Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging

Abstract

Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.

Keywords: AMPK; SIRT1; aging; health span; intervention; mTOR; senescence; signaling.

Figure 1

AMPK signaling in the cell. AMPK is composed of three subunits: the catalytic α subunit and regulatory β and γ subunits. The upstream of AMPK includes LKB1, CaMKKβ, TAK1 and PP2Cα, while the downstream pathways controlled by AMPK include ULK1/2, SIRT1, TSC1/2, SREBP1c, ACC1, HuR, p53 and GLUT1/GLUT4. Abbreviations: AMPK: adenosine onophosphate-activated kinase; LKB1: liver kinase B1; CaMKKβ: Ca²⁺/calmodulin-dependent protein kinase kinase β; TAK1: transforming growth factor β-activated kinase 1; PP2Cα: protein phosphatase 2Cα; ACC1: aminocyclopropane-1-carboxylic acid; GLUT1: glucose transporter 1; GLUT4: glucose transporter 4; ULK1/2: autophagy activating kinase 1/2; PGC1-α: peroxisome proliferator-activated receptor gamma coactivator-1α; ROS: reactive oxygen species; SIRT1: Sirtuin 1; AMP: adenosine monophosphate; ATP: adenosine triphosphate; TSC1/2: tuberous sclerosis complex 1/2 protein; mTOR: the mammalian target of rapamycin; SREBP1c: sterol regulatory element binding protein 1c; HuR: human antigen R.

Figure 2

SIRT1 signaling in the cell. SIRT1 is a well-known NAD+-dependent deacetylase that impacts several molecules to promote health. Abbreviations: STAT3: signal transducer and activator of transcription 3; NF-κB: NF-kappa B; Bax: bcl-2-associated X protein; FOXOs: forkhead box transcription factors; PPARγ: peroxisome proliferator-activated receptors; NAD+: oxidized nicotine adenine dinucleotide; NADH: reduced nicotine adenine dinucleotide.

Figure 3

Constituents of mTORC and mTOR signaling in the cell. mTORC1 includes mTOR, Raptor, mLST8, PRAS40 and DEPTOR, while mTORC2 contains mTOR, Rictor, mSIN1, Protor-1, mLST8 and DEPTOR. Abbreviations: RHEB: ras homolog enriched in brain; GDP: guanosine diphosphate; GTP: guanosine triphosphate; PRAS40: proline-rich Akt substrate 40 kDa; mLST8: mammalian lethal with Sec13 protein 8; Raptor: the regulatory-associated protein of mTOR; DEPTOR: DEP-domain-containing mTOR-interacting protein; TFEB: transcription factor EB; HIF1α: hypoxia inducible factor 1α; ATF4: activating transcription factors 4; 4EBP: 4E binding protein; eIF4F: eukaryotic initiation factor 4F; eIF4B: eukaryotic initiation factor 4B; CAD: carbamoyl-phosphate synthetase; S6K: S6 kinase; SGK1: glucocorticoid induced protein kinase 1; MDM2: murine double minute 2; Akt: protein kinase B; PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; BDNF: brain-derived neurotrophic factor; mSIN1: mammalian stress-activated protein; Protor-1: protein observed with Rictor-1; Rictor: rapamycin-insensitive companion of mTOR; PKCα: protein kinase Cα.

Figure 4

Illustration of the roles of the AMPK, SIRT1 and mTOR signaling pathways in aging. The blue arrows indicate a positive effect, and the orange arrows indicate a negative effect. Abbreviations: CR: caloric restriction; NF-κB: NF-kappa B.