3.3.3 Effect of metformin on age-related neural disorders
Metformin has been shown in many studies to have positive effects on age-related neural disorders, such as Alzheimer’s disease and Parkinson’s disease. Compared to the symptomatic treatments that are currently used, repurposed drugs such as metformin show a promising prospect by targeting these diseases closer to their root. However, the benefits of metformin found in the studies should be taken with a grain of salt, as there are also opposite outcomes and remaining risks.
Currently no drug exists to treat or slow down the development of AD. Instead, patients are treated with drugs that improve their impaired cognitive functions. Cholinesterase inhibitors, such as Aricept, Exelon, and Razadyne, prevents the breakdown of acetylcholine and improve neurological function in patients 108-110; Another treatment is Namenda, a memantine that inhibits glutamate to prevent over-excitation of the neurons in AD patients 111.
Applying metformin, an antidiabetic drug, to treat AD stems from the widely observed association between AD and type 2 diabetes mellitus (T2DM) 112. The immediate difference seen here is that unlike the other AD drugs already mentioned, metformin is not used for a specific mechanism of action but repurposed based on observation and logical reasoning, and multiple studies have committed to validate this reasoning. In a study that involves 20 non-diabetic AD patients, the patients were treated with metformin for 8 weeks and showed improved cognitive functions 112. Nonetheless, a larger study that analyzed data from 7,086 dementia patients and matching number of healthy controls from the United Kingdom-based General Practice Research Database (GPRD) concluded otherwise. Their analysis showed that individuals who did not receive any drug for diabetes mellitus (AOR=0.88, 95% CI=0.71–1.10) or those who took antidiabetic drugs (AOR=1.03, 95% CI=0.90–1.19) had a similar risk of developing AD as individuals without diabetes (AOR=1). Furthermore, long-term use of metformin increased the risk of developing AD, which was attributed by the authors to the production of A-β peptides, a hallmark for AD, induced by metformin. However, the increased risk was not confirmed in patients who had only taken metformin, and there was no trend of increasing risk of AD with increasing number of metformin prescriptions113. The increased production of A-β peptides caused by metformin was shown on cell cultures of primary cortical neurons and N2a neuroblastoma cells expressing human amyloid precursor protein (APP). Metformin upregulates the transcription of beta-secretase, which cleaves APP into A-β peptides. The study has also shown that metformin combined with insulin reduces A-β peptide levels 114. This effect was also found to be true in a mice study, in which diabetes model mice were used to evaluate AD-like brain changes and the effect of metformin on those changes. The study found that metformin attenuated the increase of total tau, phospho-tau, and activated JNK, a tau kinase, in the mice. Metformin also attenuated the decrease of synaptophysin and preserved the neural structures of the mice. However, metformin did not improve the spatial learning and memory abilities of the mice115. These studies together seem to suggest that having taken metformin in the past does not reduce the risk of AD, but metformin may be used with insulin as an effective short-term treatment of AD.
The loss of dopaminergic neurons is characteristic of PD and leads to a decreased amount of dopamine and imbalance between dopamine and acetylcholine. According to the acetylcholine-dopamine balance hypothesis, over-activation of cholinergic system activity causes motor and cognitive disturbances. Hence, the current PD drugs either provide more dopamine or reduce the amount of acetylcholine to restore the balance. Levodopa is a dopamine precursor that is commonly used to deliver dopamine to the brain, and it is often used with catechol-O-methyltransferase inhibitors to reduce side effects and release of dopamine to other parts of the body 116, 117. Monoamine oxidase inhibitors are another type of drug that acts by inhibiting the degradation of dopamine 118. Amantadine and anticholinergics also boost dopamine level in the brain, but they are less used due to a number of side effects including dry mouth, headache, nausea, orthostatic hypotension, and visual hallucinations119, 120. Like AD, current treatments of PD work as a remedy instead of neuroprotective agents.
Several studies have found metformin to alleviate PD. PD, diabetes, and dementia share the disorder of mitochondrial bioenergetics and abnormal protein folding in their pathogenesis. An analysis of a cohort of 800,000 people from the Taiwan National Health Insurance database showed that having T2DM increased the risk of PD 2.2 fold, and metformin-inclusive sulfonylurea therapy reduced the risk (HR=0.78 relative to diabetes-free, 95% CI=0.61-1.01) . A mice study suggests that the reason has to do with metformin’s ability to reduce α-synuclein release, a component of the Lewy bodies and Lewy neurites that are characteristic of PD. The researchers gave MPTP, a prodrug to a the neurotoxin MPP+, to mice to model PD 121. MPTP caused damage to the dopaminergic neurons of the mice and led to astroglial activation, which promotes inflammation in the nervous system, and increased release of α-synuclein 121, 122. Metformin was found to mitigate astroglial activation and promote methylation of protein phosphatase 2A (PP2A) that is related to α-synuclein dephosphorylation. Metformin has also been known for activating AMPK, which activates ATP production in mitochondria and restores mitochondria function. However, the timing and dosage of metformin was also critical. When MPTP and metformin were given in the same day, 75% lethality ensued in the mice. Although metformin increased the levels of BDNF and GDNF, two neurotrophic factors, high dosage (400 mg/kg) killed all the mice 121. In another study, metformin was found to rescue tumor necrosis factor type 1 receptor associated protein (TRAP1) mutation associated changes in mitochondrial protein balance. TRAP1 is a protein associated with stress sensing in mitochondria, and its absence due to mutation has been identified to increase the risk for PD. The study found that the loss of TRAP1 causes elevated mitochondrial respiration, reduced mitochond­­rial membrane potential, and imbalance of nuclear and mitochondrial protein production. Metformin was shown to reverse the imbalance and restore mitochondrial membrane potential123. In summary, metformin intervenes the pathogenesis of PD by preserving neurons, reducing inflammation, and protecting mitochondria functions. It is a promising new way to help PD patients, but further studies are still needed to understand the influence of dosage and timing.
Rapamycin
Rapamycin, also known as sirolimus, is an antifungal macrolide that is produced by streptomyces hygroscopicus . It was first discovered in the Easter Islands in the 1970s, and subsequent studies have identified various uses of rapamycin that extend beyond fighting fungal infections 124-126. Rapamycin was initially prescribed as an immunesuppressant for organ, especially kidney, transplantation127, 128. It has also been used to coat coronary stents, which prevents coronary re-narrowing after stent implantation129. However, the side effects of rapamycin, which include ulcer, diarrhea, hyperglycemia, and hyperlipidemia, which have largely impeded its widespread use.
Despite the earlier challenges, a renaissance of rapamycin came when studies consistently reported that rapamycin slowed aging in various model organisms. Consequently, this has led to a flurry of interest in repurposing rapamycin as a geroprotector 130. Although the adverse effects of rapamycin remain a major concern, new efforts to minimize them have been explored in many directions. For example, the development of rapamycin analogs, tweaking the dosage, and searching for options to combine rapamycin with other drugs have all shown promising results 131, 132.
4.1 Mechanisms of Rapamycin in improving healthspan
Rapamycin suppresses mTOR signaling by first binding to its immunophilin FK binding protein (FKBP12) and then acting upon mTORC1 and mTORC2133, 134. While the inhibition of mTORC1 extends life expectancy and confers protection for age-related diseases, mTORC2 is associated with unwanted effects such as glucose intolerance and abnormal lipid profiles. Furthermore, rapamycin can acutely suppress mTORC1, whereas mTORC2 is less sensitive to rapamycin and its inhibition can only be achieved through long-term treatment 135.
4.1.1 Rapamycin retards neurodegeneration via mTORC1 inhibition
Alzheimer’s disease is characterized by the aggregation of amyloid-β and tau in the brain tissue. Hence, mTOR signaling, the main regulator of protein synthesis and clearance, has been considered a promising target for treatment. Mice with increased mTOR activity have shown higher levels of tau and Aβlevels 136. Dysregulated mTOR activity and autophagy have been observed in patients with early Alzheimer’s disease 137. Rapamycin, the main mTOR inhibitor, has therefore been widely studied as a promising treatment for Alzheimer’s disease. Administrating rapamycin to young 3xTg-AD mice induces mTOR-mediated autophagy and reduces Aβ and tau levels138. Moreover, when administrated early, rapamycin reduces the formation of tau and Aβ plaques and tangles via mTOR-mediated autophagy before their formation 139.