2.Target nutrient-sensing pathways on aging-related diseases
Almost all life forms constantly sit on a balance between production and
maintenance. Numerous studies involving Caenorhabditis elegans (C.
elegans) , a nematode that is commonly employed as a biological model
for studying aging, Drosophila melanogaster (D. melanogaster),also known as fruit flies, mice, and humans have shown that reduced
reproduction is linked to increased lifespan 38, 39.
The reason lies in the fact that reproduction is an energetically
expensive process. Therefore, under low nutrient conditions when
reproduction is more challenging, such as during CR, in order to ensure
reproductive success, increasing somatic maintenance is necessary to
prolong the reproductively competent period and consequently, lifespan.
Hence, the signaling pathways that can sense and respond to the changing
intracellular and extracellular energy and nutrient levels grow central
in the research of anti-aging drugs. Four such pathways, the mechanistic
target of rapamycin (mTOR), 5’-AMP-activated protein kinase (AMPK),
sirtuin, and insulin/insulin-like growth factor signaling (IIS) (Figure
1), are particularly important 40.
2.1 mTOR Pathway
The mechanistic target of rapamycin (mTOR) is a protein kinase that
receives nutrient level information and coordinates a wide range of
cellular metabolic processes concerning production, growth, and somatic
maintenance, such as protein synthesis, mitochondrial function, and cell
proliferation. Low surrounding nutrients levels, especially reduced
amino acids and growth factors, have been reported to suppress mTORC1
signaling, resulting in suppressed metabolism and extended lifespan
during fasting and intermittent fasting 41. 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 42,
43.
The mTOR kinase is found in two functionally different complexes, mTORC1
and mTORC2 38. Between the two, mTORC1 is the one with
better characterized activities; under nutrient-rich conditions, mTORC1
upregulates the anabolic processes in the cell and represses autophagy
by directly acting on the unc-51 like autophagy activating kinase (ULK)
complex and inhibiting the expression of the genes that are required for
autophagy 42. Meanwhile, mTORC2 has been reported to
phosphorylate and activate Akt, which upregulates mTORC144.
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)38. Interestingly, S6K also negatively
regulates the IIS pathway by inhibiting the insulin receptor substrate 1
(IRS1), giving mTORC1 some feedback control over its upstream pathways44.
The ULK complex is made of ULK1 or ULK2 45,
autophagy-related protein 13 (ATG13), focal adhesion kinase
family-interacting protein of 200 kDa (FIP200), and autophagy-related
protein 101 (ATG101), and it is essential for autophagosome formation.
By phosphorylating ULK1, ULK2, and ATG 13 in the complex, mTORC1
prevents complex’s activation, which would otherwise promote autophagy.
mTORC1 can also inhibit autophagy by phosphorylating the transcription
factor EB (TFEB), thereby preventing its nuclear translocation that
leads to the expression of the genes required for lysosome biogenesis
and other autophagy mechanisms 42. The mTOR pathway
makes its regulatory decisions based on intracellular and extracellular
nutrient levels that are inputted either directly from the environment
or via other pathways.
The depletion of amino acids inactivates the mTOR pathway, and growing
cellular amino acid level increases its activity and terminates
autophagy 40. When intracellular amino acids level is
high, the Rag GTPases recruit mTORC1 to the outer lysosome surface, at
which mTORC1 is activated by the Ras homolog enriched in brain (Rheb).
In addition, high cellular glucose level also activates the Rag GTPases.
The amino acids availability can be communicated to mTORC1 by the taste
receptors T1R1/T1R3 as well 46.
The nutrient levels also control the mTOR pathway through the AMPK and
the IIS pathway. Once activated by nutrient scarcity, AMPK inhibits
mTORC1 by phosphorylating and activating the tumor sclerosis complex
(TSC), a component of the TSC1-TSC2 complex, which is an inhibitor of
Rheb, and by directly phosphorylating and inhibiting the Raptor
component of the mTORC1 complex 47. The IIS pathway
upregulates the mTOR pathway when nutrient is abundant through its two
branches of downstream pathways, the phosphoinositide 3-kinase/protein
kinase B (PI3K/Akt) pathway and the Ras/mitogen-activated protein kinase
(Ras/MAPK) pathway. The PI3K/Akt pathway culminates in the activation of
Akt, which then enhances mTORC1 activity by repressing the TSC1-TSC2
complex and by phosphorylating the FOXO family of transcription factors,
excluding them from the nucleus. The exclusion of FOXO3a, for example,
reduces the transcription rate of TSC1 48. Another
inhibitor of mTORC1 activity, the proline-rich Akt substrate of 40 kDa
(PRAS40), is also inactivated by Akt phosphorylation49. The Ras/MAPK pathway modulates the mTOR pathway
via RSK and ERK, both of which can activate mTORC1 by the inhibitory
phosphorylation of TSC2 47.