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.