Longevity
Almost all life forms constantly sit on a balance between production and
maintenance, and under low nutrient conditions when reproduction is more
challenging, in order to ensure reproductive success, increasing somatic
maintenance is necessary to prolong the reproductively competent period
and consequently, lifespan.5 Hence, calorie
restriction (CR) without malnutrition is one of the most reliable
approaches in extending both lifespan and healthspan in various
vertebrate and non-vertebrate species. However, CR is difficult to
sustain and implement since individuals must remain in a state of hunger
and endure feelings of starvation, fatigue, and irritations. Besides,
individuals who practiced CR are more susceptible to viral
infections6 and resistant to
wound-healing7, both of which impede its widespread
use. Alternatively, metformin and rapamycin can act as
calorie-restriction mimetics (CRM) by triggering the nutrient sensing
pathways that sense and respond to the changing intracellular and
extracellular energy and nutrient levels without actually restricting
calorie intake.8
Rapamycin and metformin target respectively the mechanistic target of
rapamycin (mTOR) and 5’-AMP-activated protein kinase (AMPK) (Fig.1). The
mTOR comprises of two complexes, mTORC1 and mTORC2, and they coordinate
a wide range of cellular metabolic processes concerning production,
growth, and somatic maintenance, such as protein synthesis,
mitochondrial function, and cell proliferation. Activated mTORC1
enhances mRNA translation and protein synthesis in the cell by
phosphorylating the p70 ribosomal protein S6 kinase (S6K) and eukaryotic
translation initiation factor 4E-binding protein 1
(4E-BP1);9 it also suppresses autophagy by
phosphorylating ULK1, ULK2, and ATG13 of the ULK complex and the
transcription factor EB, both of which essential for the autophagy
process.10 Not surprisingly, mounting studies have
shown that deregulated mTOR signaling is implicated in the aging process
and the progression of age-related disease such as cancer and
diabetes.10,11 Rapamycin suppresses mTOR signaling by
first binding to its immunophilin FK binding protein (FKBP12) and then
acting upon mTORC1 and mTORC2.12 While inhibiting
mTORC1 extends life expectancy and confers protection for age-related
diseases, inhibiting mTORC2 is associated with unwanted effects such as
glucose intolerance and abnormal lipid profiles. Nevertheless, mTORC2 is
less sensitive to rapamycin and its inhibition can only be achieved
through long-term treatment.13
AMPK is the upstream controller of the mTOR signaling pathway (Fig. 1).
Numerous studies have indicated that the activating capacity of the AMPK
signaling pathway declines with aging, and its decline disturbs
autophagy, increases cellular stress, and promotes inflammation, which
further provoke many age-associated diseases, such as cardiovascular
disease, diabetes, and cancer.9,14 Correspondingly,
increased activation of the AMPK pathway has been shown to extend
lifespan in lower organisms in response to CR and pharmaceutical agents,
such as metformin.15 Activated AMPK phosphorylates and
activates ULK1 of the ULK complex to promote autophagy as well as
activates the FOXO transcription factors that transactivate the genes
involved in detoxification, autophagy, tumorigenesis suppression, and
energy homeostasis.5 Furthermore, AMPK activation
attenuates the aging process by inhibiting NF-κB, the major regulator of
innate and adaptive immunity, and relieves ER stress and oxidative
stress by promoting the expression of mitochondrial uncoupling protein
(UCP-2).16
Metformin and rapamycin are also implicated in DNA methylation, an
omnipresent regulatory mechanism for gene expression in our genome. DNA
methylation is facilitated by DNA methyltransferases DNMT3A, DNMT3B, and
DNMT1 and adds a methyl group to the 5th carbon on
cytosine. DNA methylation usually leads to gene silencing by interacting
with transcription mechanisms, and global hypomethylation and promoter
hypermethylation are often observed in aged people.17Since DNA methylation is reversible, it is a promising target for
therapeutic interventions.
Rapamycin regulates DNA methylation by inhibiting the mTOR signaling
pathway to reduce serine production and glycolytic metabolism, which
tune down the serine and 1C metabolism that uses serine to produce SAM,
the methyl donor in the methylation reaction.18Metformin alters methylomes globally via the H19/SAHH axis. H19, a long
noncoding RNA that should be downregulated in adults, causes an aberrant
methylation profile by binding to and inhibiting s-adenosylhomocysteine
hydrolase (SAHH), which normally hydrolyzes s-adenosylhomocysteine (SAH)
and removes its inhibition of DNMT3B. Metformin activates AMPK and
upregulates let-7, a family of microRNAs that bind to and degrade
H19.19
Quite a few studies have corroborated the proposed life-extending
effects of metformin and rapamycin. Metformin has been shown to extend
healthspan and lifespan in the roundworm C. elegans (Table
1).20 Furthermore, a low dose of metformin
supplemented for middle-aged male mice’s diet lead to a 5.83% extension
of mean lifespan.21 A longitudinal study that compares
the methylation profiles of the white blood cells from 12 healthy
individuals at the beginning, 10 hours, and 7 days after metformin
treatment revealed 11 consistently differentially methylated sites. By
looking at the associated genes, regions, and networks, the study found
several related genes including CAMKK1, a regulator of AMPK and glucose
uptake, BACE2, involved in neurodegenerative disorders and insulin
production, and ADAM8, which is related to monocyte adhesion and
migration and contributes to disorders caused by excessive inflammation
such as neurodegenerative disorders, allergy, asthma, and acute lung
inflammation. As the cells were from healthy individuals, having ADAM8
in the result shows that metformin’s anti-inflammatory effect is
independent of diabetic status.22
Treating yeast with rapamycin resulted in extended lifespan in a process
that has been postulated to mimic CR.23 Heterogeneous
male mice that received a daily dosage of 2.24 mg of rapamycin per kg of
body weight beginning at the age of 20 months had 9% extended lifespan
while female mice had 14%.24 In another mice study,
the Intervention Testing Program (ITP), genetically outbred mice were
used to test the potential of multiple anti-aging manipulations
including drugs, diets, and other interventions, and rapamycin was one
of the only two drugs that had robust anti-aging
effects.25 Mice treated with rapamycin at 42mg/kg from
4-month to 22-month old had a 6-month decrease on average in epigenetic
aging compared with control mice.26 Moreover, healthy
participants in a double blind randomized study aged 65 and older who
had taken Everolimus, also a mTOR inhibitor, for 6 weeks then stopped
for 2 weeks before a flu shot was given to them had 20% stronger immune
responses compared with the control, suggesting that a low dose of
rapamycin may delay immunesenescence in the elderly instead of
suppressing their immune system.27