The Aging Metabolome—Biomarkers to Hub Metabolites

Abstract

Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging‐related pathways such as mTOR and AMPK, which are major targets of anti‐aging interventions including rapamcyin, metformin, and exercise, either directly regulate or intersect with metabolic pathways. In this review, numerous candidate bio‐markers of aging that have emerged using metabolomics are outlined. Metabolomics studies also reveal that not all metabolites are created equally. A set of core “hub” metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are nicotinamide adenine dinucleotide, reduced nicotinamide dinucleotide phosphate, α‐ketoglutarate, and β‐hydroxybutyrate. These “hub” metabolites have signaling and epigenetic roles along with their canonical roles as co‐factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging.

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

“…Additionally, there are several examples of the metabolic ability of metformin to facilitate (or impede) the transition from one cell type to another, including neuronal [52][53][54], osteogenic [55][56][57][58], adipogenic [39,59], myofibroblast and myoblast [60,61] differentiation, or monocyte-to-macrophage differentiation [62], among others. The fact that metformin targets a set of core "hub" metabolites with epigenetic properties and with emerging roles as central mediators of aging strongly supports the notion that it can regulate cell fate transitions by changing metabolite levels that allow the reorganization of specific chromatin marks [63]. Accordingly, a link between metformin-induced changes in specific metabolites (e.g., α-ketoglutarate and succinate) and the epigenetic control of cell fate transitioning has been established in a few cases [39,41,64].…”

“…Metformin restores the global levels of H3K27me3 in fibroblasts of aged individuals or from patients with premature aging syndromes such as Hutchinson-Gilford progeria or Werner syndrome, likely by directly targeting the H3K27me3 demethylase KDM6A/UTX [24]. A decrease in repression-associated H3K27me3 (and an increased activity of KDM6A/UTX) is a key feature of the global chromatin reconfiguration that takes place not only in somatic cells during physiological aging but also in the prematurely aging cells from patients with Hutchinson-Gilford progeria or Werner syndrome [63,116,117]. Gain of H3K27me3 (and loss of KDM6A/UTX activity) has been linked to extended longevity in Caenorhabditis elegans, thus suggesting that metformin-driven preservation of high levels of H3K27me3 by inhibiting KDM6A/UTX may be critical for maintaining a youthful epigenetic landscape [63,[128][129][130].…”

Effects of myocardial ischemia/reperfusion injury on plasma metabolomic profile during aging

“…Furthermore, it is not surprising that “tRNA charging pathway” (predicted as several amino acids were different between old and young groups) was the pathway most altered by age in both ischemic and control group as tRNAs are regulators of key biological processes such as protein biosynthesis and gene expression (Raina & Ibba, 2014). Of note, cellular and circulating amino acids play several roles both in young and old age such as fueling the tricarboxylic acid cycle (the Krebs cycle) in mitochondria, an organelle known to be affected by aging and by I/R injury (Ham and Raju, (2017); Martínez‐Reyes & Chandel, 2020; Sharma & Ramanathan, 2020). Impaired circulating amino acid levels may be strictly related to the altered mitochondrial function in aged mice (Ham and Raju, (2017); Martínez‐Reyes & Chandel, 2020; Sharma & Ramanathan, 2020).…”

“…Of note, cellular and circulating amino acids play several roles both in young and old age such as fueling the tricarboxylic acid cycle (the Krebs cycle) in mitochondria, an organelle known to be affected by aging and by I/R injury (Ham and Raju, (2017); Martínez‐Reyes & Chandel, 2020; Sharma & Ramanathan, 2020). Impaired circulating amino acid levels may be strictly related to the altered mitochondrial function in aged mice (Ham and Raju, (2017); Martínez‐Reyes & Chandel, 2020; Sharma & Ramanathan, 2020). Pyridoxal 5′‐phosphate savage pathway, essential cofactor of numerous metabolic enzymes and mainly involved in amino acid metabolism, was also changed with age in our study (Bode and Berg, 1991).…”

The Chemical Exposome of Human Aging

“…A gradual slowing down of metabolism with age is also documented. A very recent review on the "aging metabolome" enumerated the set of biomarkers and hub metabolites of aging, indicating critical roles for nicotinamide adenine dinucleotide (NAD + ), reduced nicotinamide dinucleotide phosphate (NADPH), αketoglutarate, and β−hydroxybutyrate with a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging (Sharma and Ramanathan, 2020). As very recently commented by Di Ciaula and Portincasa, "successful aging could begin during in utero life" (Di Ciaula and Portincasa, 2020).…”