Cardiovascular Diseases
Cardiovascular diseases (CVDs), marked by lipid-rich plaques
accumulating in blood vessels, are the leading cause of death globally,
claiming around 17.9 million lives per year.28 While
CVDs arise from a complex combination of hereditary predisposition and
environmental factors including lifestyle, aging is the dominant
factor.29 In the US, roughly 70%-75% of people who
are 60-79 years old are afflicted with CVDs.30
Dyslipidemia, insulin resistance, and chronic inflammation that commonly
occur in older people make them more susceptible to CVDs. AMPK
activation by metformin can suppress fatty-acid desaturase (FADS) genes,
reducing the circulating levels of lipid metabolites and LDL
cholesterol.31 Metformin also improves insulin
sensitivity, helps losing weight, and reduces perceived hunger and food
intake.32 Recently, growth differentiating factor 15
(GDF15) was found to contribute to the weight loss effect of metformin
by interacting with the GFRAL receptor in the central nervous system to
suppress appetite. Metformin mediates GDF15 increase by promoting
transcription of CHOP and ATF4 most prominently in the liver and
gastrointestinal system.33,34 Although metformin does
not directly affect coronary artery disease through the GDF-15 pathway,
the GDF-15 dependent weight loss effect may contribute to higher insulin
sensitivity.35 Metformin also inhibits vascular
inflammation that can lead to plaque formation by blockading the
PI3K-Akt pathway and its downstream NF-κB pathway.36Furthermore, mitochondria dysfunction and endothelial senescence
contribute to higher risks of CVDs, and activated AMPK increases SIRT3
levels and improves mitochondrial biogenesis and function by enhancing
trimethylation of H3K79 via the SIRT-DOT1L axis. SIRT3 also delays
endothelial senescence by upregulating telomere reverse transcriptase
expression.37 Less is known about the protective
effects of rapamycin, but a study found that mTOR inhibition suppressed
DNMT1 upregulation caused by disturbed flow in the blood vessels bothin vitro and in vivo .38
Metformin’s protective effects have been confirmed in both animal and
human studies. Chronic low doses of metformin given to ApoE deficient
mice that have poor lipid-clearing capabilities and age-related
atherosclerosis showed positive effects as well as reduced recruitment
of macrophages into subendothelial space of aorta and decreased levels
of pro-inflammatory cytokines.37 Bovine aortic
endothelial cells exposed to clinically relevant amounts of metformin
have increased activities of nitric oxide synthase (eNOS),
endothelium-derived nitric oxide (NO), and AMPK while no such effect is
observed in AMPK knockout mice. NO and eNOS have major roles in
maintaining vascular homeostasis and its integrity, suggesting that AMPK
activation by metformin exerts vascular-protective
effects.39,40 Treating 32 weeks old mice with
metformin at 200 mg/kg per day for 4 weeks also partially reversed left
ventricular dilatation caused by δ-sarcoglycan deficiency: the hearts
showed less fibrosis, less cardiomyocyte hypertrophy, and fewer
degenerative subcellular changes. At the same time, there were also
increased autophagy, increased AMPK activity, and suppressed mTOR
phosphorylation.41 Diabetic veterans (mostly white
male) who took metformin had lower CVDs and mortality risks compared
with those who took sulfonylureas, and similar results were obtained in
another clinical trial that compares the CVD risk associated with
glipizide and metformin.42,43 Although in these
studies it could not be determined whether the result was caused by the
benefits of metformin or damages due to sulfonylureas or both,
metformin’s protective effects could be more ascertained in the United
Kingdom Prospective Diabetes Study (UKPDS), in which metformin treatment
conferred a significantly lower incidence of myocardial infraction
(33%, P=0.005) compared with dietary therapy for diabetic
patients.44 Furthermore, several clinical trials and
meta analyses have found metformin to decrease CVD risk for not just
diabetic people, but pre-diabetic and non-diabetic people as
well.45,46