], which mitigates its inhibitory activity on NF-κB signaling [82] (Figure 1) and impairs autophagic activity leading to increased oxidative stress and activation of inflammasomes [180] and can attenuate lifespan [82]. 

As mTORC1 is able to inhibit autophagy (e.g., mitophagy or macroautophagy of altered proteins) all drugs or interventions, which can inhibit mTORC1 (e.g., caloric restriction leading to mTOR inhibition) may be potent delayer of aging processes and enhancer of lifespan via inhibition of inflammation [180] (Figure 1), by which can alleviate not only neuroinflammation but also neurodegeneration and related diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis [183,189]. Indeed, inhibition of NF-κB signaling was able to prevent age-associated features in mouse models extending their longevity [190].

2.6. Cellular Senescence

Cellular senescence can be evoked by intracellular and extracellular, genomic and epigenomic harmful stimuli and damages resulting in hallmarks of aging (e.g., age-related stress: oxidative stress and telomere shortening; metabolic, as well as ER stress; mitochondrial dysfunction, loss of proteostasis) [191–193]. 

One of the main features of aging is the enhancement of cellular senescence (irreversible cell-cycle arrest regulated by, e.g., telomere attrition/DNA damage-evoked p53-dependent DNA-damage response, in which p53 is activated). 

Excessive accumulation of senescent cells, which cells decrease tissue regeneration and are resistant to apoptosis (e.g., by upregulation of antiapoptotic Bcl-2/B cell lymphoma-2 family proteins resulting in resistance to apoptosis-inducing signals), can evoke harmful processes on surrounding cells by secretion of proinflammatory agents (SASP factors, e.g., IL-1β,) and other components (e.g., IGF-1) [2,191,194,195]. 

For example, previous studies show that acute administration of IGF-1 can promote cell proliferation and survival whereas prolonged administration of IGF-1 promotes cell growth arrest and senescence (and the latter, enhances aging processes and inhibits tumorigenesis) via through SIRT1 inhibition and increased p53 activity (by increased acetylation) [196] and suppression of autophagy (e.g., via mTOR) [197] (Figure 1).
Indeed, SIRT1 can inhibit not only DNA damage but also cellular senescence via deacetylation (inhibition) of p53 resulting in anti-aging effects [198]. In contrast with cellular senescence, cellular quiescence occurs when nutrition or growth factor levels are very low (or lack) leading to a reversible cell-cycle arrest. In this state, te the cells may impede the initiation of cell senescence [199] and have a role in the maintenance of stemness [200]. However maintaining cellular balance, the senescence of cells is a double-edged sword [2]. 

For example, cellular senescence can reduce liver fibrosis [201], promote tissue repair, and have a role in not only physiological, but also pathophysiological processes (e.g., embryogenesis and wound healing) [195] and prevent cancer development [202], but exaggerated attenuation of processes of cell senescence and accumulation of senescent cells can generate (or enhance) aging, and, as a consequence, development of age-related diseases, such as Alzheimer's disease and cancer [192,195,203–205]. 

Thus, medication for cellular senescence needs careful attention. Under glucose-deprived conditions, AMPK-induced p53 activation potentiates cellular survival (p53-dependent metabolic arrest), but excessive (lasting) AMPK activation leads to enhanced p53-dependent cellular senescence [206,207]. However, not only SIRT but also AMPK activation can improve cellular senescence via, for example, inhibition of proinflammatory mediators [5,81,82] (Figure 1).

2.7. Loss of Proteostasis and Stem Cell Exhaustion

Impaired protein homeostasis (loss of proteostasis) by age may also be in the background of aging and related diseases (e.g., neurodegenerative diseases) leading to dysregulation of protein synthesis, degradation, and protein aggregation, disaggregation, assembly, folding, and trafficking [208]. 

For example, the activity of the f ubiquitin-proteasome system and autophagy decreased with age [209], whereas the increased activity of the f proteostasis network (e.g., enhanced autophagy) extended the health span and lifespan [210]. Inhibition of mTOR pathways (e.g., by caloric restriction through decreased protein synthesis and activation of autophagy) may improve protein homeostasis and extend lifespan [211,212] (Figure 1). 

It has been demonstrated that maintained mitochondrial proteostasis prolonged lifespan and reduced Aβ protein aggregation in Alzheimer's disease models [213]. Moreover, decreased activity of the f autophagy-lysosomal pathway may have a role in the development of both Alzheimer's disease and Parkinson's disease and other neurodegenerative diseases [77]. 

Indeed, activation of mitophagy (by which autophagy-lysosomal pathwaremovesve damaged/dysfunctional mitochondria) was able to increase lifespan in worms and reverse cognitive deficits in models of Alzheimer's disease [214,215]. AMPK activation may participate in the maintenance of proteostasis via inhibition of mTOR and phosphorylation of eIF2α (eukaryotic initiation factor 2α; resulting in attenuation of protein synthesis) and via activation of autophagy [79,80] (Figure 1). Moreover, it was also demonstrated that autophagy may be enhanced via inhibition of mTOR by SIRT1 [216] (Figure 1). 

Thus, activation of AMPK/SIRT1 and inhibition of mTOR (mTORC1, but not mTORC2 because the latter is required for autophagy) activity may be a promising target in anti-aging therapy [77]. Indeed, aging and age-associated diseases can upregulate mTORC1 [69]. Stem cell exhaustion may have a role in aging anthe d appearance of age-related diseases through the loss of the f regenerative ability of cells, tissue, es, and organs. 

For example, the activity and number of hematopoietic cells and intestinal stem cells are decreased with age leading to a decrease in lymphoid cell number and adaptive immune response, an increase in the risk of anemia development and myeloid cell number, as well as malfunctions in intestinal functions [217,218]. Moreover, an age-dependent decrease in the n function of other stem cells, such as neuronal stem cells was also demonstrated [71]. 

It was suggested that stem cell aging may be evoked by several factors, such as DNA damage and mutation, cellular senescence, defects in proteostasis, mitochondrial dysfunction, and telomere attrition [63,71]. 

Thus, we can conclude that activation of AMPK/SIRTs-modulated signaling pathways, inhibition of mTOR effects (e.g., by inhibition of IIS pathway) and modulation of gene expression (e.g., by HDAC inhibitors) can alleviate aging processes (hallmarks) through direct and indirect manner (e.g., improvement of one of aging hallmarks, such as telomere attrition can improve other aging hallmarks, such as senescence and mitochondrial dysfunction), leading to extended lifespan and delay the appearance of neurodegenerative diseases.

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