Early aging and premature vascular aging in chronic kidney disease

Abstract

Aging is the progressive decline of body functions and a number of chronic conditions can lead to premature aging characterized by frailty, a diseased vasculature, osteoporosis, and muscle wasting. One of the major conditions associated with premature and accelerated aging is chronic kidney disease (CKD), which can also result in early vascular aging and the stiffening of the arteries. Premature vascular aging in CKD patients has been considered as a marker of prognosis of mortality and cardiovascular morbidity and therefore requires further attention. Oxidative stress, inflammation, advanced glycation end products, fructose, and an aberrant gut microbiota can contribute to the development of early aging in CKD patients. There are several key molecular pathways and molecules which play a role in aging and vascular aging including nuclear factor erythroid 2-related factor 2 (Nrf-2), AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and klotho. Potential therapeutic strategies can target these pathways. Future studies are needed to better understand the importance of premature aging and early vascular aging and to develop therapeutic alternatives for these conditions.

Keywords: CKD; CKD-MBD; inflammation; vascular calcification.

Figure 1:

The factors contributing to early aging in CKD. AGE: Advanced glycation end products, CKD: Chronic kidney disease, CV: Cardiovascular, ER: Endoplasmic reticulum, RAAS: Renin-Angiotensin-Aldosterone system, ROS/Oxidative stress.

Figure 2:

The major molecular pathways associated with aging and vascular aging. KEAP1 maintains Nrf-2 in the inactivated state. Oxidative stress and several medications such as resveratrol activate and translocate Nrf-2 via the dissociation of KEAP1. Activated Nrf-2 upregulates the genes encoding antioxidants such as NQO1 and HO-1/2 that, in turn, inhibit vascular calcification. Hyperphosphatemia suppresses the activity of Nrf-2. Klotho activates Nrf-2 while also increasing NO, decreasing oxidative stress and potentially improving vascular dysfunction. AMPK can be activated via metabolic stress, low energy states, AICAR, metformin, and curcumin. The activity of AMPK decreases in aging resulting in arterial stiffening and endothelial dysfunction. Activated AMPK decreases oxidative stress and elevates NO. AMPK also increases, via NAD⁺, SIRT1 activity that plays a role in inhibiting aging and vascular calcification. SIRT1 also has an antioxidant function through the transcription of FOXO3 and PGC-1α. Furthermore, SIRT1 inhibits arterial stiffening and endothelial dysfunction that result from aging. SIRT1 can be activated by resveratrol. AICAR: Aminoimidazole carboxamide ribonucleotide, AMP: Adenosine monophosphate, AMPK: AMP-activated protein kinase, ATP: Adenosine triphosphate, CKD: Chronic Kidney Disease, DMF: Dimethyl fumarate, FOXO3: Forkhead Box O3, HO-1/2: heme oxygenase-1/2, IL-1: Interleukin 1, KEAP1: Kelch-like ECH-associated protein 1, NAD+: Nicotinamide adenine dinucleotide, NaHS: Sodium hydrosulfide, NO: Nitric oxide, NQO1: NAD phosphate) dehydrogenase-1, Nrf-2: Nuclear factor erythroid 2-related factor 2, PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator-1- alpha, p16(CDKN2A): Cyclin-dependent kinase inhibitor 2A, p21 (CDKN1A): Cyclin-dependent kinase inhibitor 1, ROS/Oxidative stress, RUNX2: Runt-related transcription factor 2, SIRT1: Sirtuin 1, TNF-α: Tumor necrosis factor-α, VSMC: Vascular smooth muscle cell.