**4. Possible therapeutic interventions**

#### **4.1. Physical exercise**

The most simple and probably the most efficient way to attenuate aging is to perform physical exercise. A sedentary lifestyle with minimal physical activity on the contrary is detrimental for health comparable to smoking [123]. It is quite obvious that physical exercise is the best way to keep skeletal muscles in a healthy condition [124] and to prevent sarcopenia and frailty in old age [125]. Physical exercise does not only improve physiological parameters like maximum oxygen consumption and reduced levels of cholesterol and triglycerides in the blood, but it also improves physical and psychical conditions in old age [126]. Although a number of physiological parameters can be improved considerably by physical training, the protective function for the cardiovascular system are about twice as high as can be explained by these parameters only. Therefore there are still many open questions concerning the molecular mechanisms which are activated by physical training [127]. Very well documented is, however, the positive effect on the brain and in particular on cognitive functions and the stimulation of neuronal growth in the hippocampus, an area critically important for memory processes [128]. Physical exercise increases hippocampal volume, functional connectivity and improved connectivity between the default mode network and the prefrontal cortex [129]. In this context, it should also be mentioned that physical exercise leads to a significant improvement of memory functions in Alzheimer patients [130].

#### **4.2. Caloric restriction/dietary restriction**

is only about 10% of their regular lifespan [101]. A remarkable activity has also been demonstrated for GDF11 which improves regeneration in old organisms and serum levels of GDF11 are significantly lower in old individuals [102]. An increased regenerative activity has been

Furthermore, a number of chemokines (CCL2, CCL11, CCL12 and CCL19) have been identified via parabiosis experiments and they have been correlated with impaired neurogenesis in old individuals [107]. Other potential pro-aging factors that increase during lifetime are TGF-beta1, IL-6 and TNF-alpha [107]. Beta2microglobulin too is a systemic pro-aging factor

Another pro-aging factor is the plasminogen activator inhibitor 1 (PAI-1) which is secreted by senescent cells. It induces the accumulation of p16Ink4a leading to cellular senescence [109]. An anti-aging factor is kallistatin which inhibits oxidative stress and inflammation. It is also able to down-regulate the miRNA synthesis of miR21 and miR-34a, thereby reducing vascular senescence and aging [110]. The protein tissue inhibitor of metalloproteinase 2 (TIMP 2) was isolated from human umbilical cord. It is an anti-aging protein which revitalizes the hippocampus, increases synaptic plasticity and improves cognitive function [111]. The intercellular communication is also altered by numerous pro-inflammatory cytokines which are released by senescent cells. These cytokines are causing inflammatory processes [112]. Furthermore, inflammasomes in the cells of the innate immune system can be activated by DAMPs (damage-associated molecular patterns) [113]. DAMPS are comprised of debris of necrotic cells, amyloide fibers, HMGB1, heat shock proteins, crystals of cholesterol and uric acid. Activated inflammasomes are causing the release of interleukins IL-1beta and IL-18 [114]. These interleukins trigger inflammatory reactions in the surrounding tissue which are causing age-

Exosomes provide an additional possibility for intercellular communication. They are small lipid vesicles which are secreted by the cell and they carry proteins and functional RNAs [117]. They can contact nearby cells or they can be distributed via the circulation across the whole organism. They help the cell to get rid of toxic protein waste [118] or to contribute to intercellular communication [119]. In the latter case, predominantly miRNAs play an important function [120]. During aging, the amount of exosomes in the blood stay more or less constant. Their content, however, becomes more pro-inflammatory [121]. Recently, it has been

The most simple and probably the most efficient way to attenuate aging is to perform physical exercise. A sedentary lifestyle with minimal physical activity on the contrary is detrimental for health comparable to smoking [123]. It is quite obvious that physical exercise is the best way to keep skeletal muscles in a healthy condition [124] and to prevent sarcopenia and frailty in old age [125]. Physical exercise does not only improve physiological parameters like

shown for bone [103], brain [104], skeletal muscle [105] and heart [106].

triggering age-related cognitive impairment [108].

124 Gerontology

related diseases [115], among them Alzheimer´s disease [116].

shown that they also play a role in senescence and aging [122].

**4. Possible therapeutic interventions**

**4.1. Physical exercise**

Already in 1935 it has been demonstrated on rats that reducing the amount of food intake can extend the lifespan by 30% [131]. This experiment has been repeated many times and it turned out that animals are not only living longer but they also show less age-related deficits. During the past years, it has been demonstrated that the amount of calories is less important than the amount of proteins. Therefore the term caloric restriction has been replaced in most cases by the term dietary restriction. In addition to the amount of food, the timing of food uptake is important. Animals getting their food evenly distributed during the day did not show positive effects but animals fed only once a day did show the positive effects. Also did fasting every second day result in an increase of lifespan by 30% [132]. Altogether a great many experiments have been performed concerning this topic and results are sometimes contradictory. Some authors are pointing out explicitly that it is necessary to test many different combinations of carbohydrates and proteins in a single experiment. It has been demonstrated that a relation of 1:10 (proteins:carbohydrates) results in the longest lifespan in mice. Remarkable in this respect is the fact that the traditional diet of the population of Okinawa consists of protein to carbohydrates in a relation of 9:85 and it is well documented that the people of Okinawa have the highest life expectancy worldwide [133]. It has to be mentioned that not only permanent dietary restriction is effective but intermittent fasting too. In rats and mice as well as in humans, there are profound health benefits. Results of intermittent fasting (2 days per week or every other day) decreased insulin levels, increased resistance to stress of heart and brain, reduced inflammation, enhanced autophagy, mitochondrial health and DNA repair [134]. Concerning DNA repair, the following experiment is really remarkable: mice lacking the DNA excision repair gene Ercc1 are aging very fast with a lifespan of 4–6 months. If they are subjected to a dietary restriction of 30%, this treatment triples their lifespan [33]. The single cell senses the availability of nutrition via nutrient sensing pathways which are GH/insulin/IGF-1, mTOR, sirtuins and AMPK and via these pathways the metabolic influence on the aging process is regulated [57].

#### *4.2.1. The somatotrophic axis (GH/insulin/IGF-1)*

Attenuating the signaling of the somatotrophic axis results in an increased lifespan. This has been demonstrated in animal models, in genetic polymorphisms or functional mutations in the IGF1R gene in humans [96]. Pharmaceutical interventions to block the signaling of this pathway are being tested but there are no drugs available yet to be used in humans [96].

**4.3. Pharmacological substances**

Metformin is in use to treat diabetes type 2 since a long time already. The inhibitory effect on the synthesis of glucose in the liver is due to the activation of AMPK [141, 142]. In addition metformin inhibits mTOR and complex I of the mitochondrial electron transfer chain resulting in a reduced production of ROS. In addition metformin stimulates autophagy, dampens inflammatory processes and senescence and increases the lifespan in animal models [58, 143, 144]. There are reports claiming that metformin does not only improves the healthspan and lifespan but also reduces the risk of some cancers and shows positive effects with congestive heart failure, chronic liver disease, chronic kidney disease and multiple sclerosis (summarized in [145]). This had led some researchers to call metformin "the aspirin of the twenty-first

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This substance has been isolated from the microorganism *Streptomyces hygroscopicus* which has been found on the island of Rapa Nui, hence the name rapamycin. It is widely used as an immunosuppressant to prevent rejection after organ transplantation. The protein complex inhibited by this substance has been termed "Target of rapamycin" or TOR and it has been demonstrated that it leads to a significant increase in lifespan when applied to mice and most

Polyphenols are comprising a large group of plant secondary metabolites. They are classified into phenolic acids, lignans, flavonoids and stilbenes [147]. The most prominent member of stilbenes is resveratrol which is synthesized by many plants in particular in wine. Resveratrol activates SIRT1 which mediates the effect of caloric restriction [148]. It could be demonstrated that resveratrol increases the lifespan of some organisms, in mice only if they are fed a highfat diet [149]. In addition, resveratrol causes a number of positive effects in the cardiovascular system, cancer, diabetes type 2 inflammation and neurodegeneration [150]. As resveratrol is also stimulating autophagy and together with its neuroprotective effects, there are indications that resveratrol might also be applicable to treat Alzheimer's disease [151]. It has to be mentioned that resveratrol not only activates SIRT1 but also AMPK which explains many of its anti-oxidant and anti-inflammatory activities [152]. Furthermore resveratrol activates a number of stimulus-responsive transcription factors and inhibits cAMP-degrading phospho-

Like rapamycin and resveratrol, the polyamine spermidine also stimulates autophagy although via a different molecular mechanism. Similar to resveratrol, the stimulation of

diesterases which helps to understand its many effects [153–155].

*4.3.1. Metformin*

century" [145].

*4.3.2. Rapamycin*

*4.3.3. Resveratrol*

*4.3.4. Spermidine*

other "aging" model organisms [146].

#### *4.2.2. mTOR*

mTOR is a serine/threonine kinase which is "the grand conductor of metabolism and aging" and is either part of the multiprotein complex mTORC1 or mTORC2 [135]. Growth factors, insulin, IGF-1, amino acids and glucose are activating mTOR which in turn stimulates growth and inhibits autophagy.

Rapamycin binds to FKBP12 in this way inhibiting mTOR. Blockage of mTOR increases the lifespan in different organisms among them mice. But unfortunately there are numerous side effects which prohibit the use on a daily basis for healthy individuals [135].

#### *4.2.3. Sirtuins*

Sirtuins interact with IGF-1, mTOR and AMPK signaling pathways and regulate many other proteins involved in energy metabolism, DNA repair, cell survival, inflammation and tissue regeneration. SIRT1, for example, besides deacetylating histones H1, H3 and H4 modifies more than 50 other proteins [61]. Sirtuin-activating compounds (STACs) have gained much attention since their discovery 2003 and more than 14,000 STACs have been identified since then [61]. Essentially there are two different classes: sirtuin activators and compounds that raise NAD<sup>+</sup> levels. Using rodents numerous studies have shown that STACs promote health during aging involving protection against cardiovascular disease, diabetes type 2, neurodegeneration and even cancer [61].

#### *4.2.4. AMP-activated protein kinase (AMPK)*

AMP-activated protein kinase is a heterotrimeric protein and a key enzyme in cellular energy sensing. The alpha subunit kinase domain contains a conserved threonine which is phosphorylated by upstream kinases activating AMPK. The beta subunit binds the alpha and gamma subunits and has an additional domain to sense glycogen. The gamma domain has four sites that can bind AMP, ADP and ATP which provides AMPK with the ability to sense AMP:ATP and ADP:ATP ratios [136, 137]. These features make AMPK the centerpiece of "an energysensing pathway with multiple inputs and outputs" [136].

AMPK turns on glucose uptake, fatty acid oxidation, autophagy and mitochondrial biogenesis and it inhibits mTOR and the synthesis of lipids and proteins. It is therefore a central regulator of metabolic pathways including their effects on age-related diseases. It is also involved in the process of inflamm-aging via the regulation of the NLRP3 inflammasome during aging [138]. The capacity of AMPK signaling declines with aging which has a negative effect on the maintenance of cellular homeostasis [60]. Considering these facts, it is obvious that there is extensive research going on how to restore or boost AMPK activity by metformin [139] or by other nutraceutical compounds in particular polyphenols like resveratrol [140].

#### **4.3. Pharmacological substances**

#### *4.3.1. Metformin*

the IGF1R gene in humans [96]. Pharmaceutical interventions to block the signaling of this pathway are being tested but there are no drugs available yet to be used in humans [96].

mTOR is a serine/threonine kinase which is "the grand conductor of metabolism and aging" and is either part of the multiprotein complex mTORC1 or mTORC2 [135]. Growth factors, insulin, IGF-1, amino acids and glucose are activating mTOR which in turn stimulates growth

Rapamycin binds to FKBP12 in this way inhibiting mTOR. Blockage of mTOR increases the lifespan in different organisms among them mice. But unfortunately there are numerous side

Sirtuins interact with IGF-1, mTOR and AMPK signaling pathways and regulate many other proteins involved in energy metabolism, DNA repair, cell survival, inflammation and tissue regeneration. SIRT1, for example, besides deacetylating histones H1, H3 and H4 modifies more than 50 other proteins [61]. Sirtuin-activating compounds (STACs) have gained much attention since their discovery 2003 and more than 14,000 STACs have been identified since then [61]. Essentially there are two different classes: sirtuin activators and compounds that

during aging involving protection against cardiovascular disease, diabetes type 2, neurode-

AMP-activated protein kinase is a heterotrimeric protein and a key enzyme in cellular energy sensing. The alpha subunit kinase domain contains a conserved threonine which is phosphorylated by upstream kinases activating AMPK. The beta subunit binds the alpha and gamma subunits and has an additional domain to sense glycogen. The gamma domain has four sites that can bind AMP, ADP and ATP which provides AMPK with the ability to sense AMP:ATP and ADP:ATP ratios [136, 137]. These features make AMPK the centerpiece of "an energy-

AMPK turns on glucose uptake, fatty acid oxidation, autophagy and mitochondrial biogenesis and it inhibits mTOR and the synthesis of lipids and proteins. It is therefore a central regulator of metabolic pathways including their effects on age-related diseases. It is also involved in the process of inflamm-aging via the regulation of the NLRP3 inflammasome during aging [138]. The capacity of AMPK signaling declines with aging which has a negative effect on the maintenance of cellular homeostasis [60]. Considering these facts, it is obvious that there is extensive research going on how to restore or boost AMPK activity by metformin [139] or by

other nutraceutical compounds in particular polyphenols like resveratrol [140].

levels. Using rodents numerous studies have shown that STACs promote health

effects which prohibit the use on a daily basis for healthy individuals [135].

*4.2.2. mTOR*

126 Gerontology

*4.2.3. Sirtuins*

raise NAD<sup>+</sup>

generation and even cancer [61].

*4.2.4. AMP-activated protein kinase (AMPK)*

sensing pathway with multiple inputs and outputs" [136].

and inhibits autophagy.

Metformin is in use to treat diabetes type 2 since a long time already. The inhibitory effect on the synthesis of glucose in the liver is due to the activation of AMPK [141, 142]. In addition metformin inhibits mTOR and complex I of the mitochondrial electron transfer chain resulting in a reduced production of ROS. In addition metformin stimulates autophagy, dampens inflammatory processes and senescence and increases the lifespan in animal models [58, 143, 144]. There are reports claiming that metformin does not only improves the healthspan and lifespan but also reduces the risk of some cancers and shows positive effects with congestive heart failure, chronic liver disease, chronic kidney disease and multiple sclerosis (summarized in [145]). This had led some researchers to call metformin "the aspirin of the twenty-first century" [145].

#### *4.3.2. Rapamycin*

This substance has been isolated from the microorganism *Streptomyces hygroscopicus* which has been found on the island of Rapa Nui, hence the name rapamycin. It is widely used as an immunosuppressant to prevent rejection after organ transplantation. The protein complex inhibited by this substance has been termed "Target of rapamycin" or TOR and it has been demonstrated that it leads to a significant increase in lifespan when applied to mice and most other "aging" model organisms [146].

#### *4.3.3. Resveratrol*

Polyphenols are comprising a large group of plant secondary metabolites. They are classified into phenolic acids, lignans, flavonoids and stilbenes [147]. The most prominent member of stilbenes is resveratrol which is synthesized by many plants in particular in wine. Resveratrol activates SIRT1 which mediates the effect of caloric restriction [148]. It could be demonstrated that resveratrol increases the lifespan of some organisms, in mice only if they are fed a highfat diet [149]. In addition, resveratrol causes a number of positive effects in the cardiovascular system, cancer, diabetes type 2 inflammation and neurodegeneration [150]. As resveratrol is also stimulating autophagy and together with its neuroprotective effects, there are indications that resveratrol might also be applicable to treat Alzheimer's disease [151]. It has to be mentioned that resveratrol not only activates SIRT1 but also AMPK which explains many of its anti-oxidant and anti-inflammatory activities [152]. Furthermore resveratrol activates a number of stimulus-responsive transcription factors and inhibits cAMP-degrading phosphodiesterases which helps to understand its many effects [153–155].

#### *4.3.4. Spermidine*

Like rapamycin and resveratrol, the polyamine spermidine also stimulates autophagy although via a different molecular mechanism. Similar to resveratrol, the stimulation of autophagy is achieved by a change in the acetylation status of several proteins, but this occurs in a SIRT1-independent manner (most probably due to an inhibition of acetylases) [156]. For spermidine too, it has been demonstrated that it is increasing the lifespan of mice and all "aging" model organisms [157]. Surprisingly, the amount of this substance that is present in all cells dramatically decreases with aging [158]. In addition spermidine has neuroprotective capacities [159] and reduces the risk for cardiovascular diseases [160].

*4.3.7. Acetylcholinesterase inhibitors*

**4.4. Selective elimination of senescent cells**

**4.5. Transplantation of stem cells**

PD patients [173].

Alzheimer's disease (AD) is the most devastating aging disease. For 2013, it was estimated that more than 44 million people were affected worldwide and this number is expected to be beyond 135 million by the year 2050. Although there is presently no cure, there are a few drugs available that make life easier for AD patients. Most prominent are acetylcholinesterase inhibitors which show modest effects on improving cognitive function. The degeneration of cholinergic neurons which is seen in AD as well as Parkinson's disease dementia (PDD) leads to a reduction of acetylcholine levels. Furthermore, cholinergic pathways are not only important for the brain but also for skeletal muscle and the autonomous nervous system [172]. The increase of acetylcholine levels via inhibition of acetylcholinesterase improves cognitive function and has also beneficial effects on some of the comorbidities that usually affect AD and

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If senescent cells are not removed by the immune system they are causing organ dysfunction and are a major cause of age-related diseases [174]. The removal of senescent cells in mice has improved their health conditions considerably. The elimination of senescent cells via drugs (senolysis) [175] or to trigger apoptosis (senoptosis) is also a realistic possibility in humans. From the observation that senescent cells do not respond to their own pro-apoptotic SASP, it was concluded that they have senescent-cell anti-apoptotic pathways (SCAPs). Six such SCAPs have been identified and these SCAPs were then screened for targets sensitive to senolytic drugs [176]. A number of senolytic drugs synthetic ones as well as of plant origin have been identified in the meantime. Prominent among them is quercetin which demonstrates promising activities [166]. It has to be mentioned that not every senolytic drug is effective on each senescent cell type and often is the combination of two or three drugs much more effective. An advantage over other medications is that senolytic drugs need not be taken continuously to exert their effect but just administered intermittently [176]. The use of senolytic drugs increase hope for the treatment of diseases for which there are hardly any other therapeutic options like idiopathic pulmonary fibrosis (IPF) a devastating lung disease [177]. Another elegant approach to trigger apoptosis in senescent cells has recently been demonstrated using a synthetic peptide. This cell penetrating peptide (CPP) was deduced from the sequence of the transcription factor FOXO4 and it excludes p53 from the nucleus. Instead of residing in the nucleus p53 is docking on to mitochondria to trigger apoptosis [178]. An additional possibility

is to attack senescent cells with specific antibodies or by modified T cells [9].

Stem cells are of utmost importance for regeneration and function of all organs. Transplanting stem cells into target tissues opens the possibility to repair major defects. Here we are at the brink of breathtaking possibilities for regenerative medicine. In particular, multipotent mesenchymal stem cells offer a wide spectrum of applications however these cells are loosing a lot of their regenerative capacity during aging [179]. Substantial progress has been made by

Spermidine also stimulates the synthesis of anti-inflammatory cytokines and has a positive influence on lipid metabolism [161].

#### *4.3.5. Vitamin D*

Muscle and bone are forming a physiological unit whereby both partners are regulating each other via endocrine signals [162]. Vitamin D has an essential function within this regulatory network. A sufficient supply of vitamin D prevents loss of muscle mass (sarcopenia) and age-dependent deposition of fat in muscles [163, 164]. In addition vitamin D shows a positive effect on cognitive function in old age [165]. Mice lacking the vitamin D receptor do age prematurely and the animal model for Alzheimer's disease show better memory performance and a reduction of some markers for Alzheimer's pathology after vitamin D supplementation. Humans with Alzheimer's disease show very low blood levels of vitamin D. Altogether vitamin D is a neuroprotective substance [166].

#### *4.3.6. Soluble proteins/growth factors*

Treating age-related ailments with soluble proteins is particularly attractive because it can be performed via simple infusions. Among the best candidates, GDF11 and oxytocin have demonstrated a rejuvenating effect in old mice [92]. In a study comparing very old healthy individuals (beyond the age of 100) with 70–80-year-old persons, a set of proteins have been identified whose levels were elevated in the serum of the 100+ probands. This study correlates "successful aging" with these four proteins: Chemerin, Fetuin-A, FGF19 and FGF21 [167]. In particular, FGF21 is a "systemic enhancer of longevity" [168]. It is involved in the coordination of glucose and lipid metabolism and maintains tissue homeostasis under stress conditions. FGF21 can enhance autophagy and mice overexpressing it live up to 40% longer [168]. Another good candidate to provide a healthy lifespan is adiponectin. Adiponectin is expressed in and secreted from small adipocytes. It increases insulin sensitivity, shows anti-artherosclerotic effects and improves metabolism in skeletal muscle, liver and adipose tissue. Adiponectin activates AMPK and SIRT1 and this way it acts like an exercise mimicking factor [169]. Finally, it has to be mentioned that it also turns on catalase and superoxide dismutase reducing oxidative stress in metabolically active organs (summarized in [169]). A further "pro-youthful" factor is follistatin-like 1 (FSTL1) which together with GDF11 supports heart regeneration, as it increases the survival of cardiomyocytes [170]. Another good candidate is the soluble isoform of Klotho which increases the lifespan of mice and shows a neuroprotective function making it a good candidate for the treatment of Alzheimer's and multiple sclerosis [171].

#### *4.3.7. Acetylcholinesterase inhibitors*

autophagy is achieved by a change in the acetylation status of several proteins, but this occurs in a SIRT1-independent manner (most probably due to an inhibition of acetylases) [156]. For spermidine too, it has been demonstrated that it is increasing the lifespan of mice and all "aging" model organisms [157]. Surprisingly, the amount of this substance that is present in all cells dramatically decreases with aging [158]. In addition spermidine has neuroprotective

Spermidine also stimulates the synthesis of anti-inflammatory cytokines and has a positive

Muscle and bone are forming a physiological unit whereby both partners are regulating each other via endocrine signals [162]. Vitamin D has an essential function within this regulatory network. A sufficient supply of vitamin D prevents loss of muscle mass (sarcopenia) and age-dependent deposition of fat in muscles [163, 164]. In addition vitamin D shows a positive effect on cognitive function in old age [165]. Mice lacking the vitamin D receptor do age prematurely and the animal model for Alzheimer's disease show better memory performance and a reduction of some markers for Alzheimer's pathology after vitamin D supplementation. Humans with Alzheimer's disease show very low blood levels of vitamin D. Altogether

Treating age-related ailments with soluble proteins is particularly attractive because it can be performed via simple infusions. Among the best candidates, GDF11 and oxytocin have demonstrated a rejuvenating effect in old mice [92]. In a study comparing very old healthy individuals (beyond the age of 100) with 70–80-year-old persons, a set of proteins have been identified whose levels were elevated in the serum of the 100+ probands. This study correlates "successful aging" with these four proteins: Chemerin, Fetuin-A, FGF19 and FGF21 [167]. In particular, FGF21 is a "systemic enhancer of longevity" [168]. It is involved in the coordination of glucose and lipid metabolism and maintains tissue homeostasis under stress conditions. FGF21 can enhance autophagy and mice overexpressing it live up to 40% longer [168]. Another good candidate to provide a healthy lifespan is adiponectin. Adiponectin is expressed in and secreted from small adipocytes. It increases insulin sensitivity, shows anti-artherosclerotic effects and improves metabolism in skeletal muscle, liver and adipose tissue. Adiponectin activates AMPK and SIRT1 and this way it acts like an exercise mimicking factor [169]. Finally, it has to be mentioned that it also turns on catalase and superoxide dismutase reducing oxidative stress in metabolically active organs (summarized in [169]). A further "pro-youthful" factor is follistatin-like 1 (FSTL1) which together with GDF11 supports heart regeneration, as it increases the survival of cardiomyocytes [170]. Another good candidate is the soluble isoform of Klotho which increases the lifespan of mice and shows a neuroprotective function making it a good candidate for the treatment of Alzheimer's and

capacities [159] and reduces the risk for cardiovascular diseases [160].

influence on lipid metabolism [161].

vitamin D is a neuroprotective substance [166].

*4.3.6. Soluble proteins/growth factors*

multiple sclerosis [171].

*4.3.5. Vitamin D*

128 Gerontology

Alzheimer's disease (AD) is the most devastating aging disease. For 2013, it was estimated that more than 44 million people were affected worldwide and this number is expected to be beyond 135 million by the year 2050. Although there is presently no cure, there are a few drugs available that make life easier for AD patients. Most prominent are acetylcholinesterase inhibitors which show modest effects on improving cognitive function. The degeneration of cholinergic neurons which is seen in AD as well as Parkinson's disease dementia (PDD) leads to a reduction of acetylcholine levels. Furthermore, cholinergic pathways are not only important for the brain but also for skeletal muscle and the autonomous nervous system [172]. The increase of acetylcholine levels via inhibition of acetylcholinesterase improves cognitive function and has also beneficial effects on some of the comorbidities that usually affect AD and PD patients [173].

#### **4.4. Selective elimination of senescent cells**

If senescent cells are not removed by the immune system they are causing organ dysfunction and are a major cause of age-related diseases [174]. The removal of senescent cells in mice has improved their health conditions considerably. The elimination of senescent cells via drugs (senolysis) [175] or to trigger apoptosis (senoptosis) is also a realistic possibility in humans. From the observation that senescent cells do not respond to their own pro-apoptotic SASP, it was concluded that they have senescent-cell anti-apoptotic pathways (SCAPs). Six such SCAPs have been identified and these SCAPs were then screened for targets sensitive to senolytic drugs [176]. A number of senolytic drugs synthetic ones as well as of plant origin have been identified in the meantime. Prominent among them is quercetin which demonstrates promising activities [166]. It has to be mentioned that not every senolytic drug is effective on each senescent cell type and often is the combination of two or three drugs much more effective. An advantage over other medications is that senolytic drugs need not be taken continuously to exert their effect but just administered intermittently [176]. The use of senolytic drugs increase hope for the treatment of diseases for which there are hardly any other therapeutic options like idiopathic pulmonary fibrosis (IPF) a devastating lung disease [177]. Another elegant approach to trigger apoptosis in senescent cells has recently been demonstrated using a synthetic peptide. This cell penetrating peptide (CPP) was deduced from the sequence of the transcription factor FOXO4 and it excludes p53 from the nucleus. Instead of residing in the nucleus p53 is docking on to mitochondria to trigger apoptosis [178]. An additional possibility is to attack senescent cells with specific antibodies or by modified T cells [9].

#### **4.5. Transplantation of stem cells**

Stem cells are of utmost importance for regeneration and function of all organs. Transplanting stem cells into target tissues opens the possibility to repair major defects. Here we are at the brink of breathtaking possibilities for regenerative medicine. In particular, multipotent mesenchymal stem cells offer a wide spectrum of applications however these cells are loosing a lot of their regenerative capacity during aging [179]. Substantial progress has been made by the discovery that only four transcription factors (OCT3/4, SOX2, KLF4 and MYC) can induce reprogramming to pluripotency. Somatic cells can be transformed into young embryonic stem cells (induced pluripotent stem cells = iPSCs) [180]. From human fibroblasts such iPSCs could be generated and after specific differentiation processes used in different tissues [181]. In clinical trials, specific cells have been differentiated from iPSCs to treat Alzheimer disease, Parkinson disease, spinal cord injuries, diabetes or congestive heart failure [182]. Such a strategy for rejuvenation of old organs via stem cell therapy offers possibilities almost without limits for the future [183]. There is, however, a number of points that critically affects the success of stem cell transplantation. No matter how the replacement cells have been generated either as induced pluripotent stem cells (iPSCs) and subsequent differentiation steps or by direct transdifferentiation of somatic cells the condition of the stem cell niche is of utmost importance for regenerative success [183]. Also protein factors of the circulation effect transplanted cells massively [184]. Furthermore inflammatory processes which are often increased during aging effect stem cells dramatically as has been demonstrated for satellite cell function [185]. This demands the inhibition of inflammatory signaling as absolutely necessary.

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## **5. Conclusion**

Since the turn of the century there has been enormous progress in aging research in many fields. In this book chapter, we made a selection of aging theories and pathways that in our opinion are of great importance. To name them all would by far go beyond the scope of this article. It also has to be stated that of all the organelles in the cell we did just name mitochondria and their role in the aging process. But there is rising knowledge that all organelles have their specific share to aging. In the focus of this article were especially pathways and mechanisms on the cellular level. We did neglect that basically each organ and tissue has its private aging mechanisms [186, 187]. Therefore we believe that aging research will move on from cells toward tissues/organs and whole organisms. The possibilities that epigenetics will provide to increase health span look breathtaking, however, they cannot be really estimated to their full extend today yet. Much more realistic seems the application of stem cells which will provide regenerative medicine with fabulous opportunities. A very positive effect for an increased healthspan for almost all people will be possible if we will be able to boost autophagy without side effects. A similar effect on health span and the prevention of age-related diseases can be expected if it will be possible to eliminate senescent cells. Taken together there are really good chances that in the near future it will be possible to help many humans to live a healthy aging.
