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.

Keywords: aging; hub metabolites; metabolomics.

Figure 1

Outline of metabolomic workflow for biomarker discovery in aging biology. Analytical workflow for biomarker analysis involves a number of possible platforms for performing sample preparation (from tissues and bio fluids like urine, feces, and cerebrospinal fluid (CSF)), sample extraction (protein precipitation (PPT), solid phase extraction (SPE), and liquid–liquid extraction (LLE)). Data acquisition (NMR) followed by MS (using matrix associated laser desorption ionization [MALDI], desorption electrospray ionization [DESI] laser ablation electrospray ionization [LAESI], direct ionization in real‐time [DART], secondary ion MS [SIMS] or electrospray ionization [ESI]), and data analysis using local software resources or via cloud computing.

Figure 2

Hub metabolites and signaling mechanisms that promote longevity. The aging metabolome can be viewed as two layers comprised of i) hub metabolites (NAD⁺, NADPH, αKG, and ketone bodies such as βHB) and ii) signaling mechanism involving regulation of aging‐related signaling, epigenetic, and stress responsive pathways. Large green arrows indicate the pro‐longevity effects of their supplementation, red T's indicate inhibitory effects on enzymes/pathways and green arrows indicate activation of enzymes/pathways.

Figure 3

Mitochondrial TCA as the hub for integrating metabolism and signaling in the aging network. The four hub metabolites (red boxes) are interconnected via the mitochondrial TCA cycle. NAD⁺ is utilized during the TCA cycle to generate NADH and is regenerated during oxidative phosphorylation and during formation of lactate from pyruvate. NAD can also be produced by dietary supplementation of precursors of NAD such as nicotinamide (NAM) that is converted to nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyl transferase (NAMPT). NADP is synthesized from NAD via the enzyme NAD kinase (NADK) that is localized to the cytoplasm and mitochondria. NADPH is generated during the pentose phosphate pathway (PPP) and used in biosynthetic and redox responsive pathways. αKG is a TCA intermediate, either generated from pyruvate or from glutamine by the enzyme αKG dehydrogenase (αKGDH). βHB, a ketone body, serves as an anaplerotic source for acetyl‐CoA in the TCA cycle. It is generated during starvation/fasting via the β‐oxidation of lipids in the liver and transported to tissues such as skeletal muscle and brain or can be generated by ketogenic amino acid (e.g., BCAA during exercise).